RxPG News : Public Health

Progress made on group B streptococcus vaccine

Fri, 30 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) WHAT: Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have completed a Phase II clinical study that indicates a vaccine to prevent Group B Streptococcus (GBS) infection is possible. GBS is the most common cause of sepsis and meningitis in newborns in the United States, according to the Centers for Disease Control and Prevention (CDC). It can also cause severe illness in pregnant women, the elderly and adults with chronic illnesses. Colonization of the genital or gastrointestinal tract is a critical risk factor for infections due to GBS.

The researchers, led by Sharon L. Hillier, Ph.D., from the Magee-Womens Research Institute at the University of the Pittsburgh, found that the vaccine used in the study can cause a modest but sustained reduction in genital and gastrointestinal GBS bacterial colonization.

The GBS bacterium, which is commonly found in the gut and genital tracts, can infect the fetus during gestation and birth or after delivery. Pregnancy-related infections can lead to serious consequences for women including stillbirth. Currently, one-third of pregnant women in the United States test positive for asymptomatic GBS and receive antibiotics during labor to prevent infection of the newborn. Although this antibiotic strategy is highly effective, the broad use of antibiotics in pregnant women is of concern to public health officials. Many women are allergic to penicillin and penicillin-type antibiotics that are the preferred treatment, and GBS is increasingly resistant to other common antibiotics.

Dr. Hillier and her colleagues conducted a double-blind, randomized trial of the GBS vaccine that included a total of 650 sexually active, non-pregnant women ages 18 to 40 who were GBS-negative in the vagina and rectum at the beginning of the study. Approximately one-half of the women were in the control group and received a licensed tetanus and diphtheria toxoids (Td) vaccine instead of the GBS vaccine. The women were followed for 18 months after they were vaccinated and checked for GBS bacteria at regular intervals. The goal of the study was to see whether vaccination could prevent or decrease colonization by one of the most common subtypes of GBS bacteria: Type III.

Although the vaccine had a modest effect on bacterial colonization (36 percent in the vagina and 43 percent in the rectum), it provided some protection over the entire period of the study. The GBS vaccine also was found to be safe and well-tolerated, and elicited a strong immune response. The next step to prevent GBS disease would be to develop vaccines that provide protection against a broader range of GBS types and test them in clinical trials.

WHEN: Dr. Hillier will present these findings on Friday Oct. 30, 2009, at 10:00 a.m. at the 47th Annual Meeting of the Infectious Diseases Society of America in Philadelphia.

WHO: Fran A. Rubin, Ph.D., Program Officer for Group A streptococci, Group B streptococci, Maternal Immunization Respiratory Diseases Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases

NIH launches 2009 H1N1 influenza vaccine trials in HIV-infected pregnant women

Fri, 09 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The first clinical trials to test whether the 2009 H1N1 influenza vaccine can safely elicit a protective immune response in pregnant women launched yesterday, and a trial to conduct the same test in HIV-infected children and youth will begin next week. The International Maternal Pediatric Adolescent AIDS Clinical Trials Group is conducting the studies, which are sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health.

These studies are important because HIV infection and pregnancy both increase the risk for a poor immune response to the normal 15-microgram dose of seasonal influenza vaccine given to the general population, says NIAID Director Anthony S. Fauci, M.D. Moreover, children, young people and pregnant women are at higher risk for more severe illness from the 2009 H1N1 influenza virus than other groups, and HIV-infected individuals in these populations may be particularly vulnerable.

Because of the increased vulnerability of these populations, these trials are testing whether doses of licensed 2009 H1N1 influenza vaccine that are higher than doses being tested in other groups can safely elicit protective immune responses in HIV-infected children, youth and pregnant women, adds Lynne Mofenson, M.D., chief of the Pediatric, Adolescent and Maternal AIDS Branch in NICHD.

One trial will enroll 130 HIV-infected pregnant women ages 18 to 39 years who are in their second or third trimester (14 to 34 weeks) of pregnancy. The other trial will enroll 140 children and youth aged 4 to 24 years who were infected with HIV at birth.

Thirty-five sites and eight sub-sites across the United States and Puerto Rico are eligible to conduct the trials. Each volunteer will receive two 30-microgram doses of 2009 H1N1 influenza vaccine 21 days apart. (In contrast, the NIAID studies of 2009 H1N1 influenza vaccine in HIV-uninfected children, youth and pregnant women are testing doses of 15 and 30 micrograms.)

Safety data will be collected and monitored closely by the study investigators and an independent safety monitoring committee. The strength and longevity of the immune response elicited by the vaccine will be gauged in several ways.

The study team will take blood samples from the pregnant women after each dose and three and six months after delivery to measure the concentration of antibodies the women produce against 2009 H1N1 influenza virus and how strong that antibody response remains over time. After the women give birth, study staff will sample umbilical cord blood to measure the concentration of maternal antibodies against the H1N1 virus that were transferred to the infants through the placenta. The study team also will collect small blood samples from the infants at 3 and 6 months of age to measure their level of maternally derived antibody protection from the virus over time. The infants will not receive vaccine.

Similarly, in children and young people, the strength and longevity of the immune response will be gauged by testing blood samples taken 21 days after the first dose, 10 days after the second dose, and six months after entering the study.

The vaccine, manufactured by Novartis Vaccines and Diagnostics, contains inactivated 2009 H1N1 influenza virus, so it is impossible to become infected with the virus by receiving the vaccine. The vaccine does not contain adjuvant, a substance added to some vaccines to improve the body's response to vaccine.

Research on seasonal influenza vaccine and vaccines for other diseases in HIV-infected and other populations suggest that higher doses of vaccine tend to elicit stronger immune responses. These stronger responses, in turn, increase the concentration of protective antibodies in the bloodstream, which likely is beneficial to both the vaccinated individual and, if pregnant, to her fetus. This is the rationale for testing whether higher doses of licensed 2009 H1N1 influenza vaccine elicit a protective immune response in HIV-infected individuals and whether that protection is transferred to the fetuses of vaccinated pregnant women.

NIAID announces vaccine adjuvant discovery contracts

Thu, 08 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has awarded six new research contracts to discover and characterize novel adjuvants, substances that can be added to vaccines to enhance the protective immune response they induce.

The goal of these awards is to find safe new adjuvants that will boost the effectiveness of vaccines, says NIAID Director Anthony S. Fauci, M.D. Adjuvants can be used not only to enhance the immune response to a vaccine and thereby offer better protection but also to extend the vaccine supply if needed, enabling more people to be vaccinated with fewer doses.

Currently, the only vaccine adjuvant approved for use in the United States is an aluminum mixture known as alum.

NIAID has awarded a total of approximately $60 million over five years for these contracts. The awardees will identify novel compounds with the potential to be vaccine adjuvants. All compounds will be tested in animal models and human cells to determine how well they stimulate the immune response. The investigators also will examine and describe the cellular reactions the compounds induce.

The goal of these awards is not only to identify new adjuvant candidates but also to describe how these candidates work, says Helen Quill, Ph.D., chief of NIAID's basic immunology research branch. We would hope that these adjuvant candidates will become part of a robust pipeline leading to the development of many different vaccines.

The awardees of the adjuvant contracts will work to identify and characterize novel adjuvants that trigger receptors of the inborn, or innate, immune system. These receptors recognize and bind small molecules that are unique to harmful microorganisms. Binding stimulates an immediate innate immune response, a broadly protective reaction. The innate immune response also is required for the development of the highly specific antibody and T-cell responses that characterize long-term immunity.

The investigators also will seek to identify the cellular receptor for each of the novel adjuvant candidates, determine how it triggers the innate immune response, and then make changes to the adjuvant to improve its ability to induce the innate immune response. Although a number of innate immune receptors already have been described, many more likely exist and are expected to be uncovered in the course of these projects.

The award of these contracts is an integral part of NIAID's long-range plan to expand the adjuvant pipeline, says Daniel Rotrosen, M.D., director of NIAID's Division of Allergy, Immunology, and Transplantation, which oversees these awards. A first round of NIAID contracts, awarded in 2003, limited the discovery of novel adjuvants to those that stimulated the only group of innate immune receptors known at the time. With this second round of awards, we intend to increase the number of adjuvant candidates by expanding the research scope to include all known innate immune receptors.

The institutions receiving contracts for 2009 are

Lessons learned from H1N1 virus pandemic

Thu, 08 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A comprehensive study has revealed, for the first time, the impact of swine flu on the health of the general public in Australia and New Zealand.

The lessons learned in Intensive Care Units (ICUs) across the two countries on the impact of the H1N1 (swine flu) virus are being shared with countries in the Northern Hemisphere to help them prepare for their upcoming flu season.

The three-month study, conducted at the height of the pandemic between June and August, reveals that 722 patients were admitted to ICUs and that at the peak of the epidemic up to 20 per cent of ICU beds were occupied by patients with swine flu infection.

The study was co-coordinated by the Monash University-based Australian and New Zealand IntensiveCare Research Centre (ANZIC-RC). The study involved all ICUs in Australia and New Zealand with the affected patients being treated in 109 of these units. The study was conducted utilising the resources of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG).

Dr Ian Seppelt, a specialist in Intensive Care Medicine and based at Sydney's Nepean Hospital, saidthe impact of the virus on ICUs across Australia and New Zealand was dramatic.

Intensive Care Units specialise in the management of patients with life-threatening illness and thesurge of patients with H1N1 placed substantial strain on staff and resources. The most severely affected patients had pneumonia affecting both lungs that was caused by the virus. The number of patients admitted to ICUs with this complication represented a 600 per cent increase compared toprevious years, Dr Seppelt said.

Clinical Associate Professor Steve Webb, from the Intensive Care Unit at Royal Perth Hospital, wasanother key researcher on the project and said the information, which surfaced from the study willbenefit other countries about to head into their winter flu season.

Unlike previous 'seasonal' influenza strains, which impact heavily on elderly people and people withsevere coexisting medical conditions, the H1N1 virus affected a different profile. Critical illness due toswine flu was most common in infants and middle aged people; with pregnant patients, the overweight,and indigenous patients particularly affected. Overall, about one-third of patients admitted to anICU because of swine flu had no underlying health problems. Associate Professor Webb said.

Professor Rinaldo Bellomo, Foundation Chair of the ANZICS CTG and Director of Intensive CareResearch at Austin Health, Melbourne said the results of the study would be shared with health authorities in other countries to assist them better prepare for their flu season.

We have come through our flu season and our assessment of the impact of the H1N1 strain will assist them prepare for any outbreak. The H1N1 virus has taken hold in many countries already, but many countries in the Northern Hemisphere will benefit from the lessons we have learned, Professor Rinaldo Bellomo said.

Fortunately a vaccine is now available to prevent the complications of swine flu and it is important thatall members of the community and especially those with risk factors, consider being vaccinated, hesaid.

Research ensures 50 million vaccinated against deadly brain infection

Tue, 06 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Research at the University of Liverpool has supported the vaccination of more than 50 million people against a zoonotic brain infection that affects thousands of children across Asia every year.

The infection, called Japanese encephalitis (JE), is found in pigs and wading birds and transmitted by mosquitoes in areas of Southeast Asia and the Western Pacific. The World Health Organisation (WHO) estimates that JE affects approximately 50,000 people a year and kills around 15,000. Those that survive the infection can be left brain damaged.

Scientists at Liverpool, in collaboration with Asian governments, the WHO and the Program for Appropriate Technology in Health (PATH), are improving understanding of the disease and developing immunisation programmes to control it, with the support of funds from the Bill and Melinda Gates Foundation.

Children in poor rural communities are particularly vulnerable to the infection, but as a result of improved diagnostics and clinical management, vaccinations against the disease have now reached more than 50 million children and the programme continues across Asia.

Professor Tom Solomon, Head of the University's Brain Infection Group, said: Japanese encephalitis invades the central nervous system and can cause seizures, paralysis and in severe cases, death. Approximately 50 per cent of people who survive the infection are left with physical and mental illness, which could include personality changes. It affects children between the ages of one to 15, but adults, including tourists to the region, can contract the disease also.

Although we knew this disease was important, five years ago it was virtually unrecognised due to the difficulty in diagnosing cases. It causes disability more often than it causes death, but with no standard method of quantifying the disability, it was difficult for governments to make decisions on introducing vaccines. We have been developing ways of diagnosing JE and measuring the outcome of the infection, and these methods are now being used in many countries across Asia.

Previously scientists used highly specialised laboratories to grow cultures of the virus, but these facilities were not widely available across Asia. The Liverpool team, and partner institutions, have developed simple blood tests that allow medics to detect antibodies of the disease, a procedure that can be performed in hospitals and regional labs to provide accurate diagnosis.

Scientists have been working to enhance disease detection by developing surveillance guidelines, which helps medics build a database of all patients that enter hospitals with symptoms of the infection. The system allows authorities to monitor the number of people infected so that appropriate measures can be taken to protect against the disease. The team have also developed a standard method of quantifying the disabilities caused by JE. This gives a profile of the disease and shows how to characterise the disabilities children may have after the infection has left the body.

As a result of these new measures many governments across Asia are beginning to effectively control JE through vaccination.

HIV vaccine regimen demonstrates modest preventive effect in Thailand clinical study

Thu, 24 Sep 2009 03:59:36 PST

( from http://www.rxpgnews.com ) In an encouraging development, an investigational vaccine regimen has been shown to be well-tolerated and to have a modest effect in preventing HIV infection in a clinical trial involving more than 16,000 adult participants in Thailand. Following a final analysis of the trial data, the Surgeon General of the U.S. Army, the trial sponsor, announced today that the prime-boost investigational vaccine regimen was safe and 31 percent effective in preventing HIV infection.

These new findings represent an important step forward in HIV vaccine research, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, which provided major funding and other support for the study. For the first time, an investigational HIV vaccine has demonstrated some ability to prevent HIV infection among vaccinated individuals. Additional research is needed to better understand how this vaccine regimen reduced the risk of HIV infection, but certainly this is an encouraging advance for the HIV vaccine field.

We thank the trial staff in Thailand and the United States for their years of effort in successfully conducting this study and the study participants and the people of Thailand for their long-standing support of HIV vaccine research, Dr. Fauci adds.

The Thai Phase III HIV vaccine study, also known as RV144, opened in October 2003. The placebo-controlled trial tested the safety and effectiveness of a prime-boost regimen of two vaccines: ALVAC-HIV vaccine (the primer dose), a modified canarypox vaccine developed by Sanofi Pasteur, based in Lyon, France, and AIDSVAX B/E vaccine (the booster dose), a glycoprotein 120 vaccine developed by Vaxgen Inc., and now licensed to Global Solutions for Infectious Diseases (GSID), based in South San Francisco, Calif. The vaccines are based on the subtype B and E HIV strains that commonly circulate in Thailand. The subtype B HIV strain is the one most commonly found in the United States.

Led by principal investigator Supachai Rerks-Ngarm, M.D., of the Thai Ministry of Public Health's Department of Disease Control, the study was sponsored by the U.S. Army in collaboration with NIAID, Sanofi Pasteur and GSID. The trial, conducted in the Rayong and Chon Buri provinces of Thailand, enrolled 16,402 men and women ages 18 to 30 years old at various levels of risk for HIV infection. Study participants received the ALVAC HIV vaccine or placebo at enrollment and again after 1 month, 3 months, and 6 months. The AIDSVAX B/E vaccine or placebo was given to participants at 3 and 6 months. Participants were tested for HIV infection every 6 months for 3 years. During each clinic visit, they were counseled on how to avoid becoming infected with HIV.

In the final analysis, 74 of 8,198 placebo recipients became infected with HIV compared with 51 of 8,197 participants who received the vaccine regimen. This level of effectiveness in preventing HIV infection was found to be statistically significant. The vaccine regimen had no effect, however, on the amount of virus in the blood of volunteers who acquired HIV infection during the study.

The Thai study demonstrates why the HIV vaccine field must take a balanced approach to conducting both the basic research needed to discover and design new HIV vaccines and, when appropriate, testing candidate vaccines in people, says Margaret I. Johnston, Ph.D., director of NIAID's Vaccine Research Program within the Division of AIDS. Both avenues provide critical information that will continue to help us better understand what is needed to develop a fully protective HIV vaccine.

NIAID and the collaborating partners are working with other scientific experts to determine next steps, including additional research of the RV144 vaccine regimen and the need to consider the impact of these new findings on other HIV vaccine candidates.

Individuals who acquired HIV infection while participating in the Thai trial have been provided access to HIV care and treatment, including highly active antiretroviral therapy based on the guidelines of the Thai Ministry of Public Health.

New vaccine strategy might offer protection against pandemic influenza strains

Mon, 18 May 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A novel vaccine strategy using virus-like particles (VLPs) could provide stronger and longer-lasting influenza vaccines with a significantly shorter development and production time than current ones, allowing public health authorities to react more quickly in the event of a potential pandemic.

Ted Ross, Ph.D., an assistant professor at the University of Pittsburgh's Center for Vaccine Research, will present his laboratory's latest data on the efficacy of VLP vaccines for potential pandemic strains, such as H5N1 and 1918 influenza, today at the 109th General Meeting of the American Society for Microbiology in Philadelphia.

Virus-like particles look just like a live virus, but they are hollow shells without a genome inside and they cannot reproduce, Ross explained. Because they look like the virus, they evoke a more robust immune response against the real thing.

Ross and his colleagues have already made VLP vaccines that have been tested in early clinical trials and appear to provide complete protection against both the H5N1 avian influenza virus and the 1918 Spanish influenza virus.

There is a debate in the influenza community about priming the human population for potential pandemic strains such as H5N1 or 1918, Ross said. Some researchers advocate adding these strains to the annual flu vaccine. They might not match the next pandemic flu strain exactly, but could provide some of protection.

Others contend that it might be premature, as well as costly, to vaccinate people against a virus that may never emerge, he said.

The current injectable vaccine for seasonal influenza is a trivalent, inactivated vaccine. It consists of three different influenza strains that are grown in eggs and then inactivated, or killed, by chemicals that break them into tiny pieces. Because they no longer look like the circulating virus, conventionally made vaccines strains do not elicit as strong an immune response as VLP vaccines. Because it is made with live, attenuated virus, the inhaled, mist-based vaccine can elicit a strong immune response but can also increase the risk of side effects.

VLPs can be quickly and easily produced in several ways, including growing them in cell cultures or in plants. Also, if the genes in the disease virus are identified, then researchers can generate particles for a vaccine without an actual sample of the agent.

The sequence for the recent H1N1 'swine flu' virus was online and available to scientists long before physical samples could be delivered, Dr. Ross noted. It would have been possible to produce VLPs in quantity in as little as 12 weeks while conventional vaccines require physical samples of the virus and production can take approximately nine months.

One VLP-based vaccine already is on the market, namely the human papilloma virus (HPV) vaccine.

Xenophobic face of new flu in US

Wed, 06 May 2009 11:11:43 PST

( from http://www.rxpgnews.com ) Washington, May 6 - The influenza A - flu virus came from Mexicans, most likely Mexicans who are in the US illegally: the comment, spiced up with references to Mexicans as 'primitive' and as 'leeches', cost Boston radio talk show host Jay Severin his job.

The problem is that in the face of a new influenza virus whose consequences are still uncertain, he is not the only one in the US who has started to accuse illegal immigrants, particularly those who hail from Mexico, of being the source of the problem.

Above all, he is not the only one who is using the latest health scare to support anti-immigration rhetoric and a call for closing the border between the US and Mexico.

'Make no mistake about it: Illegal aliens are the carriers of the new strain of human-swine avian flu from Mexico,' said another radio talk show host, Michael Savage.

Savage, who apparently has not yet lost his job, went even further in whipping up public emotions.

'Could this be a terrorist attack through Mexico? Could our dear friends in the radical Islamic countries have concocted this virus and planted it in Mexico knowing that you, - Janet Napolitano, would do nothing to stop the flow of human traffic from Mexico?' he said, in comments quoted in the website Media Matters for America.

The Washington-based NGO National Immigration Forum has monitored the large number of comments of this type that emerged over the past ten days as the fear of an influenza pandemic increased in US media.

'Unfortunately there are people who abuse media power to make money with ignorant messages of fear and racism,' Forum spokeswoman Katherine Vargas told DPA.

'They take advantage of a public health issue to spread lies which only add to the confusion. This is a public health issue, not an immigration issue,' she stressed.

The topic is particularly thorny at a time when illegal immigrants within the US are fighting to resolve their situation, which President Barack Obama has promised to tackle this year.

And yet the fact that the first confirmed death of the new flu virus within the US was a 23-month-old toddler of Mexican origin did not help ease the tension.

The case was confirmed last week and happened in Houston, Texas.

'The child was not a United States citizen,' said local councillor Toni Lawrence. 'We need to do things for Houston and not for anybody else.'

For Maria Jimenez, an activist for the rights of immigrants in Houston who works for the organisation Dignidad, the issue is 'absurd' but also dramatic, given the awful mistakes that it leads to.

'It is absurd because - is not a case of undocumented migrants, and the fact that they refer to that proves that it is a xenophobic reaction more than a reality,' Jimenez said.

She had been in contact with the dead toddler's family.

'What is worrying is that, as always, the anti-immigrant sector uses pressure methods before political sectors, it is an irresponsible attitude on the part of local officials,' said Jimenez, herself of Mexican origin.

'The point is that there are people who are using this to incite anti-immigration anger,' Teresa Puente, a professor of journalism at Columbia College, Chicago, said in the blog Latina Voices on Latin American women.

The fact that almost all the confirmed cases in the US correspond to US citizens does not seem to inhibit the arguments of conservative observers on immigration.

For Maria Jimenez, the issue bears an added risk.

'I am scared that, in the face of this xenophobia, many undocumented immigrants do not dare to go to medical centres -, which could be worse,' she noted.

James Rodriguez, Houston councillor in the district where the Mexican boy died, spoke along similar lines.

'At this time, the treatment of all cases is more imperative than any discussion on immigration status,' he said in a statement Friday.

He was reacting to his colleague Lawrence's comments, saying they had 'negatively alarmed many residents throughout the city'.

For Cesar Espinosa, director of the immigrant organisation America para Todos - in Houston, said only one thing remained to be done for the coming months.

'We will have to work with the community and show that we do not bring microbes,' he said shrugging his shoulders.

Novel lung cancer vaccine shows promise in fighting early-stage lung cancer

Mon, 06 Apr 2009 03:59:36 PST

( from http://www.rxpgnews.com ) CHICAGO - An experimental vaccine that triggers the patient's immune system to identify and attack specific tumor cells is showing new promise for the treatment of early lung cancer. Thoracic surgeons at Rush University Medical Center are researching the vaccine called MAGE-A3 Antigen-Specific Cancer Immunotherapeutic, which is designed to kill cancer cells without harming normal cells. Rush is one of only five hospitals in Illinois offering the vaccine.

The MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell LunG Cancer Immunotherapy) study is a randomized, double-blind and placebo controlled trial that will enroll patients with MAGE A-3-positive, non-small-cell lung cancers. The experimental vaccine targets MAGE-A3, a protein expressed in certain cancer cells but not in normal cells. Thirty-five percent of non-small-cell lung cancers have this protein which also is present in some melanomas and head and neck cancers.

The principle is that you can possibly teach a patient's immune system to eliminate cancer cells that express certain proteins such as the MAGE-A3 protein, said Dr. Anthony Kim, thoracic surgeon and principal investigator of the study at Rush. In a trial of early-stage lung cancer patients whose tumors expressed MAGE-A3, preliminary results showed that the vaccination reduced the risk of recurrence and the need for repeat surgery.

The vaccination may be a promising alternative treatment solution for lung cancer patients that may not be ideal candidates for chemotherapy. Many surgically treated lung cancer patients are not able to tolerate the side effects of chemotherapy.

Surgery is the standard treatment for patients with early-stage lung cancer, but approximately 50 percent of patients who have surgery ultimately die of lung cancer.

Adding the tumor vaccine to surgery has the potential to boost the survival rate by 10 percent, which was the figure that was observed in the initial phase of the MAGE-A3 trial, said Kim. This is a potential alternative for patients that otherwise would not undergo chemotherapy treatment either because of their tumor stage or other co-morbidities such as their age or other medical problems.

A total of 182 patients with non-small-cell lung cancers were included in the early phase of the study sponsored by GlaxoSmithKline, which is developing the vaccine therapy. All the patients had cancers expressing MAGE-A3, the tumor-specific antigen. After having surgery to remove the tumors, 122 patients were randomly assigned to treatment with the MAGE-A3-targeting vaccine and 60 patients received placebo vaccines. The preliminary research shows that the treatment was well tolerated by patients and the MAGE-A3-treated patients seemed less likely to have recurrences and die from their disease than the placebo-treated patients. Further studies need to be completed to test the safety and efficacy of the vaccine.

Patients were given five injections every three weeks at the beginning of treatment and then eight injections every three months later for a total of 27 months. Earlier phases of the study indicate the immunotherapy treatment was well tolerated by patients.

New Test to Establish In-Vivo Safety of Dengue Vaccine

Mon, 16 Feb 2009 16:35:46 PST

( from http://www.rxpgnews.com ) Washington, Feb 16 - Researchers have developed a test to determine whether vaccines against a virus that infects 100 million people annually, now ready for clinical trials, should really protect patients from infection, or would make it more dangerous for them.

'Our study shows that the new test is likely superior to the standard test in its ability to tell whether a patient's response to a vaccine is safe,' said Xia Jin, associate professor of medicine at the University of Rochester Medical Centre - and co-author of the study.

Cases of tropical, mosquito-borne dengue fever have been expanding globally for more than 50 years, with nearly a third of the human population in 100 countries now at risk of infection with the four types of dengue virus.

Infection with the dengue flavivirus, which is related to West Nile Virus and Yellow Fever, annually results in an estimated half a million hospitalisations and 22,000 deaths, mostly among infants, according to WHO.

After decades of absence in the US, the disease is causing illness again along the Texas-Mexico border, experts say and add that widespread dengue infection in the continental US is a real possibility.

A typical dengue infection confines a patient to bed for more than a week with fever and severe limb pains, but most recover. In less than five percent of cases, however, dengue hemorrhagic fever - and dengue shock syndrome -, often deadly complications, develop just as the fever breaks.

Mostly affecting babies between five and eight months, DHF causes victims to vomit and pass blood in their feces and urine. If diagnosed quickly, patients respond to intensive hospital treatment and fluids, but mortality can reach 15 percent when undiagnosed.

DSS comes when the infection has caused so much fluid to leak out of capillaries that there is not enough blood to supply organs. As of 2008, there were no antiviral drugs designed to treat dengue and no drug candidates in late-stage development, said an URMC release.

These findings were published in Clinical and Vaccine Immunology.

Ireland Cancer Center researcher finds most triple-negative breast cancers express muc-1 target

Fri, 12 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) CLEVELAND: Research out of the Ireland Cancer Center of University Hospitals Case Medical Center has found that the vast majority of triple negative breast cancers express the MUC-1 target. This first-of-its-kind finding, presented today at the San Antonio Breast Cancer Symposium, has paved the way for an upcoming vaccine trial for patients with early stage triple negative breast cancer that could potentially prevent recurrence of this aggressive type of breast cancer.

Joseph Baar, MD, PhD, Director of Breast Cancer Research at the Ireland Cancer Center, and colleagues analyzed 53 tumors and determined that 92 percent of them expressed MUC-1. These findings support their theory that this MUC-1 protein on breast cancer cells could be a target for a novel vaccine using the patient's immune system to target and kill cancer cells.

Dr. Baar has received a prestigious grant from the National Cancer Institute and the Avon Foundation to begin the vaccine trial in January 2009 for women with early stage triple negative breast cancer to see if this vaccine can raise their immune response against MUC-1. If it does, then a later study would be undertaken to determine whether the generation of such an immune response leads to an increase in patients' relapse-free survival rates, thereby preventing recurrence. The vaccine will be administered following standard therapy of surgery, radiation and chemotherapy.

This vaccine trial has the potential to rev up patients' immune response to the MUC-1 protein and shut down the tumor's ability to grow, says Dr. Baar. Women with this aggressive triple negative breast cancer have an increased risk of recurrence and we are hoping to provide them with protection against the return of this deadly disease. Our findings that have been presented at the San Antonio Breast Symposium provide us a strong basis for this trial.

Triple negative breast cancer is a highly aggressive form which comprises 10-15 percent of newly diagnosed early stage breast cancer. Most triple negative tumors are high grade and have a high incidence of recurrence and metastases (spreading to other organs). Unlike other types of breast cancer, there is no standard follow-up treatment for triple negative breast cancer to prevent recurrence.

This is an important study because there has traditionally been nothing to offer women with triple negative breast cancer beyond standard therapy, says Stanton Gerson, MD, Director of the Ireland Cancer Center. This vaccine trial has the potential to lay the groundwork for a new standard of care for women with this aggressive form of breast cancer.

Immunology Center will continue to drive standard methods, better science

Thu, 11 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) The Rochester Human Immunology Center (RHIC) has been awarded a $4 million renewal of its grant from the National Institute of Allergy and Infection Disease (NIAID). The renewal enables RHIC to continue leading the field of immunology in a worldwide effort to standardize how researchers use complex technologies like flow cytometry that are central to the discovery of new treatments.

When standardization is achieved, researchers will be better able to compare data collected worldwide, with the results of many studies combined into massive datasets to guide the construction of hyper-accurate computer models of the mechanisms of disease. Such simulations will yield scientific conclusions that are dramatically more valid and reproducible in areas like infectious disease, transplantation and cancer, researchers said. The resulting sophistication in understanding of the human immune system, and of how it responds to influenza, HIV or smallpox for instance, will guide the more precise design of near-future vaccines.

Since its founding four years ago, the RHIC has proven that it can drive the development of standard operating procedures, having helped more than 39 investigators and teams standardize their testing, and lending expertise that helped lead to the winning of 22 major grants. As an internationally known resource, the RHIC is part of working groups seeking to standardize methods for analyzing flu viruses and HIV in partnership with the Division of Microbiology and Infectious Diseases at NIAID, the HIV Vaccine Trials Network and the New York Influenza Center of Excellence.

Standardizing test methods to achieve comparable results goes far beyond being able to compare apples to apples, said Sally Quataert, Ph.D., director of Core Facilities for the University of Rochester School of Medicine and Dentistry, and co-principle investigator for the grant renewal. Validated methods assure researchers that their experimental results are good science, and truly meaningful. Standard methods also directly contribute to translational science, where the results of studies are more readily affirmed by regulatory bodies, and with fewer conflicting studies.

Prior to 2004, Quataert was director of Immunobiological Laboratory Services at Wyeth Vaccines Research in Rochester for seven years. Her industry background prepared her to apply Good Laboratory Practice (GLP) standards to academic studies, making them more likely to withstand scrutiny by the U.S. Food and Drug Administration as sound evidence that new treatments are safe and effective. If applied internationally, such standards would make drug candidates discovered at universities much easier to license to industry, with potential to increase the number of new drugs becoming available.

Also recently joining the RHIC executive committee was Tim Bushnell, Ph.D., director of the Flow Cytometry Core at the University of Rochester Medical Center. Bushnell's active role in the International Society of Analytical Cytology (ISAC) has positioned RHIC, not just to develop expertise, but also to take a leading role in the groups that are shaping related standards worldwide.

Flow cytometry is a method of counting and sorting cells that have been labeled by fluorescent markers which correspond with physical and chemical qualities of the cell. Modern flow cytometers can analyze thousands of cells in real time to unravel the complex interactions driving disease processes. The devices beam laser light into a stream of liquid which carries the cells to be analyzed. Detectors catch the patterns of fluorescent light that bounce off single cells as they pass through the laser. The cells have been prepared with fluorescent dyes that absorb the laser light and emit light at lower frequencies in scatter patterns that reveal information about the cell.

Modern instruments have multiple lasers and fluorescence detectors, with 18 fluorescence detectors now commonplace in larger research institutions. Increasing the number of lasers and detectors enables more precise identification of target cell populations by their characteristics. Four years ago, the RHIC had eight-color flow cytometry, but has since upgraded to 11- and 18-color cytometers with support from the Medical Center and its Clinical Translational Science Institute (CTSI). Researchers receive training on flow cytometry and other key discovery techniques and gain access to a growing suite of RHIC equipment. With the renewal of the NIAID grant, the center will continue to develop and standardize immunological methods.

Beyond general leadership and standard setting, the center will take the lead in the next five years in helping the field to make better use of three cutting-edge technologies of immense importance. The goal is to advance technologies to maturity so that they can be applied widely, with the new standards communicated through publications, the RHIC Web site and symposia.

The first technology is arrayed image reflectometry, which promises to be very useful in large-scale analysis of immune responses against multiple disease-causing proteins like those encountered during influenza outbreaks. Immune system proteins can be coated with a thin film that prevents light from reflecting off of them, but that become more reflective as the proteins bind to disease-related proteins. When several proteins to be tested are attached to a biochip, a great many proteins can be analyzed for little cost.

The grant renewal will also bring together RHIC experts in cytometry and in a second new technology: quantum dot nanostructures. These microscopic machines have optical qualities that can be harnessed to measure cellular qualities via flow cytometry with more precision than fluorescent dyes. Like dyes, the dots can be designed to inhabit certain regions of the cell, or cling to certain proteins, so that their number and characteristics can be measured. Dyes are an older technology, limited in number and with overlapping emission spectra, which means they interfere with each other. RHIC teams will seek to establish new Q-dot production methods to replace and extend dye capability. As RHIC machinery gets more complex, it will become increasingly able to pick apart and to build accurate immune cell models.

Thirdly, the team will seek to design better gating procedures. Flow cytometry separates cell types by brightness into groups, and gating is the process by which researchers select which cells go into each group. The current process in many labs is arbitrary, tedious and has poor reproducibility between operators because research teams select patterns of cell characteristics by eye. The field of flow cytometry is in desperate need of high-speed automation to process the mountains of data generated by the tests, and when gating the results, researchers said. The current process is greatly slowing the pace of discovery as research teams do double duty with lab work and time-consuming computational work.

One unique capability that drove the RHIC renewal was that the Medical Center has a world-leading core of biostatisticians along with leading immunologists. Led by Hulin Wu, Ph.D., chief of the Department of Biostatistics and Computational Biology, the biostatistics team within RHIC will seek to establish statistically-rigorous, automated gating protocols for flow cytometry analysis that will greatly increase the reproducibility of data and the speed of flow cytometry lab by lab.

1918 Spanish flu records could hold the key to solving future pandemics

Sun, 09 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Ninety years after Australian scientists began their race to stop the spread of Spanish flu in Australia, University of Melbourne researchers are hoping records from the 1918 epidemic may hold the key to preventing future deadly pandemic outbreaks.

This month marks the 90th anniversary of the return of Australian WWI troops from Europe, sparking Australian scientists' race to try and contain a local outbreak of the pandemic, which killed 50 million people worldwide.

Researchers from the University of Melbourne's Melbourne School of Population Health, supported by a National Health and Medical Research Council grant, are analysing UK data from the three waves of the pandemic in 1918 and 1919.

They hope that modern high-speed computing and mathematical modeling techniques will help them solve some of the questions about the pandemic which have puzzled scientists for close to a century.

Professorial Fellow John Mathews and colleagues are analysing the records of 24,000 people collected from 12 locations in the UK during the Spanish flu outbreak including Cambridge University, public boarding schools and elementary schools.

He says gaining a better understanding of how and why the virus spread will help health authorities make decisions about how to tackle future pandemics.

In the 1918/19 pandemic, mortality was greatest among previously healthy young adults, when normally you would expect that elderly people would be the most likely to die,'' Professor Mathews says We don't really understand why children and older adults were at lesser risk.

One explanation may be that children were protected by innate immunity while older people may have been exposed to a similar virus in the decades before 1890 which gave them partial but long-lasting protection.

Those born after 1890 were young adults in 1918. They did not have the innate immunity of children and as they weren't exposed to the pre-1890 virus they had little or no immunity against the 1918 virus. We can't prove it but it is a plausible explanation.

Another striking feature is that the pandemic appeared in three waves, in the summer and autumn of 1918 and then the following winter.

One theory being examined to explain why some people were only affected in the second or third wave is that because of recent exposure to seasonal influenza virus they had short-lived protection against the new pandemic virus.

The attack rates in the big cities weren't as high and this is probably because many people had been exposed to ordinary flu viruses, giving short-lived immunity,'' he says.

In the English boarding schools, where there was social demarcation, children were probably less exposed to seasonal influenza viruses in earlier years; without that protection, pandemic attack rates were much higher than in ordinary government elementary schools.

If we can provide a detailed time course of epidemics and the attack rates at different times, that information can be extremely useful in determining how a future pandemic might progress,'' says Professor Mathews.

He says initial findings point strongly to the value of short-lived immunity to provide protection or partial protection against the early waves of a virus.

This is particularly important when considering the stockpiling of drugs and vaccines to protect the community against a virus.

The early implications of our study are that there may be benefit in providing short-lived immunity that is broadly based rather than specific,'' he says.

If another flu pandemic were to come along and you have a vaccine, it may be better to use it even if it is against a different sub-type of the virus.

Pneumococcal vaccine could prevent numerous deaths, save costs during a flu pandemic, model predicts

Tue, 28 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A new predictive model shows that vaccinating infants with 7 valent pneumococcal conjugate vaccine (PCV7)--the current recommendation--not only saves lives and money during a normal flu season by preventing related bacterial infections; it also would prevent more than 357,000 deaths during an influenza pandemic, while saving $7 billion in costs.

Keith P. Klugman, PhD, professor of global health at Emory University's Rollins School of Public Health, will present results of the research using the predictive model at the joint ICAAC/IDSA meeting in Washington, DC, Oct. 25-28. (Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Disease Society of America.

Bacterial infections, particularly pneumococcal disease, can follow a viral illness such as flu and cause secondary infections that worsen flu symptoms and increase influenza-related risk. Bacterial infections may have been the cause of nearly half of the deaths of young soldiers during the 1918 flu pandemic.

We've known for years that bacterial infections can develop after influenza, says Klugman. Unlike the 1918 flu pandemic, which preceded the antibiotic era, we now have vaccines that can prevent these types of pneumococcal infections. This model shows what a dramatically different outcome we could expect with standard PCV vaccination.

Klugman and colleagues at Harvard University, i3 Innovus in Medford, Ma. and Wyeth Research constructed a model to estimate the public health and economic impact of current pneumococcal vaccination practices in the context of an influenza pandemic.

Since 2000 the Centers for Disease Control and Prevention (CDC) Immunization Practices Advisory Committee (ACIP) has been recommending PCV vaccinations for infants and children.

The new predictive model was used to compare the results of no PCV vaccination to the current routine vaccination of infants less than two years old. The researchers assessed the effect of vaccination policies under both normal and pandemic influenza conditions. They included both direct vaccination effects in vaccinated individuals and indirect vaccination effects (called herd immunity) in the unvaccinated. For manifestations of pneumococcal disease, they included invasive pneumococcal disease (meningitis or bacteremia), all-cause pneumonia and all-cause acute otitis media (ear infections). The model's estimates were based on the 1918 pandemic.

The new model predicted that current pneumococcal vaccination practices reduce costs in a typical flu season by $1.4 billion and would reduce costs by $7 billion in a pandemic. In a pandemic, they would prevent 1.24 million cases of pneumonia and 357,000 pneumococcal-related deaths.

Our research shows that routine pneumococcal vaccination is a proactive approach that can greatly reduce the effects of a future flu pandemic, says Klugman. Countries that have not yet implemented a pneumococcal vaccination program may want to consider this as part of their pandemic flu preparedness.

Groundbreaking, lifesaving TB vaccine a step closer

Tue, 07 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at Aberystwyth University, following a number of years of investment by the Biotechnology and Biological Sciences Research Council (BBSRC), have licensed ground-breaking research to a non-profit product development partnership working to develop new, more effective vaccines against Tuberculosis (TB). This development will give hope that significantly better prevention and treatment of TB will be available within the next few years.

The Aeras Global TB Vaccine Foundation, which was founded to develop new, cost-effective TB vaccines for use in the developing world, has licensed a discovery of a protein that is able to 'wake up' dormant Mycobacterium tuberculosis bacteria that cause TB. The research and the fundamental knowledge that came out of it could be used to develop a vaccine that either stops infecting TB bacteria from taking hold or, for the one in every three people world-wide who are already carrying a latent TB infection, prevents dormant bacteria from 'waking up'. Another possible strategy could be to deliberately 'wake up' dormant bacteria in a controlled way so they can be destroyed with antibiotics.

In the late 1990s, researchers funded by BBSRC discovered a new family of proteins that were able to resuscitate bacteria found harmlessly in and around the human body. When 'awoken' from dormancy the bacteria were then much more susceptible to attack from antibiotics. The team led by Professors Mike Young and Doug Kell at Aberystwyth University together with Prof Arseny Kaprelyants of the Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, identified the gene in the bacterium that produced the protein and went on to discover the corresponding genes in M. tuberculosis. This research has now been licensed by Aeras after years of development. Aeras plans to take its recombinant BCG (AERAS-407) vaccine, based in part on the Aberystwyth work, to clinical trial in 2009.

Prof Young, now based in Aberystwyth University's newly formed Institute of Biological, Rural and Environmental Studies, said: Current TB treatments can go on for over six months and can still leave bacteria in the body that can cause the disease when they resume active growth and multiplication. Our discovery, which is now being developed into a vaccine, might help prevent the establishment of persistent infections in the first place or, alternatively, it might prevent persisting organisms in individuals with latent TB from reawakening at all.

TB kills around 1.7 million people around the world every year. I hope that our research will now be rapidly translated into a vaccine that can help as many of these people as possible.

Dr Alf Game, BBSRC Deputy Director of Research, said: This discovery came out of research in the basic biology of a different bacterium. It shows that we need to strive to understand the fundamental workings of the world around us and from that we can identify how to tackle challenges, such as dangerous diseases, that we all face.

USU researchers awarded $5.6 million NIH grant to fight deadly viruses

Fri, 27 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the Uniformed Services University of the Health Sciences (USU) have been awarded a $5.6 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to develop and test vaccines and treatments for the deadly Nipah and Hendra viruses.

Christopher C. Broder, Ph.D., USU professor of microbiology and immunology and director of the university's interdisciplinary program in Emerging Infectious Diseases, is the principal investigator of the grant from NIAID. The grant was awarded to continue work on vaccines and therapeutics for Nipah and Hendra that his group has been working on for the past several years. The award will support a continued collaboration with investigators at Australia's Commonwealth Scientific and Industrial Research Organization (CSIRO) Livestock Industries, Australian Animal Health Laboratory (AAHL) and Australian Biosecurity Cooperative Research Center (AB-CRC) in Geelong, Victoria.

Hendra and Nipah are recently emerged paramyxoviruses that are highly pathogenic and can cause lethal infections in several animals and in humans. Since their initial discovery in Australia and Malaysia, sporadic Hendra outbreaks have been reported from 1995 to 2007, while Nipah has caused at least nine outbreaks between 1998 and 2008. Human case fatality rates have approached 75 percent, and there has been evidence of human-human transmission. The most recent appearance of Nipah in 2008 claimed the lives of several children.

In earlier work, Katharine Bossart, Ph.D., a former graduate student in Broder's laboratory who now works with the Australian Animal Health Laboratory in Geelong, developed a subunit vaccine for Nipah and Hendra composed of a piece of the virus known as the G glycoprotein. In other recent studies, Broder's group, in collaboration with researchers from the National Cancer Institute, developed a potent Nipah and Hendra virus neutralizing human monoclonal antibody (m102.4).

We now have the critical resources needed to evaluate the therapeutic potential of both vaccines and perhaps more importantly a potent human antibody against both Nipah virus and Hendra virus, that could help control outbreaks in geographical regions susceptible to these emerging viruses, and result in a real benefit to those people at risk of infection and disease caused by these deadly agents, said Broder.

Previously, Broder and colleagues demonstrated that a cell surface protein called Ephrin-B2 is a functional receptor for both the Hendra and Nipah viruses. Ephrin-B2 is highly conserved in animals, and this finding shed light on how the viruses can infect such a wide range of hosts. The receptor is found on cells in the central nervous system, as well as in cells lining blood vessels. It is essential for central nervous system development and blood vessel growth in the embryos of humans and other mammals.

The research has led to four inventions on which USU and HJF have filed patent applications. The first patent application, Soluble forms of Hendra Virus and Nipah Virus G glycoprotein, covers the production and use of a recombinant soluble G glycoprotein. This protein has utility as a vaccine, in the development of pharmaceutical compositions and in diagnostic assays.

The second patent application, Compositions and Methods for the Inhibition of Membrane Fusion by Paramyxoviruses, covers the use of a novel peptide sequence of the soluble F glycoprotein, to block fusion of the virus with the host cell. This peptide can be used as a prophylactic, and/or to treat infections, and antibodies developed using this peptide can be utilized in diagnostic assays.

A third patent application, Soluble forms of Hendra and Nipah Virus F glycoprotein covers the production and use of a new recombinant soluble F protein. The remaining patent application, Human Monoclonal Antibodies Against Hendra and Nipah, filed in conjunction with the National Institutes of Health, covers the production and use of monoclonal antibodies which could be used as a therapeutic for people already infected with the disease.

New HIV browser gives researchers access to valuable data from vaccine trials

Thu, 29 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) SANTA CRUZ, CA--A new HIV data browser developed by the University of California, Santa Cruz, and the nonprofit organization Global Solutions for Infectious Diseases (GSID) will give researchers access to a wealth of data collected during clinical trials of an AIDS vaccine. Although the vaccine did not succeed in preventing infections, the clinical trial generated a huge amount of valuable data for researchers studying how the virus evolves and causes new infections.

Modeled on the UCSC Genome Browser, the GSID HIV Data Browser is the brainchild of Phillip Berman, professor and chair of biomolecular engineering in UCSC's Baskin School of Engineering. Berman helped oversee the clinical trials, which ended in 2003, when he was senior vice president for research and development at VaxGen, the company that developed the vaccine and conducted Phase III clinical trials in North America, Europe, and Thailand.

After the trials concluded, I spent a couple of years trying to think what was the most important thing I could do for HIV research, Berman said. I concluded it was using new technology to preserve the data from these clinical trials and present it in a form useful to the scientific community.

In 2004, Berman cofounded GSID, based in South San Francisco and dedicated to combining knowledge and expertise from the biotechnology industry and the public health sector to address infectious disease problems in the developing world. He joined the UCSC faculty in 2006.

Despite the fact that the vaccine trial didn't work, a huge amount of useful information was obtained, Berman said. The North American trial included about 60 different clinical sites in North America and one site in the Netherlands. Of particular value to researchers are the genetic sequences of the viruses that infected participants during the trial.

The trial represented the only up-to-date broad survey of virus sequences from new infections that had ever been carried out, Berman said. Every time there was a new infection in the vaccine or placebo group, the virus was sequenced. The sequence information provides the best picture we have about what the immune system sees when there is a new infection.

This is important, Berman said, because other major repositories of HIV sequence data are not annotated for the time after infection, the clinical status of the patient, or the histories of the specimens sequenced. That limits their usefulness for studying such a rapidly evolving virus.

HIV is highly mutable and evolves in response to attacks by the immune system. As a result, HIV isolated from a patient years after the initial infection is genetically different from the virus that caused the infection in the first place. A vaccine should target the most infectious form of the virus, Berman said. Yet all the vaccines tested so far have been based on viruses isolated from patients with longstanding infections.

A current hypothesis in HIV vaccine research is that the antigenic structures of HIV viruses that mediate new infections differ from those recovered from people long after infection, Berman explained. The specimens in this set represent the largest group from new infections that has ever been collected.

Besides viral genome-sequence data, the database links to a repository of preserved specimens (blood samples and cells) that researchers can access from GSID and the National Insitutes of Health (NIH) for further study.

This is the first time that an HIV sequence database has been linked to a specimen repository and a database of clinical information, Berman said. These clinical specimens are longitudinal, collected from the same person during a two-year follow-up period. This will allow investigators to study the evolution of the virus and the evolution of the immune response and clinical outcomes.

At UCSC, Berman teamed up with the Genome Browser group to develop a browser for the sensitive clinical data collected during the vaccine trial. Jim Kent, associate research scientist for the UCSC Genome Browser and principal investigator on the project, said it was the first time his group had worked with data from participants in a clinical trial.

This data must be handled differently and great care taken with confidentiality, Kent said. We learned from this project how to build the infrastructure to cope with that. This will be useful for other medical projects, such as cancer genomics, in the future.

Fan Hsu, director of proteomics for the UCSC Genome Browser, said the emphasis on security was very different from past projects. Before, everything we have worked on is totally open, totally public. With the GSID project, only authorized users can access the data, so we needed to set up special controls, Hsu said.

How to display the very large number of HIV sequences on the browser was another challenge. Our original genome browser has only one reference genome. For this HIV database, we have about 350 infected people and more than 1,000 sequences, he said.

Hsu and software developer Galt Barber adapted the genome browser software to accommodate the large number of HIV sequences and the data security along with interactive selection criteria for viewing the data. As the project evolved, Hsu also coordinated the transfer of the software to GSID. The UCSC team, which also included Erich Weiler, Robert Kuhn, and Ann Zweig, worked nights and weekends to bring the new browser online.

The resulting GSID HIV Data Browser is a customized version of the UCSC Genome Browser. It provides researchers with searchable demographic and clinical data from volunteers who became HIV infected during the VaxGen clinical trial. The browser allows users to align viral sequences with one another and with reference or consensus sequences.

This is something where the university can make a difference, because the private sector is not so interested in vaccines; they're not so profitable, Kent said. There is very little economic incentive to develop an AIDS vaccine, but there is a tremendous humanitarian incentive.

Kent hopes that just as the UCSC Genome Browser has continued to build the collaborative nature of the genomics research community, this HIV data browser will help motivate the AIDS research community to work together and pool their data.

Vaccine development efforts have been repeatedly frustrated. An HIV vaccine candidate developed by the pharmaceutical company Merck recently failed in clinical trials cosponsored by NIH. The recent failure of the Merck HIV vaccine has thrown the field into turmoil, Berman said. All the best ideas for an HIV vaccine in the past 20 years have failed. The information in this database is now more critical than anyone could have imagined. It tells us what's being transmitted.

The next phase of the HIV browser project involves releasing the sequence data from infected participants in the Phase III clinical trial that VaxGen conducted in Thailand.

In the future, the database will be expanded to allow associations between virus sequences, clinical data, immune response data, and host genetics, Berman said. We hope to eventually include data from other HIV vaccine trials sponsored by the NIH, private companies, and other HIV vaccine research organizations.

Method for fast human antibodies against flu could find broad use

Wed, 30 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists have developed a new, faster way to create human monoclonal antibodies against infectious disease by tapping the immune system at the peak of its powers.

Researchers from Emory University School of Medicine and Oklahoma Medical Research Foundation report that they can generate high-affinity monoclonal antibodies against influenza virus a month after vaccinating human volunteers.

Their results are described in an advance online publication in the journal Nature.

This method could find broad application towards almost any infectious disease, says Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

As a first example, doctors could quickly generate human antibodies against a pandemic flu strain as a stop-gap therapy or to protect people from infection. In this study, the antibodies were not tested on influenza virus strains with pandemic potential, such as the H5N1 strain although such studies are underway.

Ahmed and postdoctoral fellow Jens Wrammert, PhD, from the Emory Vaccine Center and Emory University School of Medicine, collaborated with Don Capra, PhD, and Patrick Wilson, PhD, immunology researchers at the Oklahoma Medical Research Foundation.

With just a few tablespoons of blood, we can now rapidly generate human antibodies that can be used for immunization, diagnosis and treatment of newly emerging strains of influenza, Wilson says. In the face of a disease outbreak, the ability to quickly produce infection-fighting human monoclonal antibodies would be invaluable.

With a detailed look at the antibodies stimulated by booster vaccination, the scientists also were able to address an issue that confounds health authorities trying to predict which viral strains will prevail in the upcoming flu season.

Doctors have worried about a phenomenon called original antigenic sin, where immunizing someone against a certain strain can handicap them in responding to a related strain.

We found that these early B cell responses are able to focus on the new virus, even though the immune system has seen related viruses before, says Wrammert, who is the paper's first author. B cells are the white blood cells that make antibodies.

The authors conclude that original antigenic sin is uncommon for healthy adults receiving influenza vaccination.

The methods previously used to make human monoclonal antibodies can be relatively laborious, Ahmed says. They involve sifting through human B cells and looking for those that make the right antibodies, or vaccinating mice and humanizing the mouse antibody genes by altering them so that they resemble human antibodies.

To make human antibodies against influenza, the Emory and University of Oklahoma researchers isolated antibody-secreting cells (plasma cells) from volunteers' blood a week after vaccination and cloned the antibody genes from these antibody-secreting cells.

A simplified method of giving rabies vaccine

Tue, 22 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A simplified economical method of giving rabies vaccine is just as effective as the expensive standard vaccine regimen at stimulating anti-rabies antibodies.

A clinical trial in healthy volunteers has found that a simpler and cheaper way of using rabies vaccines proved to be just as effective as the current most widely used method at stimulating antibodies against rabies. The trial is published in this week's PLoS Neglected Tropical Diseases.

Dr Mary Warrell (Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, United Kingdom) and colleagues, who conducted the trial with a vaccine in routine use, say that the simplified method has the advantages of requiring fewer clinic visits, being more practicable, and acceptable, and having a wider margin of safety, especially in inexperienced hands. It would therefore, they say, be suitable for use anywhere in the world where there are financial constraints, and especially where two or more patients are likely to be treated on the same day.

All human deaths from rabies result from failure to give adequate prophylaxis. After a rabid animal bite, immediate wound cleaning, rabies vaccine and injections of anti-rabies antibody (immunoglobulin) effectively prevent fatal infection. But anti-rabies immunoglobulin is very rarely available in developing countries, and so prevention relies on giving people bitten by rabid animals effective vaccine treatment.

The vaccines that are currently approved by the World Health Organization, which are usually injected into the muscle, are prohibitively expensive, and so are unaffordable in developing countries. In Africa, for example, the average cost of an intramuscular course of vaccine is $US 39.6, equivalent to 50 days' wages.

Two economical regimens, involving injecting small amounts of vaccine into the skin (intradermally) at 2 or 8 sites on the first day of the course, with subsequent booster doses are available in a few places. With the 8-site method, a large dose of vaccine is given on the first day only, whereas with the 2-site method the same dose is divided between the first and third days, entailing an extra visit to the clinic. However, practical or perceived difficulties have restricted widespread uptake of these economical methods. Dr Warrell and colleagues therefore set out to test a new, similar simplified regimen, involving injections at 4 sites on the first day.

They vaccinated healthy volunteers to compare the antibody levels induced by the 4-site intradermal regimen with those induced by the current 2-site and 8-site intradermal regimens and the gold standard intramuscular regimen favored internationally. All of the economical intradermal regimens worked just as well as the intramuscular method at stimulating anti-rabies antibodies.

The authors conclude that the results provide sufficient evidence that the simplified 4-site regimen now meets all the criteria necessary for its recommendation for use wherever the cost of vaccine is prohibitive.

New vaccine may give long-term defense against deadly bird flu and its variant forms

Thu, 17 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) WEST LAFAYETTE, Ind. - A new vaccine under development may provide protection against highly pathogenic bird flu and its evolving forms, according to researchers at Purdue University and the Centers for Disease Control and Prevention who discovered the new preventative drug and have tested it in mice.

Unlike traditional influenza vaccines, the new vaccine could be produced quickly and stored for long periods in preparation for a pandemic of dangerous disease-causing avian influenza - H5N1 - and its variants, said Suresh Mittal, a Purdue virologist. In an earlier study with mice, he and his colleagues found that the vaccine protected against H5N1 for a year or longer. Because the studies have only been done in mice, it's not yet known whether the same results will be obtained in humans.

We want to have a vaccine that can be stored in advance and have the potential to provide protection for a period of time until we can change the vaccine to match the latest form of avian influenza, Mittal said. The combination of flu genes that we've used to produce the vaccine, I think, will provide that capability.

The importance of having a long-lasting, broadly protective vaccine is that it would give some cross-protection against new viruses with pandemic potential caused by mutations in currently circulating H5N1 viruses. This would give scientists time to develop a better vaccine that would match the latest form of the bird flu.

Mittal and his colleagues, including Suryaprakash Sambhara, the CDC principal investigator on the project, report their findings on the vaccine in the April 15 issue of The Journal of Infectious Diseases. In the December issue of Clinical Pharmacology and Therapeutics, Mittal, Sambhara and their collaborators published their findings of the long-lasting capabilities of the vaccine.

In humans we want a vaccine to be fully effective for at least a year, said Mittal, a professor of comparative pathobiology. How long it will last in humans, we don't know yet.

To produce the new vaccine, the scientists used a mutated common cold virus, known as an adenovirus, as a delivery system for important genes from two types of the H5N1 avian influenza. The adenovirus is incapable of multiplying and so cannot cause illness to people. By using the adenovirus vector technology, a couple of problems with existing vaccines used to fight annual flu outbreaks are solved.

Problems with current influenza vaccines include that they are made from eggs, a process that can take as long as six months. The vaccine Mittal and his research team has developed isn't grown in eggs, making vaccine production much faster.

Additionally it would be difficult under normal conditions to produce the hundreds of millions of doses needed to protect everyone at risk for highly pathogenic forms of bird flu. With the beginning of a pandemic, since H5N1 decimates poultry populations, the egg supply needed to produce vaccines would be drastically cut.

The new vaccine uses an adjuvant, molecules added to the vaccine that stimulate the body's immune system, so that lower doses of the vaccine can be used. The adjuvant also allows the vaccine to be stockpiled so more people can be vaccinated, and it helps the vaccine protect against variant forms of the H5N1. The only FDA-approved H5N1 vaccine protects against only that specific strain of flu and only works in about 60 percent of those immunized with a high dose.

Adenoviral vector-based pandemic vaccines are an attractive option for developing countries where egg-independent cell-based vaccine technologies for other vaccines already are available, Sambhara said. Since this process is already in place, our vaccine could be produced locally at an affordable price.

Since H5N1 has been known, it has changed so that there are now two main subgroups, called clades. Within one of the clades, five subclades have emerged. This has complicated the task of developing a perfect match vaccine for the highly pathogenic bird flu. Other avian influenza viruses exist, but they have not proved to be as lethal to humans or other animals as has H5N1.

Influenza viruses are classified according to the combination of two types of proteins found on the virus cell surface. Different combinations of the 16 types of hemagglutinin (H) protein and nine types of neuraminidase (N) protein form a large number of influenza viruses for which birds are the natural hosts.

New, often more dangerous flu strains develop when the H and N combinations change and combine with other genes from circulating influenza viruses. When the genes of a human or swine influenza mix with an avian variety, a highly pathogenic human flu likely will result, Mittal said.

The first bird-to-human H5N1 case was recorded in 1997 in Hong Kong. The deadly virus has been documented in more than 60 countries, according to the World Health Organization (WHO). Though it mainly has struck wild birds and poultry, there have been more than 300 human cases in 14 countries in the past decade with a 60 percent fatality rate. Most of the human cases have occurred in people who live and work closely with their poultry, but a few cases have been documented of the disease spreading from person to person.

In a typical case, WHO this week reported the most recent fatality - the death of a 30-year-old Egyptian woman who became ill on April 2 after handling sick birds. She did not respond to the antiviral treatment Tamiflu, which can be given after contact with a flu carrier.

The next step in the bird flu vaccine project will be to test the vaccine on new viruses that are appearing, Mittal said.

The scientific team's vaccine work is being developed by PaxVax Inc., which has licensed the technology. Mittal is a scientific adviser for the company but has no financial stake in the commercial development of the vaccine, nor do his colleagues.

Vaccine/antibody therapy effective, milder side effects in melanoma and ovarian cancer

Mon, 18 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) BOSTON--One of the shortcomings of a therapy that uses millions of identical antibodies to boost the immune system's attack on cancer cells is that many patients whose tumors recede in response to the treatment also experience serious inflammatory problems, such as severe diarrhea and rashes. In a new study, a team led by Dana-Farber Cancer Institute researchers shows that giving periodic infusions of such monoclonal antibodies to patients who have received a widely used cancer vaccine unleashes a strong immune response to tumors, with less-harsh side effects.

The study, to be published online by the Proceedings of the National Academy of Sciences on the week of Feb. 18, reflects efforts to untangle the benefits of monoclonal antibody therapy from its drawbacks, which result from a too-aggressive immune system assault on normal, healthy tissue. Besides demonstrating the potential usefulness of a vaccine-and-antibody approach, the new study suggests a way of refining treatment strategies even further, based on the biological events that antibody treatment sets in motion.

We now have a better understanding of how the treatment works -- by increasing the ratio of tumor-killing to immune system-suppressing cells, says the study's lead author, Stephen Hodi, MD, of Dana-Farber. This suggests techniques for further focusing the immune system to attack the cancer with less 'fallout' for normal tissue.

The study focused on a molecular socket, or receptor, on the surface of the immune system's CD4+ T cells, which guide an attack on infected or cancerous cells. The receptor, known as CTLA-4 (for cytotoxic T lymphocyte-associated antigen), functions as a kind of shut-off valve for CD4+ T cells: When the receptor is stimulated, it causes the T cells to become inactive, quieting the immune response. Blocking CTLA-4 with a monoclonal antibody -- a protein uniquely fit for the job -- offers a way to keep the immune response at full force.

Studies and clinical experience have shown that CTLA-4-targeting monoclonal antibodies do increase the immune system's tumor-destroying activities in some patients. But many of these patients also develop serious inflammatory conditions, raising the possibility that the therapeutic and harmful effects of the treatment are linked.

The current study involved a cancer vaccine made from patients' own tumor cells. The vaccine is created by removing tumor cells from the body, irradiating them so they stop growing, and inserting a gene that causes them to produce a protein called GVAX. When the cells are then re-infused into patients, GVAX acts like a siren to the immune system, prompting a more energetic attack on cancer cells throughout the body.

Unfortunately, these results are rarely lasting. Most patients treated with the vaccine eventually die as their disease resumes its progress.

For that reason, researchers have begun studying whether combining GVAX vaccines with monoclonal antibody therapy could lengthen remissions, since blocking CTLA-4 could bolster the immune response spurred by the vaccine. And there was reason to think the combination could tamp down the inflammatory problems associated with antibody therapy alone.

Using a vaccine to provoke a stronger immune response to cancer may enable us to use lower levels of CTLA-4 blockers, which could reduce the severity of their side effects, Hodi explains.

In an earlier study, he and his colleagues demonstrated that a single infusion of anti-CTLA-4 antibodies caused extensive tumor destruction in all five metastatic melanoma and ovarian cancer patients who had previously been immunized with a GVAX vaccine.

The new study, a joint effort of Dana-Farber's melanoma program and Cancer Vaccine Center, tested the combination in a larger number of participants. Eleven melanoma patients were infused with a CTLA-4-blocking antibody (Ipilumimab (R)) one to four months after receiving GVAX, and every two to three months thereafter, as needed.

In contrast to previous, more intensive antibody doses, none of the patients had severe side effects, although they all developed mild, low-level inflammatory conditions (usually a rash that went away in a few days). Moreover, in eight of the participants, tumors throughout the body either receded or became stable. The three other patients experienced less dramatic improvements that became apparent after several months of therapy.

Similarly encouraging results were obtained in nine patients with advanced ovarian cancer, although two of them did develop severe inflammatory problems. Although large die-offs of tumor tissue were less common than in the melanoma group, some of the ovarian cancer patients did experience such results.

To understand what was happening at a basic cellular level, researchers studied tumor samples from six patients following antibody treatment. They found that tumor death was greatest in samples with high ratios of CD8+ T cells -- the foot soldiers of immune system attack -- to FoxP3+ regulatory T cells, which can reduce the immune response.

Our results suggest that combination therapies of GVAX vaccine and CTLA-4-blocking antibodies could be enhanced by agents that target regulatory T cells such as FoxP3+, remarks Hodi, who is also an assistant professor of medicine at Harvard Medical School. Future work will focus in that direction.

T cell immunity enhanced by timing of interleukin-7 therapy

Tue, 05 Feb 2008 08:24:37 PST

( from http://www.rxpgnews.com ) MADISON -- That the cell nurturing growth factor interleukin-7 can help ramp up the ability of the immune system to remember the pathogenic villains it encounters is well known.

But precisely how this natural protein works its magic on the cells of the immune system is not well understood. Now, however, in research that may have implications for developing vaccines against HIV and cancer, a team of scientists from the University of Wisconsin-Madison has found that the timing of interleuin-7 therapy is critical for increasing the number of killer cells that zero in on and destroy virus-infected cells.

Writing in the current online issue (Feb. 1, 2008) of the Journal of Clinical Investigation, a team led by UW-Madison School of Veterinary Medicine Professor of pathobiological sciences Marulasiddappa Suresh reports that therapeutic administration of interleukin-7 can be linked to a stage of early infection to effectively increase the number of a type of killer cell that recognizes and selectively assassinates virus-infected cells.

These cells need to get interleukin-7 for their survival, explains Suresh, of the killer immune cell known as CD8 T cells, a type of white blood cell that attacks virus-infected cells, foreign cells and cancer cells. Interleukin-7 is produced in very small amounts in bone marrow, spleen, and the thymus, but scientists have been able to isolate and synthesize the agent, which is now in pre-clinical testing for a variety of conditions.

This is one of the most exciting cytokines in pre-clinical human trials, says Suresh. The idea is that it might be used as an immune restorative agent. It is absolutely essential for normal development and functioning of the immune system.

Effectively stimulating the immune system -- the complex of organs and cells that defends the body against infection and disease -- is a grail of biomedical science in the fight against infectious diseases.

Suresh explains that upon infection, the body unleashes an army of T cells to fight infected or rogue cells. But when the body perceives an infection may be contained, the number of T cells it deploys is dramatically reduced. However, a certain number of T cells, known as memory cells and that are capable of recognizing a recently vanquished foe, remain. Stimulating memory T and B cells is the basis of vaccination, but vaccines often do not induce a sufficient number of memory CD8 T cells.

Despite the promise of interleukin-7 as a means to bolster immunity, an optimal treatment regimen has yet to be determined.

In studies in mice, Suresh and his colleagues found that T cell memory is best enhanced when interleukin-7 is administered during a phase of infection when the number of T cells is ramping down.

In the new Wisconsin study, Suresh's group gave interleukin-7 to mice during different stages of a viral infection. They found that by administering interleukin-7 when the number of T cells is in decline, it is possible to increase the number of memory CD8 T cells that remain to stand guard and protect against re-infection.

"The purpose of the immune response is to expand these cells," says Suresh, explaining that T cells act like serial killers, snuffing one infected cell after another until the viral infection is controlled.

During the expansion phase of infection, when the body is generating the most T cells, administration of interleukin-7 seems to have no effect, according to Suresh. But during the contraction phase, memory is increased.

"We tried this in a DNA vaccine and it works," says Suresh. "Even with the weakest vaccine, we could increase the memory cells and improve protection against infection. What this shows is that the number of memory cells are not predetermined. You can increase them and interleukin-7 drives their proliferation."

Drug aimed at 2 bioterror agents blocks live viral infection, Weill Cornell team reports

Wed, 19 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 19, 2007) -- Two deadly and highly infectious viruses -- both potential bioterror threats -- may have met their match in a new drug developed by scientists at Weill Cornell Medical College in New York City.

Hendra and Nipah viruses are related, newly recognized zoonotic viruses that can spread from their natural reservoir in fruit bats to larger animals -- including pigs, horses and humans.

The mode of transmission isn't clear, but is thought to be relatively easy -- either by close contact with an infected host or by breathing in the microscopic pathogens. Infection often leads to a fatal encephalitis, and there is currently no effective treatment against these illnesses.

However, in breakthrough research conducted last year, researchers at Weill Cornell manipulated a peptide (protein) related to a third pathogen, parainfluenza virus, that appeared to block pseudo Hendra and Nipah viruses from entering and infecting human cells.

Now, this entry inhibitor approach has proven effective in blocking the infection of live virus in animal cells, pointing the way to a drug that could be stockpiled to help stop an outbreak in humans.

Those findings appeared recently in the Journal of Virology.

We have now tested the peptide-based entry inhibitor in monkey cells to show that it does effectively block infection with both live Hendra and Nipah, explains study senior researcher Dr. Anne Moscona, a professor of pediatrics and of microbiology and immunology at Weill Cornell Medical College, and an attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Public health officials have sounded alarm bells ever since Nipah virus first emerged in pigs and then humans living in Southeast Asia. More recently, cases of Hendra virus began to show up in horses and their human handlers in Australia.

Experts who drew up the U.S. National Institute of Allergy and Infectious Diseases' Biodefense Research Agenda have included both viruses as potential bioterror agents.

Theoretically, it's possible to go out into the field and collect Hendra virus from bats, for example, Dr. Moscona says. We've been urgently working on this because right now there's absolutely nothing that can be done to stop this fatal, transmissible illness.

Luckily, prior research at Weill Cornell had laid out some important groundwork. The study's lead author, Dr. Matteo Porotto, has worked for years studying these types of microorganisms, using the parainfluenza virus as his model.

We were able to develop the strategy that we describe in this paper because our work on parainfluenza had already helped us understand how these viruses fuse with host cells, says Dr. Porotto, assistant professor of microbiology in the Department of Pediatrics at Weill Cornell Medical College.

Based on that work, Drs. Porotto and Moscona knew that when the receptor-binding molecule on the virus -- simply called G -- binds to the surface of the cell, it activates a special fusion protein. This fusion molecule has to then undergo some shape changes to turn itself into a six-helix bundle. Once that's done, it helps the virus fuse with, and enter, the cell, Dr. Porotto explains.

However, the Weill Cornell team discovered that a peptide specific to the parainfluenza virus fusion protein (F) can inhibit this shape-changing step -- stopping fusion cold.

Surprisingly, this parainfluenza F-peptide turned out to be even more effective at inhibiting Hendra virus fusion than peptides derived from the Hendra virus itself, Dr. Moscona says. It also appears to do much the same thing with the Nipah virus, inhibiting fusion there, too.

The team discovered just why the F peptide works so well in a collaboration with Dr. Min Lu, associate professor of biochemistry at Weill Cornell. These peptides act like door jambs -- their particular shapes prevent 'doors' in the viral 'fusion protein' from closing as they should. The parainfluenza peptide's shape simply makes it a better door jamb, Dr. Porotto said.

Much of this research is modeled on insights gained from two decades of investigation into another lethal virus, HIV. In fact, T-20, or Fuzeon -- one of the earliest effective HIV-suppressing drugs -- acts on a similar principle to block that virus' entry into cells.

The next step, according to the researchers, is to use what they've learned to design even more effective peptides that should work even better.

However, one issue with peptides is that you have to be concerned about how long they are going to last in the bloodstream, Dr. Moscona says. So, we are also developing methods of sustained-release -- for example, encasing the peptide in a polymer pellet that would be injected under the skin. The pellet would then release the drug slowly over the course of a week. That could form a viable method suitable for stockpiling, she says.

Poxvirus ability to hide from the immune system may aid vaccine design

Thu, 15 Nov 2007 04:59:37 PST

( from http://www.rxpgnews.com ) The cowpox virus, a much milder cousin of the deadly smallpox virus, can keep infected host cells from warning the immune system that they have been compromised, researchers at Washington University School of Medicine in St. Louis have found. The scientists also showed that more virulent poxviruses, such as the strains of monkeypox prevalent in Central Africa, likely have the same ability.

The study's authors say the finding will help efforts to design new vaccines for use against cowpox, monkeypox and, if it ever became a concern again, smallpox. Researchers working on the next generation of poxvirus vaccines are hoping to minimize the risk of vaccination and to make the vaccines protective against a broader range of viruses.

Poxvirus vaccines are cross-protective, meaning that immunization from one poxvirus appears to confer protection from other poxviruses, but there are significant risks associated with adult administration of the current vaccine, says senior author Wayne Yokoyama, M.D., professor of pathology and immunology and of medicine and a Howard Hughes Medical Institute investigator. There are also efforts underway to see if recombinant poxvirus vaccines can convey protection against a broader range of viruses, including HIV and cytomegalovirus.

In addition, the finding is likely to help scientists understand why one strain of poxvirus is more dangerous than another. The results appear Nov. 15 in Cell Host and Microbe.

Three decades ago, doctors eliminated the deadliest poxvirus, smallpox, using another poxvirus, vaccinia, as a vaccine. But a few smallpox samples remain in government facilities in the United States and Russia, and those samples have led to concern that terrorists might try to obtain smallpox and use it in a bioterror attack.

Additionally, other species of poxvirus continue to be sources of human disease and, occasionally, deaths. Outbreaks of cowpox, which Edward Jenner used to demonstrate the concept of vaccination in the late 1700s, still occur. In addition, multiple outbreaks of the monkeypox virus, which can cause smallpox-like disease in humans, have occurred in Africa and the United States in the past decade.

To help clinicians better prepare for the possibility of a new natural poxvirus outbreak or a bioterror attack using a poxvirus, Minji Byun, a graduate student in Yokoyama's laboratory, led a laboratory study of interactions between the cowpox virus and the immune systems of mice. Byun collaborated with Xiaoli Wang, M.D., Ph.D., instructor in the laboratory of Ted Hansen, Ph.D., professor in the Department of Pathology and Immunology. The research was supported in part by the Midwest Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Research (MRCE), a multi-institutional research center anchored at Washington University School of Medicine.

Normally the immune system in mice and humans can learn of a viral invasion through a group of molecules known as the major histocompatibility complex (MHC) class I. Because these molecules sit on the surfaces of cells and display samples of proteins from inside the cells, they act as identification badges, in effect telling immune system sentinels, here's what I'm made of. When immune T cells see virus-derived protein fragments in a cell's MHC class I display, they assume it's been infected and initiate an immune system attack.

But Byun and her colleagues found that cowpox was preventing MHC class I from ever getting to the surface of infected cells. They linked the suppression to a cowpox virus protein, CPXV203, showing that it binds to MHC class I. This binding yanks MHC class I off course by targeting it to the cellular recycling machinery. Once in the recycling loop, MHC class I cannot escape to the cell surface.

Other viruses have similar strategies for immune system evasion, but this is the first study showing that the poxviruses that are most closely related to smallpox virus can use this approach, says Byun.

A search of the genomes of monkeypox virus revealed a similar protein in the more virulent family of virus strains found in Central Africa. But the less virulent strains active in Western Africa tend to have truncated versions of the proteins similar to CPXV203, leaving them unable to act on MHC class I.

When researchers eliminated the CPXV203 gene and infected mouse cells with the modified cowpox virus, they found it still was able to suppress the appearance of MHC class I on infected cell surfaces, but not as thoroughly.

There's likely another viral mechanism that produces the same result, Byun speculates. But it has to be acting on MHC class I in a different way because a search through the cowpox genome failed to reveal any other viral proteins with the same key module as CPXV203.

Pharmaceutically blocking CPXV203 and other similar immune evasion proteins may be tough, according to Yokoyama, because that would disrupt an important natural protein recycling process, potentially causing significant side effects. He believes the finding is more likely to be useful to vaccine scientists. Many vaccines are composed of weakened forms of the microbes they protect against, and the modified cowpox lacking CPXV203 is likely less virulent.

Yokoyama plans additional studies of poxvirus-immune system interaction in live mice.

Mice help researchers understand chlamydia

Mon, 29 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Genetically engineered mice may hold the key to helping scientists from Queensland University of Technology and Harvard hasten the development of a vaccine to protect adolescent girls against the most common sexually transmitted disease, Chlamydia.

Dr Michael Starnbach from Harvard Medical School is in Australia to work with QUT on a joint research project using a mouse model to study how the immune system responds to infections such as Chlamydia.

Ultimately the idea is to understand enough about how Chlamydia interacts with cells and how the immune system responds to those infected cells, to be able to understand which components of the immune system need to be stimulated to fight the Chlamydia infection, Dr Starnbach said.

At Harvard we have been working on the basic biology of how the immune fighter cells known as T-cells respond to infection.

When a person is infected with Chlamydia, the organism enters into the outermost cells of the genital tract and stays there and replicates within those cells.

Once they're hidden within the cells, only the T-cells can recognise that the cells are infected.

T-cells are able to recognise cells that are infected and destroy those cells, ultimately eliminating the organism from the body.

Dr Starnbach said the mouse model being developed by QUT and Harvard would see mice genetically engineered with T-cells that were specifically directed to protect against the mouse strain of Chlamydia.

In doing this we will be able to learn things about what is involved in protecting mice against Chlamydia infection and then mimic those responses with vaccines, he said.

Professor Peter Timms along with Professor Ken Beagley, from QUT's Institute of Health and Biomedical Innovation, are heading a QUT research team working with Dr Starnbach.

QUT has already identified certain proteins that may be able to be incorporated into vaccines to protect against Chlamydia infection, Professor Timms said.

We've been testing these proteins and, by working with Harvard, we hope to build on this research.

Professor Timms said, with rates of Chlamydia infection in some Australian communities as high as 12 per cent of the female population, there was a real need to develop a vaccine.

Chlamydia is the most common sexually transmitted disease in the world and results in infertility in women and long-term chronic pelvic pain, he said.

There are antibiotics to treat Chlamydia, but there's no vaccine to prevent it. In many cases women don't know they are infected because there are not really any physical signs or symptoms, so by and large they don't get treatment.

XDR TB in South Africa traced to lack of drug susceptibility testing

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) In South Africa, the 2001 implementation of the World Health Organization�s anti-tuberculosis program may have inadvertently helped to create a new strain of extensively drug-resistant tuberculosis (XDR TB). In a new study published in the December 1 issue of Clinical Infectious Diseases, currently available online, researchers tracked the developing drug resistance of one particular strain of Mycobacterium tuberculosis over 12 years. They found that at the time of the 2001 adoption of the DOT+ strategy for multi-drug resistant strains, the strain was already resistant to one or more of the drugs mandated by that strategy, thus allowing the strain to survive and develop resistance to additional drugs.

�The spread of a highly transmissible strain of drug-resistant tuberculosis has been facilitated by applying standard treatment regimens for susceptible and multi-drug resistant tuberculosis in the absence of drug resistance surveillance,� said one of the authors, A. Willem Sturm, MD, of the University of KwaZulu-Natal�s Nelson R. Mandela School of Medicine in South Africa. �Public health programs for the treatment and control of infectious diseases need to be supported by drug resistance surveillance programs.�

Like all bacteria, M. tuberculosis can evolve and develop resistance to the drugs that have historically killed them. The strategy that has been used to limit the development of drug-resistant TB is to treat the patient with multiple drugs so that if one drug is ineffective, then the others will ensure the elimination of the bacteria.

Drug-resistant M. tuberculosis develops when tuberculosis patients cannot or do not comply with the medication regimen. A second line of drugs has been used to treat those infected with drug-resistant TB. This second-line medication regimen was adopted in South Africa in 2001 to treat drug-resistant TB.

Unfortunately, at least one strain of M. tuberculosis in South Africa had already developed resistance to one or more of these second-line drugs by the time they were introduced. Drug susceptibility tests would have warned doctors that the standard second-line regimen was unlikely to help the patient but was likely to lead to additional drug-resistance, but these tests were not performed or were not available. Indeed, the reduced efficacy of the regimen allowed the strain to survive and, over time, develop resistances to other drugs.

The authors recorded the development of resistance to seven drugs in just over a decade in one strain of M. tuberculosis. There are very few treatment options for patients infected with XDR TB. For the most part, patients are given drugs that had been used to treat tuberculosis but which were abandoned when today�s first-line drugs became available. The older drugs were abandoned because they were less effective or more toxic.

The authors call for an increased use of drug resistance surveillance programs to help forestall the development of drug-resistance in M. tuberculosis.

Influenza: Insights into cell specificity of human vs. avian viruses

Tue, 09 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Rotterdam, The Netherlands � Researchers have identified which sites and cell types within the respiratory tract are targeted by human versus avian influenza viruses, providing valuable insights into the pathogenesis of these divergent diseases. The report by van Riel et al, �Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals,� appears in the October issue of The American Journal of Pathology and is accompanied by a commentary and highlighted on the cover.

Differences in cellular expression of target molecules correspond to host specificity of influenza viruses. They also define which organs or tissues are infected within the host. For example, highly pathogenic H5N1 avian influenza virus targets cells deep within the lower respiratory tract whereas human influenza virus is thought to target cells of the upper respiratory tract, including the trachea.

To better elucidate the differences between low and highly pathogenic avian influenza virus versus human influenza virus, researchers led by Dr. Thijs Kuiken of Erasmus MC, Rotterdam, The Netherlands, used a technique called virus histochemistry. This method examines the attachment pattern of influenza virus to isolated respiratory tissues, thus identifying the cells targeted by the virus.

When human viruses were tested, both attached strongly to the trachea and bronchi, but virus binding to the bronchioles and alveoli (deeper within the lung) was less abundant in comparison. In contrast, viral attachment of avian viruses was rare in the trachea but more abundant in the bronchioles and alveoli. Further, the cellular targets in the alveoli also differed: human virus preferred type I pneumocytes whereas avian virus bound type II pneumocytes and alveolar macrophages. Interestingly, low and highly pathogenic avian influenza viruses attached to the same cell types, demonstrating that factors other than binding ability must contribute to the pathogenicity.

These data are consistent with the differences in human disease presentation, with human influenza causing tracheobronchitis and highly pathogenic avian influenza causing severe pneumonia. But which animal models are the best for studying the disease in humans To answer this question, the authors next assessed the pattern of virus attachment in animal models used for influenza studies. Of several mammals tested, ferrets, cats, and pigs most closely resembled the human patterns of virus attachment for avian influenza viruses, thus demonstrating their usefulness as models of infection and disease.

These studies �improve our understanding of the pathogenesis of human respiratory tract disease from both human and avian influenza A virus infection,� state the authors. Combined with the results obtained with different animal models, they may lead to a better understanding of the factors that are critical for virus binding and infection, enabling the future development and testing of feasible control strategies.

Patients with pneumonia who received pneumococcal vaccine have lower rate of death, ICU admission

Mon, 08 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Among patients hospitalized with community-acquired pneumonia, those who had previously received the pneumococcal vaccine had a lower risk of death and admission to the intensive care unit than patients who were not vaccinated, according to a report in the Oct. 8 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Community-acquired pneumonia is a common condition resulting in considerable illness and death, according to background information in the article. A vaccine against Streptococcus pneumoniae, one of the causes of pneumonia�23-valent polysaccharide pneumococcal vaccine (PPV)�has been available since 1983. Most guidelines recommend PPV for those at high risk of developing pneumonia, including older adults and nursing home residents. However, some doubts have been raised about the effectiveness of PPV, and vaccination rates remain below the target 80 percent to 90 percent in these populations.

Jennie Johnstone, M.D., and colleagues at the University of Alberta, Edmonton, Canada, collected data on 3,415 patients with community-acquired pneumonia admitted to six hospitals between 2000 and 2002. The patients� vaccination status was determined through interviews, medical record reviews, contact with primary care physicians and records from the regional office of community health.

Of the patients, 22 percent had been vaccinated with PPV, and 624 died or were admitted to the intensive care unit (ICU). Those who had been vaccinated with PPV were less likely to die or be admitted to the ICU than those who had not been vaccinated (10 percent vs. 21 percent). This finding was mostly a result of lower ICU admissions�less than 1 percent of those vaccinated were admitted to the ICU, compared with 13 percent of those who were not vaccinated. Results were similar when the researchers looked only at patients older than 65 or those living in nursing homes�groups for whom universal PPV vaccination is recommended.

�In addition to improved clinical outcomes, our results suggest that there may also be an associated reduction in costs associated with pneumococcal vaccination, a health economic benefit that has not been captured in previous cost-effectiveness analyses of this vaccine,� the authors write. �Specifically, much of the benefit in our study was in terms of reduction in the need for costly ICU admissions; previous cost analyses have been restricted to examining the benefits of preventing pneumococcal disease but may have not adequately captured the possibility of attenuating the severity or mitigating the cost of disease in those for whom pneumonia is not prevented.�

Although 2,416 of the patients were eligible for vaccination upon being discharged from the hospital, only 215 (9 percent) received PPV at this time. �We believe that our results further the emphasize the importance of adopting current adult pneumococcal vaccination guidelines, particularly since only 22 percent of our population were vaccinated before their hospitalization and less than 10 percent of eligible patients were vaccinated before hospital discharge,� the authors conclude.

NIH grant supports UCSF research exploring early HIV infection

Mon, 08 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A team led by researchers at the UCSF Positive Health Program has been named to receive $15 million over five years to expand understanding of the complex interactions between HIV and the immune systems of newly infected patients following HIV transmission.

The grant is being awarded by the National Institute of Allergy and Infectious Diseases, an arm of the National Institutes of Health.

�The program will provide an important platform for innovative research into HIV transmission and early infection in patients and aims to provide new clues for developing a vaccine and improving therapeutic outcomes,� said the grant�s primary investigator, Frederick Hecht, MD, professor of medicine at the UCSF Positive Health Program at San Francisco General Hospital Medical Center.

The research will be based on two clinical cohorts of recently infected patients: the

�The inclusion of the Brazil cohort allows us to look at two HIV subtypes simultaneously. Subtype C predominates in Sub-Saharan Africa and subtype B predominates in North America, though both are common in Southern Brazil. This provides us with a natural research study for understanding competing HIV subtypes,� said Hecht.

The overall grant aims to understand the viral and host factors that favor or block HIV transmission on a biological level and the factors that favor good control of early HIV infection by newly infected patients. The program is composed of four projects.

One project, led by Hecht, will focus on the transmission and persistence of two types of HIV resistance mutations. Some are caused by infection with HIV variants that have resistance mutations caused by exposure to antiretrovirals. Understanding how easily these mutations occur and how long they persist is important for long-term forecasting of the effectiveness of antiretroviral regimens in populations.

The other types of resistance mutations are those that allow the virus to escape an infected patient�s specific T-cell immune responses. HIV mutates constantly, thereby escaping attack from the body�s targeted T-cell defenses that are meant to kill the virus, and eventually eludes effective control in most individuals. Understanding this process could assist in vaccine development.

A second project, led by Steven Deeks, MD, of the Positive Health Program, examines properties of the outside of the HIV virus�the envelope�and how they influence HIV transmission and evolve in a newly infected individual after transmission. These envelope properties determine which cells most easily will succumb to infection with the virus. In addition, the envelope properties of HIV may affect the virus�s capacity to damage the immune system and determine how readily it is transmitted.

A third project, led by the UCSF-affiliated Gladstone Institute of Virology and Immunology�s Robert Grant, MD, MPH, is focused on superinfection, which is infection with a second HIV virus on top of a preexisting infection. The project will study how readily this occurs in early HIV infection�which appears to be the most vulnerable period for superinfection�and what factors may prevent it.

The fourth project, led by Douglas Nixon, MD, PhD, of the UCSF Division of Experimental Medicine, tests whether new immune responses, following HIV transmission to a newly infected patient, help to reverse some of the mutations that allowed the virus to escape immune responses in the HIV-individual who transmitted the virus.

Scripps research scientists develop innovative dual action anthrax vaccine-antitoxin combination

Thu, 04 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The immune response generated in rats by the new agent protects against lethal toxin exposure after only one injection, and is faster and stronger than any currently available vaccine.

The new study, led by Scripps Research scientists Anette Schneemann and Marianne Manchester, and Salk Institute Professor John A.T. Young, was published in the October 5 issue of the journal PLoS Pathogens (Volume 3, Issue 10).

�The new anti-anthrax agent that we developed is an important and potentially critical development for anyone who works with the bacterium or those who might be exposed to it in a bioterrorism attack,� Schneemann said. �While other strategies are being pursued to develop improved anthrax vaccines, none of these offer the distinct advantage of combining the function of a vaccine with a potent antitoxin.�

Concerns about anthrax-a potentially fatal disease caused by the spore-forming, gram-positive bacterium Bacillus anthracis-as a weapon of bioterrorism has prompted increased efforts to develop better antitoxins and vaccines. The current vaccine, which was developed in the 1950s, is safe and effective, but requires multiple injections followed by annual boosters. Current anthrax treatment involves antibiotics such as ciprofloxacin and doxycycline that attack the bacteria but provide no protection against the dangerous toxins secreted by the bacteria.

The new study introduces a highly effective dual-action compound that leapfrogs current efforts to develop a second-generation anthrax vaccine. In the research, the scientists created a �multivalent display,� with several sites of attachment for recombinant protective antigen protein (PA), the primary component of the current anthrax vaccine, rather than only one. Virus-like particles coated with PA were found to produce a potent toxin-neutralizing antibody response that protected rats from the lethal anthrax toxin after only a single immunization.

The antitoxin strategy arose from the discovery of the anthrax toxin receptor, ANTXR2, in the Young lab. �The new anti-anthrax agent is based on a multivalent display of ANTXR2 on the surface of an insect virus,� explains Schneemann. �Our approach was based on the assumption that a multivalent display of recombinant protective antigen protein would induce a far more potent immune response. That turned out to be correct.�

Specifically, the new vaccine-antitoxin combination is based on the multivalent display (180 copies) of the PA-binding von Willebrand A (VWA) domain of the ANTXR2 cellular receptor on the Flock House virus. The chimeric virus-like particle platform, which produces protective immunity and has been shown to be safe, inhibited lethal toxin action in in vitro and in vivo models of anthrax infection.

In fact, rats survived exposure to the toxin four weeks after a single injection of the new double-acting agent. This result suggests an extremely rapid production of neutralizing antibodies without the use of an adjuvant, a secondary agent that helps stimulate the immune system and is often used to increase the vaccine response-key goals for the development of third-generation anthrax vaccines.

In addition to its use against anthrax, Schneemann notes that creating a multivalent platform may also have the potential to work against other infectious agents.

�One important reason for the success of this project is that it arose from the multidisciplinary and highly collaborative efforts of our team of microbiologists, structural biologists, and immunologists,� said Manchester, who headed a National Institutes of Health (NIH)-funded program project grant that supported the work.

Flu vaccine in painless skin patches under development at Emory, Georgia Tech with NIH grants

Wed, 03 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Flu vaccine delivered through painless microneedles in patches applied to the skin could soon be an alternative to delivery through hypodermic needles, according to researchers at Emory University and the Georgia Institute of Technology. Using new grants from the National Institutes of Health (NIH) totaling approximately $11.5 million over five years, researchers from the two institutions plan to develop a new vaccine product using the microscopic needles.

A vaccine administered through a skin patch would have a number of advantages, including less discomfort to the recipients, lower cost and reduced production time, says Richard Compans, PhD, professor of microbiology and immunology in the Emory School of Medicine. Potentially, individuals could administer the vaccine to themselves, perhaps after receiving it in the mail.

The Georgia Tech and Emory team plans to develop and assess the effectiveness of transdermal patches that include arrays of microscopic needles containing or coated with vaccine. They hope to design patches that could be stored for long periods of time at room temperature and that will increase the breadth and duration of immunity to influenza � perhaps with smaller amounts of vaccine.

We expect that this research will lead to a better way of delivering the flu vaccine, which will allow more people who need it to receive the immunization in a convenient and effective way, says Mark Prausnitz, PhD, a professor in the Georgia Tech School of Chemical and Biomolecular Engineering. Beyond that, the possibility of replacing a hypodermic needle with a microneedle patch should significantly impact the way that other vaccines are delivered.

The project team has extensive experience in microneedle development, influenza vaccines, vaccine delivery systems, product development and interdisciplinary collaboration. Beyond influenza, the research could have implications for immunization programs in developing countries, where eliminating the use of hypodermic needles could make vaccines more widely available and address the problem of disease transmission caused by the re-use of conventional hypodermic needles.

In April the NIH awarded a $32.8 million, seven-year contract to Emory, along with the University of Georgia, to establish the Emory/UGA Influenza Pathogenesis and Immunology Research Center, for which Dr. Compans is principal investigator. The center is working to improve the effectiveness of flu vaccines through a number of different projects studying how influenza viruses attack their hosts, how they are transmitted, and what new immune targets might be identified for antiviral medicines.

Dr. Prausnitz and his colleagues have been working since the mid 1990s to develop microneedle technology for painless drug and vaccine delivery through the skin. Much smaller than conventional hypodermic needles, the microneedles in the arrays are made of titanium, stainless steel or various polymers--including some that could dissolve into the skin, carrying vaccine with them. The Georgia Tech team has also developed manufacturing processes for microneedle patches and tested the ability of the needles to deliver proteins, vaccines, nanoparticles, and small and large molecules through the skin.

We expect microneedles to be less painful than conventional hypodermic needles because they are too small to significantly stimulate nerve endings, says Dr. Prausnitz. The NIH grants will allow us to move forward with perfecting the manufacturing process, refining the techniques for optimally inserting the microneedles into the skin and ensuring that vaccine delivered this way produces the necessary immune response.�

Second pathway behind HIV-associated immune system dysfunction identified

Sun, 30 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH) may have discovered a second molecular �switch� responsible for turning off the immune system�s response against HIV. Last year members of the same team identified a molecule called PD-1 that suppresses the activity of HIV-specific CD8 T cells that should destroy virus-infected cells. Now the researchers describe how a regulatory protein called CTLA-4 inhibits the action of HIV-specific CD4 T cells that control the overall response against the virus. The report will appear in the journal Nature Immunology and is receiving early online release.

�We�ve shown that a known regulator of the immune system, CTLA-4, is present in elevated levels on the virus-specific CD4 cells that should be managing the body�s response against HIV, says Daniel Kaufmann, MD, of PARC and the MGH Infectious Disease Unit, a co-first author of the paper. �We also found that CTLA-4 expression rises as HIV infection progresses and that the molecule switches off CD4 cell function in a way that appears to be reversible.�

Expression of the CTLA-4 protein is known to be elevated on activated T cells, those that have encountered a pathogen and are multiplying rapidly to mount an immune response. Studies in cancer patients have shown that the molecule serves to dampen the immune response, and some preliminary investigations in animals and humans have suggested a potential role in HIV infection. The current study was designed to examine how CTLA-4 may be involved in the dysfunction of HIV-specific T cells that leads to the immune-system breakdown of AIDS.

The researchers first found that CTLA-4 was overexpressed on the HIV-specific CD4 T cells of infected individuals who had not yet received antiviral treatment. Levels were highest in those with symptoms of acute infection and second highest in chronically infected participants. CTLA-4 expression was lowest among a group of participants whose immune systems were naturally able to suppress HIV replication without antiviral medications � �elite controllers� in whom viral levels are too low to be detected.

Elevated CTLA-4 expression also correlated with signs of disease progression � increased viral load and reduced overall CD4 count. While antiviral treatment caused viral loads to drop significantly after treatment began, it resulted in only modest and slow drops in CTLA-4 expression. In vitro tests of the effects of blocking the CTLA-4 molecule improved the function of HIV-specific CD4 cells. Comparing the effects of blocking CTLA-4 with those of blocking PD-1 or both molecules produced functional improvements that varied considerably between participants, signifying a complex relationship between the pathways controlled by the two molecules.

�Both of these pathways contribute to dysfunction of HIV-specific T cells and both may be considered targets for therapeutic intervention. But since their mechanisms are so complicated, further study is needed before clinical trials can be planned,� says Kaufmann, an instructor in Medicine at Harvard Medical School (HMS).

�Understanding why the immune system fails to control HIV is essential for development of vaccines and new therapies� said Bruce Walker, MD, director of PARC-MGH and senior author of the study. �These studies suggest that the immune system is turning itself off prematurely in HIV-infected persons, and the big challenge now is to figure out if we can turn it back on, getting it to do what it is supposed to do, without causing collateral damage in the process.� Walker is a professor of Medicine at HMS and a Howard Hughes Medical Institute (HHMI) investigator.

Chronic infection persists by targeting stromal cell network in lymphoid organs

Tue, 18 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One of the biggest challenges to treating infectious diseases and developing preventive vaccines is the ability of many chronic infections to suppress the immune T-cell response over time. An Emory-led team of scientists has discovered one important way in which chronic viral infections are able to evade the immune response. The research is reported this week online in the Proceedings of the National Academy of Sciences.

Using a mouse model, the scientists found that a chronic strain of lymphocytic choriomeningitis virus (LCMV) targeted a type of stromal cells in the lymphoid organs called fibroblastic reticular cells (FRC). In contrast, an acute strain of the virus had little effect on the FRC cells. FRC provide a three-dimensional framework used by immune cells to travel and interact with other immune cells within the lymphoid organs (spleen and lymph nodes). These FRC are important for the initiation of immune responses to infections. The researchers found that widespread infection of the FRC caused a disruption of the function of these important stromal cells.

Last year a group of Emory scientists led by Rafi Ahmed, PhD, and graduate student Daniel Barber and their colleagues discovered in mice another way in which the immune reaction to chronic infections is blocked -- a pathway called PD-1 that blocked the response to the chronic strain of LCMV.

The current research was conducted by Scott N. Mueller, PhD, a postdoctoral fellow in the laboratory of Dr. Ahmed, a Georgia Research Alliance Eminent Scholar and director of the Emory Vaccine Center. The team also included scientists from the Emory Transplant Center and Emory School of Medicine, the University of California, San Francisco (UCSF), the University of California, Los Angeles (UCLA), Harvard Medical School and the Dana-Farber Cancer Institute.

The research team discovered that infection of FRC may involve the previously discovered PD-1 pathway. The major ligand (binding molecule) for PD-1, PD-L1, is upregulated on FRC after infection. The PD-1 pathway may inhibit interactions between CD8+ T cells and FRC, preventing destruction of the FRC architecture in the spleen. This may help the virus to remain in infected FRC and contribute to long-term viral persistence.

This research helps explain how the T-cell response can be suppressed in chronic viral infections, says Dr. Mueller. As we learn more about the intricate mechanisms involved we will be able to develop better treatments, and potentially preventive vaccines, for chronic infections such as those caused by HIV and hepatitis C viruses.

New nanoparticle vaccine is more effective but less expensive

Sun, 16 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Good news for public health: Bioengineering researchers from the EPFL in Lausanne, Switzerland, have developed and patented a nanoparticle that can deliver vaccines more effectively, with fewer side effects, and at a fraction of the cost of current vaccine technologies.

Described in an article appearing online September 16 in the journal Nature Biotechnology, the vaccine delivery platform is a deceptively simple combination of nanotechnology and chemistry that represents a huge advantage over current vaccine methods. This technology may make it possible to vaccinate against diseases like hepatitis and malaria with a single injection. And at an estimated cost of only a dollar a dose, this technology represents a real breakthrough for vaccine efforts in the developing world.

A vaccination is an injection of a non-virulent form of a pathogen or molecule from a pathogen (known as an antigen), to which the immune system responds, destroying and then developing a �memory� for the pathogen. Later, when a virulent form of the pathogen comes along, this memory kicks in and the intruder is quickly eradicated. Most vaccines protect against viruses or bacteria, but vaccine techniques are also being explored as a way to kill cancer cells.

Thanks to recent advances, an immune response can be triggered with just a single protein from a virus or bacterium. Recent research has also shown that the best way to get sustained immunity is to deliver an antigen directly to specialized immune cells known as dendritic cells (DCs).

This technique is not yet used clinically because there are two difficulties to overcome in targeting the DCs: first, there are not very many of these cells in the skin or muscle, where injections are usually made, so obtaining an adequate immune response with a single injection is difficult; and second, activating the DCs requires co-delivering a �danger signal� of some sort, otherwise the immune system will just ignore it. Current approaches mimic bacterial molecules already known to the immune system, but this can cause side effects or even be toxic.

EPFL professors Jeff Hubbell and Melody Swartz and PhD student Sai Reddy have engineered nanoparticles that completely overcome these limitations. At a mere 25 nanometers, these particles are so tiny that once injected, they flow through the skin�s extracellular matrix, making a beeline to the lymph nodes. Within minutes, they�ve reached a concentration of DCs thousands of times greater than in the skin. The immune response can then be extremely strong and effective.

In addition, the EPFL team has also engineered a special chemical coating for the nanoparticles that mimics the surface chemistry of a bacterial cell wall. The DCs don�t recognize this as a specific invader, but do know that it�s something foreign, and so a low-level, generic immune reaction known as �complement� is triggered. This results in a particularly potent immune response without the risk of unpleasant or toxic side effects.

�People have been exploring nanoparticles for a while,� says Hubbell. �Our ideas -- to activate complement as a danger signal, and to exploit the slow interstitial flow towards the lymph nodes � are completely new. But it meant that our particles had to be much smaller than anything currently being developed. No other labs have managed to engineer so many levels of functionality into nanoparticles that are smaller than biologically occurring particles,� he adds. �The beauty of it is that once we have developed the recipe, any lab can make them.�

Cost and logistics are important factors, especially for use in developing countries. Unlike other nanoparticle vaccine technologies that degrade in water and thus require expensive drying and handling procedures, the EPFL team�s nanoparticles won�t degrade until they are in the body. They are in liquid form and don�t require refrigeration, so preparation and handling costs are reduced, and they are easy to transport.

The group is collaborating with the Swiss Tropical Institute in Basel to determine the strength and duration of the immune response in the context of a nanoparticle malaria vaccine. Toxicity studies are also in the works. Swartz says that the team is also planning to use this technique to target cancer cells.

�If, as we hope, this vaccine technique can confer sustained immunity with a single injection for around a dollar a dose, without toxic side effects, it could have a real impact on public health, in the developing world as well as right here at home,� says Swartz. �More study is required to achieve these goals,� she adds, �but we have every reason to believe this technique could be in use within five years.�

Novel HIV vaccine created at The Wistar Institute funded for clinical development

Fri, 31 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (PHILADELPHIA) � A promising new HIV vaccine created at The Wistar Institute has received funding for clinical development aimed at moving the vaccine into human clinical trials as soon as possible.

With $13.3 million in funding over five years, the planned trials will be conducted under the auspices of the Integrated Preclinical/Clinical AIDS Vaccine Development Program of the National Institute of Allergy and Infectious Diseases. The Wistar Institute scientists will collaborate with researchers at Emory University, the University of Pennsylvania, Harvard School of Public Health, MRC/UVRI Uganda Research Unit, and the National Institute for Communicable Diseases in South Africa. The start date for the project is September 1.

�We believe our vaccine, which is built on a novel chimpanzee virus backbone, has unique immunological advantages over other HIV vaccines currently in testing,� says Hildegund C.J. Ertl, M.D., professor and Immunology Program leader at The Wistar Institute. Ertl, principal investigator for the newly funded project, is also director of the Wistar Institute Vaccine Center. �In preclinical studies, the vaccine induced a vigorous immune response in monkeys, and we are hopeful it will do the same in humans.�

Many vaccines currently in development are based on modified human adenoviruses, known as vectors, that incorporate genetic elements from target pathogens to stimulate a protective immune response to those pathogens. These vaccines can work well, but there is an unaddressed problem with this approach, which is that many people receiving the vaccines will have pre-existing immunity to the human viruses upon which they are based, largely negating their effectiveness. About 45 percent of adults in the United States, for example, have pre-existing immunity to a strain of human adenovirus being used as an HIV vaccine vector in current clinical trials.

To circumvent this potential difficulty, the Wistar-led team has developed a series of vaccine vectors based on chimpanzee adenovirus strains, which possess the immunological strengths of human adenoviruses without their drawbacks. The Wistar vaccine will undergo early stage clinical testing for safety and then for its ability to induce an immune response. In the latter trial, the vaccine will be given as a four-part series of inoculations.

Another important aspect of the new HIV vaccine is that it seeks to stimulate a cellular immune response to HIV rather than an antibody response. The cellular immune response corresponds to the T-cell arm of the immune system, while the antibody response corresponds with the B-cell arm of the immune system.

�Based what we know about HIV and the immune system�s response to the virus, it may not be possible to create a vaccine that generates antibodies able to neutralize HIV,� says Ertl. �For this reason, we and others are now focusing our attention on developing a vaccine that stimulates the production of anti-HIV CD8+ T cells, which have been shown to reduce viral load, although they do not prevent infection. Our vaccine has induced unprecedented levels of activated CD8+ T cells in experimental animals, and we are eager to see if it can perform as well in humans.�

Binghamton University researchers investigate evolving malaria resistance

Thu, 30 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Funded by a $1.5 million grant from the National Institutes of Health, scientists at Binghamton University, State University of New York, hope to understand how the malaria parasite Plasmodium falciparum evolved resistance to the once-effective medication chloroquine.

�Malaria is responsible for 1-3 million deaths a year, most of whom are children under 5 in sub-Saharan Africa,� said J. Koji Lum, associate professor of anthropology and biological sciences, principal investigator for the grant. �This is equivalent to the death toll from the attacks of 9/11 every eight to 24 hours.�

Lum and Ralph Garruto, professor of biomedical anthropology and a co-investigator on the grant, together have about 11,000 archived human blood samples from malarious regions of the Pacific collected from the 1950s to the present. The samples will be analyzed and researchers will document the accumulation of genetic changes that resulted in chloroquine�s treatment failure in the Pacific.

Malaria is relatively easy to eliminate in places that have a good health-care infrastructure. In the developing world, particularly in the tropics, the disease is treated primarily through chemotherapy, Lum said.

The problem is that parasites develop resistance to the drugs over time. This study will help scientists understand how malaria parasites evolved resistance to chloroquine. They also hope to learn lessons that may be relevant to current treatments and their interactions with the disease. Ultimately, a better understanding of past episodes of drug resistance evolution will help doctors get the maximum possible impact from newer drugs.

Other studies have had to rely on theoretical modeling of resistant parasites to infer how they evolved. Lum and Garruto expect to be able to directly observe the accumulation of the nine mutations in the transporter gene that confer resistance to chloroquine. They�ll study parasites collected during the past 50 years and stored in the freezers of the NIH-BU Biomedical Anthropology archive.

�This funding will allow us to do a little bit of time traveling,� Lum said.

Lum considers malaria the most important infectious disease in human history. It continues to exact a devastating toll, in part because the resulting loss of education, work and young lives creates a cycle that makes it nearly impossible for nations to rise from poverty.

To eliminate malaria, countries must treat their entire populations, even asymptomatic adults. But there�s rarely enough money and medicine for developing nations to do that, Lum explained. Doctors focus their energies on the young, people who are clearly ill. Adults who have developed some level of immunity to malaria end up as reservoirs for parasites, continuing to spread the illness without ever feeling sick.

IAVI, CDC and USMHRP release new data redefining laboratory reference ranges in Africa

Tue, 21 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (SEATTLE, August 21, 2007) Leading researchers from the International AIDS Vaccine Initiative (IAVI), the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Military HIV Research Program (USMHRP) presented final results today from a collection of independent studies reexamining the medical criteria for including African volunteers in AIDS vaccine trials. The findings, presented at the AIDS Vaccine 2007 Conference in Seattle, suggest that many healthy Southern and East Africans have, in the past, been excluded from participating in trials based on laboratory reference ranges that were developed for Western populations and may not be appropriate locally. Implementation of the results of the studies should improve participation of African volunteers in clinical trials for new drugs and vaccines against emerging infectious diseases currently ravaging Africa, including AIDS, TB and malaria, and enable clinicians to better monitor and define adverse events in trials.

In the first reference range studies conducted on such a large scale, researchers from the involved organizations examined the blood tests of approximately 5,500 clinically healthy HIV-negative volunteers across a dozen clinical sites in four African countries. For some markers, the studies revealed differences between the norms usually found in healthy Africans and the reference values developed for populations in North America and Europe.

These studies are important for a range of research on neglected diseases, from HIV vaccines to malaria and TB drug therapy, said Anatoli Kamali, an epidemiologist with the Medical Research Council/Uganda Virus Research Institute and the Protocol Chair of the IAVI-sponsored study. For the first time, African volunteers seeking to participate in trials will now be evaluated according to blood reference ranges that accurately reflect their populations. Furthermore, we will now be able to interpret laboratory abnormalities detected during vaccine or drug clinical trials more accurately in Africa.

We are excited about these findings. Localized reference parameters could significantly help us to improve recruitment for clinical trials in less-industrialized nations, as well as better evaluate the health of our volunteers throughout the course of these studies, said Mark de Souza, Director, International Laboratory Program, USMHRP. In one of its trials in Uganda, the USMHRP screened out 58% of potential participants because of lab abnormalities using Western ranges. In a second trial, the screen-out rate decreased to 23% using a norm localized for the trial site. In addition, says de Souza, With local ranges, we can better detect reactions to candidates, enlist a more typical cohort in the trial and thus test it on the most representative group of volunteers, possibly significantly accelerating the search for HIV vaccines for those countries hardest hit by the epidemic.

As part of their two-year study, IAVI and its partners examined blood chemistry and hematology parameters, as well as evaluated kidney and liver functions and the immunological health of thousands of volunteers. Individuals with clinical symptoms or abnormal physical exams and anyone infected with HIV, hepatitis B or C, or untreated syphilis were excluded from the study. These studies should be valuable to anyone designing trials of preventive medicines or vaccines for these parts of Africa, concluded Pat Fast, Executive Director of Medical Affairs, IAVI. Improving participation in AIDS vaccine trials among populations in desperate need of new AIDS technologies is the first step in ultimately reaching our goal of ending the AIDS crisis.

Currently, Africa remains the epicenter of the AIDS pandemic with 2.8 million new infections annually. In 2006 alone, almost two-thirds (63%) of all persons infected with HIV were living in sub-Saharan Africa. IAVI and partners, as well as CDC and the USMHRP, and other international organizations plan larger-scale trials of promising vaccine candidates over the coming years in the Eastern and Southern region of Africa and elsewhere.

Tumors use enzyme to recruit regulatory T-cells and suppress immune response

Thu, 16 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One way tumors fly under the radar of the immune system is by using IDO, an enzyme used by fetuses to help avoid rejection, to recruit powerful regulatory T cells that turn down the immune response, researchers say.

It was known tumors assemble a protective barrier of regulatory T cells, or Tregs, but how they are such able recruiters was an unknown, says Dr. David Munn, pediatric hematologist/oncologist at the Medical College of Georgia Cancer Center.

People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body, Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue.

Research published online Aug. 16 in The Journal of Clinical Investigation shows IDO, which seems to play a powerful role in tumor survival despite the relatively few number of cells in the tumors draining lymph nodes, directly activates existing Tregs which become strongly suppressive within a day. The number doesnt change a lot, but their activation state changes hugely, says Dr. Munn, corresponding author.

Studies in a tumor animal model show this rapid conversion occurs only in lymph nodes connected to tumors.

The findings further define a tumors survival strategy of first recruiting IDO, which helps recruit Tregs. Tregs then up-regulate the PD-L1/PD-L2 pathway, which has been shown to play an important role in the immune suppression caused by AIDS.

For the first time it creates a link between IDO, regulatory T cells and this novel pathway we dont know much about, says Dr. Munn. Interestingly its a link that appears to come full circle because, as researchers at the University of Perugia in Italy showed in 2003, in the test tube at least, Tregs also help recruit more IDO.

IDO appears to be a sort of linchpin; its a crossroads where a number of mechanisms, some of which are more powerful than IDO itself, come together, says Dr. Munn. Tregs, for example, are much more powerful than IDO. If you take a mouse and remove IDO, it compensates just fine. If you remove Tregs, the mouse dies. But if the tumor uses IDO to recruit and activate Tregs, that is a leverage point.

Therapies aimed at these new leverage points will be most effective when packaged with other emerging and existing treatments, he says.

The FDA has approved early clinical trials of the IDO inhibitor, 1MT, in coming months. A team, led by longtime collaborator Dr. Scott Antonia, hematologist/oncologist and co-leader of the Immunology Program at the H. Lee Moffitt Cancer Center and Research Institute, will begin phase 1 trials of 1MT in patients with lung and other tumors shortly. MCG is pursuing FDA approval to begin trials of the combination of 1MT and chemotherapy in breast cancer patients. Dr. Munn notes that while the IDO inhibitor seems to be a safe drug that doesnt cause autoimmune disorders in mice, it wont be used in patients with autoimmune disorders because it could worsen the disorders.

By combining IDO with chemotherapy, researchers hope to wipe the slate clean of the tumors manipulation of the immune response, says Dr. Munn. We have found that once the tumor gets a hold of the immune system, just giving an IDO inhibitor does not restore everything to normal. The tumor has too much influence on the immune system at that point.

Standard doses of chemotherapy reduce immune system function, creating a window where IDO likely can be more effective. That window may work for cancer vaccines too, which are still under study and getting mixed reviews. Recent reports indicate vaccines can actually increase the number of Tregs in mice with tumors, a problem when fighting cancer but a possible opportunity in which an IDO inhibitor might improve efficacy, Dr. Munn says. An antibody to the PD-L1/PD-L2 already under study in cancer may be another component of a total anti-tumor package.

We have data from a mouse model that while 1MT works modestly by itself, it works significantly better when combined with chemotherapy, says Dr. Munn. I think immunotherapy needs to learn from the finding with multi-agent chemotherapy, which is you need to orchestrate more than one approach. If you give one drug over and over again, the tumor invariably figures out a way to escape, so you always have to combine different strategies. Multiple approaches also reduce the chance of needing toxic levels of any of them.

Early clinical trials of the IDO inhibitor ideally will benefit patients for whom more standard therapies have failed and enable scientists to verify laboratory findings in people, Dr. Munn says. Scientists will carefully monitor Tregs to see if they show evidence of being activated by IDO now that they know what that looks like and de-activated by the IDO inhibitor. Theyll also have to see if Tregs circulating in the bloodstream are good indicators of whats happening or whether tumor biopsies will be needed.

IDO inhibitors potential against tumors as well persistent viruses such as HIV arose out of work MCG scientists, led by Dr. Munn and his long-time collaborator Dr. Andrew L. Mellor, director of the MCG Immunotherapy Center and Georgia Research Alliance Eminent Scholar in Immunogenetics. Their work published in Science in 1998 showed fetuses use IDO indoleamine 2,3-dioxygenase to locally disable a pregnant womans immune system and avoid rejection. They showed then that one way IDO suppresses the immune response is by degrading tryptophan, a natural amino acid important to T cells.

Later, they found that tumors and certain viruses such as HIV also appear to use IDO for protection from the immune response. However, the fact that IDO-expressing cells make up less than 1 percent of the cells in a tumor or its draining lymph node led MCG researchers to look for a population of powerful allies within the immune system that could explain the suppressive impact. Tregs seemed like a good choice. The 2003 paper by Italian scientists, followed by a 2006 paper that showed naïve T-cells exposed to IDO differentiated into Tregs, helped cement that some sort of relationship existed, prompting MCG researchers to further explore the relationship in a tumor animal model.

Its only been in the last year or two that people have begun to realize Tregs spend most of their time in a sort of resting state where they have the potential to be suppressive but are not at that moment, says Dr. Munn. That would make sense, because you dont want your immune system always shut off.

Anthrax vaccine produces immunity with nanoparticles, not needles

Wed, 15 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) ANN ARBOR, Mich. A vaccine against anthrax that is more effective and easier to administer than the present vaccine has proved highly effective in tests in mice and guinea pigs, report University of Michigan Medical School scientists in the August issue of Infection and Immunity.

The scientists were able to trigger a strong immune response by treating the inside of the animals noses with a nanoemulsion a suspension of water, soybean oil, alcohol and surfactant emulsified to create droplets of only 200 to 300 nanometers in size. It would take about 265 of the droplets lined up side by side to equal the width of a human hair.

The oil particles are small enough to ferry a key anthrax protein inside the nasal membranes, allowing immune-system cells to react to the protein and initiate a protective immune response. That primes the immune system to promptly fight off infection when it encounters the whole microbe.

Besides eliminating the need for needles, the nanoemulsion anthrax vaccine has another advantage, the researchers say: It is easy to store and use in places where refrigeration is not available.

An effective and easy-to-administer vaccine would be a valuable tool for health authorities dealing with any future attack in which a terrorist might spread anthrax microbes. The researchers say a nasal nanoemulsion-based anthrax vaccine, if it proves effective in humans, could be given easily to people even after they are exposed in an anthrax attack, along with antibiotics. With some diseases, vaccines given after exposure are used to boost the speed of the immune response.

Anthrax spores can remain in the environment or even in the lungs of exposed individuals for some time. Nasal vaccination could be given to build up immunity after anthrax exposure and improve the outcome of other treatments, says Anna Bielinska, Ph.D., the papers lead author and a scientist at the Michigan Nanotechnology Institute for Medicine and Biological Sciences at the U-M. She is also an assistant research professor in the Allergy Division of Internal Medicine at the U-M Medical School.

In the 2001 attack in which anthrax spores were mailed to members of Congress and reporters, some anthrax-exposed individuals were given antibiotics but not the existing anthrax vaccine, because it requires six injections over a period of six months and may cause adverse reactions.

In the new study, the U-M team combined the nanoemulsion and a recombinant protein of Bacillus anthracis to make the vaccine, which they gave first to mice in either one or two applications. They found the animals developed several types of effective immune response. The vaccine produced both systemic and cellular immunity, meaning that the body produces antibodies and primes specific cells throughout the body to fend off anthrax infection. The vaccine also induced immunity on the mucous membranes of the nose and lungs, where inhaled anthrax spores enter the body and start a process that can cause illness and death.

We saw protective immunity in the animals after only two administrations rather than six, says James R. Baker, Jr., M.D., director of the Michigan Nanotechnology Institute for Medicine and Biological Sciences and the senior author of the study. He is the Ruth Dow Doan Professor in the Department of Internal Medicine and chief of the Division of Allergy and Clinical Immunology in the U-M Medical School.

After administering the vaccine, the researchers challenged the immune systems of immunized guinea pigs with injections of 1,000 times the lethal dose of Bacillus anthracis spores. All the animals survived, whereas none of the control animals did.

When the researchers delivered large doses of Bacillus anthracis spores directly into the animals nasal tissue, they found that 40 percent to 70 percent of the immunized animals survived.

Because of the biosafety restrictions on the use of anthrax, these challenge experiments were done at the Batelle Memorial Institute and the University of Texas Medical Branch, which have labs federally approved for handling the pathogen.

The experiments so far have shown that the vaccine had no significant side effects and produced effective immunity for at least six months. The Michigan Nanotechnology Institute will seek funding to learn if the vaccine can produce immunity in primates as it does in rodents. Safety studies in humans are also in the early planning stage.

Scientists at the U-M earlier developed the nanoemulsion technique, which has been used to develop treatments for herpes and toenail fungus. The Michigan Nanotechnology Institute for Medicine and Biological Sciences was established at U-M in 2005 to develop and market medical and biological applications of nanotechnology. Patent applications for the nanoemulsion technology have been filed and exclusively licensed to NanoBio Corporation, an Ann Arbor, Mich.-based biotechnology company in which Baker has a financial interest.

HPV vaccine does not appear to be effective for treating pre-existing HPV infection

Tue, 14 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) For women with human papillomavirus (HPV) infection, use of the HPV-16/18 vaccine will not accelerate reduction of the virus and should not be used to treat the infection, according to a study in the August 15 issue of JAMA.

HPV vaccines were designed to prevent HPV infection and the development of cervical precancers and cancer. Some research has suggested that HPV vaccines could help clear the virus in women already infected, according to background information in the article.

Allan Hildesheim, Ph.D., of the National Cancer Institute, Bethesda, Md., and colleagues conducted a study to address the question of whether women positive for HPV DNA should be encouraged to receive HPV-16/18 vaccination to induce or accelerate clearance of their infections. The trial was conducted in two provinces of Costa Rica and included 2,189 women age 18 to 25 years who were positive for HPV DNA. Participants were randomly assigned to receive three doses of HPV-16/18 vaccine (n = 1,088) or a control hepatitis A vaccine (n = 1,101) over 6 months.

There was no evidence that HPV vaccination significantly altered rates of viral clearance. At the 6-month visit, rates of clearance were 33.4 percent vs. 31.6 percent for HPV-16/18 among participants who received the HPV vaccine and the control vaccine, respectively. At the 12-month visit, rates of clearance among participants in the HPV group and the control group, respectively, were 48.8 percent vs. 49.8 percent for HPV-16/18.

There was no evidence of vaccine effects with further analysis on selected study entry characteristics reflective of disease extent, including HPV-16/18 antibody results, cytologic results, and HPV viral load. Similarly, no evidence of vaccine effects was observed in analyses stratified by other study entry parameters thought to potentially influence clearance rates and efficacy of the vaccine, including time since sexual initiation, oral contraceptive use, cigarette smoking, and concomitant infection with Chlamydia trachomatis or Neisseria gonorrhoeae.

These findings have important clinical implications. For example, in countries where HPV DNA testing is incorporated in cervical cancer screening and prevention efforts, adult women who have abnormal Papanicolaou test results induced by HPV infection and/or who test positive for an oncogenic HPV type using the clinically available HC2 test might be interested in receiving the HPV vaccine to treat their existent infection, the authors write. our results demonstrate that in women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used for purposes of treating prevalent infections.(JAMA. 2007;298(7):743-753. Available pre-embargo to the media at

DNA vaccine against multiple sclerosis appears safe, potentially beneficial

Mon, 13 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A newly developed DNA vaccine appears safe and may produce beneficial changes in the brains and immune systems of individuals with multiple sclerosis, according to an article posted online today that will appear in the October 2007 print issue of Archives of Neurology, one of the JAMA/Archives journals.

In patients with multiple sclerosis (MS), the immune system attacks the myelin sheaths that protect nerve cells in the brain and spinal cord, according to background information in the article. The nerve cells axon, which transmits messages to other neurons, is eventually destroyed. The cause of MS is unknown, but evidence points to the involvement of immune cells and antibodies that recognize and attack specific substances in the myelin, such as myelin basic protein. Certain cytokines, small proteins produced by cells that trigger inflammation, also may play a role.

Amit Bar-Or, M.D., of the Montreal Neurological Institute and colleagues tested a DNA vaccine, BHT-3009, that encodes a full-length human myelin basic protein. Between 2004 and 2006, the researchers administered the vaccine to 30 patients with relapsing-remitting MS [characterized by symptomatic periods and periods of remission] or secondary progressive MS [when symptoms progressively worsen, but there still may be periods of remission]. After one, three, five and nine weeks, participants received intramuscular injections of placebo or BHT-3009 (in doses of .5 milligrams, 1.5 milligrams or 3 milligrams), with or without 80-milligram pills of atorvastatin calcium, a lipid-lowering drug previously shown to be effective in autoimmune conditions. After 13 weeks, participants who initially received placebo received four injections of BHT-3009.

Magnetic resonance imaging (MRI) and other safety evaluations were performed at the beginning of the study, and again after five, nine, 13, 26, 38 and 50 weeks. BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI and produced beneficial antigen-specific immune changes, the authors write. These changes included a reduction in the number of cytokine-producing CD4+ T cells (a type of white blood cell) specifically targeting myelin proteins. This reduction was found in the blood as well as in the cerebrospinal fluid of three patients who voluntarily underwent lumbar puncture after completing the course of BHT-3009. Atorvastatin did not appear to provide additional benefit.

There were no increases in clinical relapses, disability, drug-associated laboratory abnormalities, adverse events or the number and volume of contrast-enhancing [visible on MRI] lesions on brain MRI with BHT-3009 treatment compared with placebo, the authors write. In fact, there was a trend toward a decrease in the number and volume of contrast-enhancing lesions in the brain in patients treated with BHT-3009 compared with placebo.

Based on these results, a phase 2b triala randomized clinical trial in approximately 290 patientsof BHT-3009 is already under way. If successful in MS, antigen-specific DNA vaccines can be developed for prevention or treatment of related diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and myasthenia gravis, the authors conclude.

Study reveals gaps in vaccine financing for underinsured children

Tue, 07 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A national survey of state immunization program managers reveals gaps in coverage for the current vaccine financing system, suggesting that many underinsured children may not receive recommended vaccinations, such as for pneumonia and meningitis, according to a report in the August 8 issue of JAMA.

The number and cost of new vaccines routinely recommended for children and adolescents has increased considerably since 2003. New or expanded recommendations for meningococcal conjugate, tetanus-diphtheria-acellular pertussis (Tdap), hepatitis A, influenza, rotavirus, and human papillomavirus vaccines have led to a 7.5-fold increase in the cost to fully vaccinate a child in the public sector (from $155 in 1995 to $1,170 in 2007), the authors write.

Childhood vaccines in the U.S. are financed by a patchwork of public and private sources. Anecdotal reports from state policy makers and clinicians suggest that new gaps have arisen in financial coverage of vaccines for children who are underinsured (i.e., have private insurance that does not cover all recommended vaccines). In 2000, approximately 14 percent of children were underinsured for vaccines in the United States, requiring families to either pay out-of-pocket for the cost of vaccines not covered or forego receiving vaccines, according to background information in the article.

Grace M. Lee, M.D., M.P.H., of Harvard Medical School, Childrens Hospital Boston and Harvard Pilgrim Health Care, Boston, and colleagues examined the status of financing and distribution of new pediatric vaccines at the state level. For the 2-phase study, the researchers interviewed nine state immunization program managers and subsequently interviewed and surveyed 48 state immunization program managers from January to June 2006.

The researchers found that many states were not able to provide state-purchased vaccines for underinsured children in the private sector, public sector, or both. For example, for vaccines given in the private sector, 46 percent of states did not provide publicly purchased varicella (chickenpox) vaccine to underinsured children and 70 percent of states did not provide publicly purchased meningococcal conjugate vaccine to the underinsured. For vaccines given in the public sector, 17 percent of states were unable to provide publicly purchased pneumococcal conjugate vaccine to underinsured children and 40 percent were unable to provide publicly purchased meningococcal conjugate vaccine. This meant that underinsured children were not able to receive state-purchased vaccine in either the private or public sectors in these states. None of the vaccines we studied was covered for all underinsured children in the United States, the authors write.

Due to limited financing for new vaccines, 10 states changed their policies for provision of publicly purchased vaccines between 2004 and early 2006 to restrict access to selected new vaccines for underinsured children. The most commonly cited barriers to implementation in underinsured children were lack of sufficient federal and state funding to purchase vaccines.

Assuming 14 percent of children are underinsured in the United States, we estimate that 2.3 million children are unable to receive state-purchased meningococcal conjugate vaccine in the private sector, and 1.2 million children are unable to receive this vaccine even if they are referred to the public sector, they write. Current trends in health insurance products, including enrollment in high-deductible health plans that may or may not provide immunizations or other preventive benefits before a high deductible has been met, are likely to increase the magnitude of this gap and must be carefully monitored.

(JAMA. 2007;298(6):638-643. Available pre-embargo to the media at

Study suggests nonpharmaceutical interventions may be helpful in severe influenza outbreaks

Tue, 07 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) An analysis of non-pharmaceutical interventions used in the U.S. during the 1918-1919 influenza pandemic, such as closing schools and banning public gatherings, found an association between these interventions and reduced death rates, suggesting that non-pharmaceutical interventions may play a role in planning for future influenza pandemics, according to a study in the August 8 issue of JAMA.

The influenza pandemic of 1918-1919 is among the most deadly contagious events in human history, resulting in approximately 40 million deaths worldwide, including 550,000 in the United States, according to background information in the article. The historical record demonstrates that when faced with a devastating pandemic, many nations, communities, and individuals adopt what they perceive to be effective social distancing measures or nonpharmaceutical interventions including isolation of those who are ill, quarantine of those suspected of having contact with those who are ill, school and selected business closure, and public gathering cancellations. One compelling question emerges: can lessons from the 1918-1919 pandemic be applied to contemporary pandemic planning efforts to maximize public health benefit while minimizing the disruptive social consequences of the pandemic as well as those accompanying public health response measures the authors write.

Howard Markel, M.D., Ph.D., of the University of Michigan Medical School, Ann Arbor, and colleagues assessed the non-pharmaceutical interventions implemented in 43 cities in the continental United States from September 1918 through February 1919 to determine whether city-to-city variation in death rates were associated with the timing, duration, and combination of non-pharmaceutical interventions. The researchers conducted historical archival research and statistical and epidemiological analyses. Non-pharmaceutical interventions were grouped into three major categories: school closure; cancellation of public gatherings; and isolation and quarantine.

There were 115,340 excess pneumonia and influenza deaths (excess death rate [EDR], 500/100,000 population) in the 43 cities during the 24 weeks analyzed. Every city adopted at least one of the three major categories of non-pharmaceutical interventions. School closure and public gathering bans activated concurrently represented the most common combination implemented in 34 cities (79 percent); this combination had a median (midpoint) duration of four weeks (range, 1-10 weeks) and was significantly associated with reductions in weekly EDR. The cities that implemented non-pharmaceutical interventions earlier had greater delays in reaching peak rates of death, lower peak rates of death, and lower total number of deaths. There was a statistically significant association between increased duration of nonpharmaceutical interventions and a reduced total number of deaths.

These findings contrast with the conventional wisdom that the 1918 pandemic rapidly spread through each community killing everyone in its path. Although these urban communities had neither effective vaccines nor antivirals, cities that were able to organize and execute a suite of classic public health interventions before the pandemic swept fully through the city appeared to have an associated mitigated epidemic experience, the authors write.

Our study suggests that nonpharmaceutical interventions can play a critical role in mitigating the consequences of future severe influenza pandemics and should be considered for inclusion in contemporary planning efforts as companion measures to developing effective vaccines and medications for prophylaxis and treatment. The history of U.S. epidemics also cautions that the publics acceptance of these health measures is enhanced when guided by ethical and humane principles.

Immune mechanism could help explain transient immune suppression often seen in acute infections

Thu, 02 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists have discovered that at the same time the immune system is vigorously attacking invading viruses or bacteria, it is unexpectedly reducing its production of a particular type of factor that directs the movement of immune cells. The new finding, which could help explain the transient immune suppression often seen during acute infections, shows that the immune system is even more complex than previously believed.

Results of the research by Emory scientists, along with colleagues at the University of California, San Francisco, will be published in the Aug. 3, 2007 issue of the journal Science. The research was conducted by Scott N. Mueller, PhD, postdoctoral fellow in the laboratory of Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar. The team also included Emory microbiologist Bogumila Konieczny and collaborators at the University of California, San Francisco and Cytos Biotechnology in Switzerland.

The research team, in a mouse study, focused on homeostatic chemokines--one of two major categories of molecular traffic cops in the immune system that directs the movement of immune cells. Also called lymphoid chemokines, these chemokines are responsible for guiding immune cells to the lymph nodes and spleen in healthy individuals and directing the cells to respond to antigens from invading viruses or bacteria.

Until now, scientists have believed these lymphoid chemokines were expressed in a steady state throughout life and that only a second type of chemokineÑknown as inflammatory chemokines--were expressed at varying levels in response to the threat of an invading pathogen. Inflammatory chemokines direct immune cells to go to particular sites, such as lung or skin, and fight off attackers during an active infection. The scientists discovered, however, that lymphoid chemokines do not remain in a steady state after all, but are reduced during the time of an active immune response.

The findings could help scientists devise better dosing schedules for multi-dose vaccines and also could provide a better understanding of how the immune system responds to multiple infections. A likely result is a lowering of the body's ability to respond to a second infection.

If you have an acute viral infection, your immune system may be suppressed in its ability to respond to secondary infections during that brief period, Dr. Mueller says. If you have a nasty flu infection in the lung, for example, you are more susceptible to secondary bacterial infections, and this chemokine reduction could contribute to that.

The wonderful thing about immune cells is their ability to travel through the entire body, searching for pathogens and foreign antigens, said Dr. Mueller. There has been considerable research performed on both groups of chemokines and their role in the immune response and immune trafficking. We know how important the lymphoid chemokines are in controlling the way cells move in the body. Until now, however, we believed these were expressed at a steady level in the immune tissues in healthy individuals.

The discovery of this basic phenomenon--that these lymphoid chemokines are reduced during an immune response--was quite a shock to us. It illustrates another dramatic level of complexity in the immune system and demonstrates in greater detail how the traffic of immune cells is regulated.

Dr. Mueller believes the down-regulation of lymphoid chemokines, which occurs for a one- to two-week period during the height of an immune response, may be the body's way of shutting down the immune response and avoiding excessive and damaging inflammation. In addition, reducing these immune factor could be beneficial for the immune cells that are actively responding to a virus, he points out.

In a massive inflammatory response to infection, many immune cells divide into great numbers of cells, Dr. Mueller explains. Once the immune response is complete, 95 percent of those cells die and leave a smaller population of memory cells to circulate in the body and protect against subsequent infections by that same pathogen. Certain factors, or substrates, such as interleukins and cytokines, are important to nurture and keep these responding cells alive in the lymphoid tissues, but there is competition for the nurturing substrates between the cells that are actively responding to an infection and cells not responding. The down-regulation of lymphoid chemokines could be the body's way of keeping non-responding cells out of the competition, says Mueller.

Dr. Mueller also believes the discovery could have important implications for vaccine development, particularly those vaccines that require a prime/boost strategy, where giving a second dose too early, when chemokines are reduced, could make that dose less effective.

Phase II study of therapeutic vaccine shows efficacy in patients with metastatic colorectal cancer

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PHILADELPHIA A therapeutic cancer vaccine has shown effectiveness when given alongside chemotherapy to patients with metastatic colorectal cancer in a phase II trial, according to researchers at Oxford BioMedica (UK) Ltd. The study found that six of the 17 metastatic colorectal cancer patients in the study showed tumor shrinkage, classified as complete or partial responses following independent expert review.

The study, reported in the August 1 issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, was designed to demonstrate the safety and immunogenicity of the vaccine, called modified vaccinia Ankara-encoding 5T4 (TroVax®), when used alongside standard chemotherapy. The research was funded by Oxford BioMedica which is developing the vaccine in partnership with Sanofi-Aventis.

Unlike preventative vaccines, such as the human papillomavirus vaccine to prevent cervical cancer, TroVax is a therapeutic vaccine, designed to stimulate the immune systems of patients who already have cancer. The vaccine consists of an attenuated (non-disease causing) version of the vaccinia virus modified to deliver the gene for 5T4, a protein found in many tumors.

The idea is that the modified virus enters cells, produces the tumor protein and stimulates the immune system, said lead study author Richard Harrop, Ph.D., vice president of clinical immunology at Oxford BioMedica. To give a vaccine alongside chemotherapy might seem counterintuitive, since chemotherapy can weaken the immune system, but our study shows that TroVax could be complementary to standard chemotherapy, enhancing the immune response to tumors.

The target of this immuno-therapy approach is a tumor antigen called 5T4, a protein embedded within the membrane of cancer cells. The protein is rarely found in normal tissues, but is produced at high levels by a wide range of human cancers, including colorectal, renal, gastric and ovarian. The production of 5T4 has been associated with cancer metastasis and poor prognosis for patients.

Typically, the immune system doesnt pay attention to this molecule, so by producing 5T4 artificially in combination with the danger signals associated with a viral infection, we are demanding that the immune system take notice, Harrop said. TroVax causes cells at the

injection site to produce 5T4 in a way which agitates the immune system into producing antibodies and killer T cells. It is hoped that these two components of the immune system then migrate to tumors and kill them without harming any normal tissues.

In essence, its like turning up your stereo in the hopes that it will attract the police to your neighbors rowdy party, Harrop said.

Harrop and his colleagues administered the vaccine to 17 patients with metastatic colorectal cancer just before, during and after the patients were treated with the standard chemotherapy regimen FOLFOX which consists of the agents: 5-fluorouracil, folinic acid and oxaliplatin.

Through the course of the study, the researchers monitored the patients for an immune response to 5T4. Eleven of the 17 patients who received the complete course of vaccinations (six injections) mounted strong immune responses to the 5T4 tumor protein. Of these 11 patients, six exhibited significant shrinkage of their tumors and one patient no longer had any detectable tumors. Researchers noted no complications stemming from TroVax vaccination or any other evidence that would call into question the safety of the vaccine.

While the study was not designed to prove that patients survived longer than would normally be expected, the researchers noted that, on average, the overall median survival was 68 weeks in all 17 vaccinated patients and 118 weeks in the 11 patients who received all six vaccinations.

According to Harrop, the researchers are currently testing the vaccine in a phase III trial in renal cancer patients in the U.S. and Europe and Sanofi Aventis is planning a phase III study in colorectal cancer.

New target for HIV/AIDS drugs and vaccine discovered

Thu, 26 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers from Rome, Italy, describe a finding in the August 2007 print issue of The FASEB Journal that could lead to new drugs to fight the HIV/AIDS virus, as well as new vaccines to prevent infection. It has been known that HIV proteins disable the antibody-forming part of the immune system (the homeland defense or acquired immune system). In this report, researchers demonstrate for the first time how the HIV-1 Nef viral protein delivers a one-two punch to the bodys innate immune system (our early warning system composed of dendritic and natural killer cells). First, Nef hijacks dendritic cells (DCs) to upset the function of natural killer (NK) cells. Second, after blocking this first line of defense against the immune system, Nef uses DCs and NK cells to create a microenvironment that actually makes it easier for HIV/AIDS to replicate.

According to Maria Giovanna Quaranta of Instituto Superiore de Sanità and first author of the article, The findings described in this work may have several implications for AIDS treatment: the understanding of Nef function, mechanism of action, and cellular partners might aid the discovery of suitable drugs able to block the activity of this smart protein. Quaranta added, An exciting possibility is the design of a vaccine including a mutated Nef protein unable to assist the virus in the control of its host.

The research findings also raise another intriguing possibility: Nef proteins may be able to boost or suppress DC and NK cell activity. If so, it may prove to be a valuable new therapeutic approach for people with diseases and disorders that involve overactive or underactive immune responses. DCs and NK cells play critical roles in the bodys initial defense against infection. DCs are instrumental in identifying foreign invaders to the body and then orchestrating an immune response that ultimately removes them. NK cells are among the first cells summoned by DCs to help isolate and contain the infection until more potent reinforcements can be manufactured to eradicate the virus or bacteria. When DC cells can no longer adequately manage the immune response and when NK cells can no longer contain infections, the likelihood of survival without medical intervention is relatively low.

HIVs relatively rapid evolution has given it an ability to handle all our bodies can throw at it and more, said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. Now that we know how the viral protein disables the innate as well as the acquired arm of our immune system, we can begin to design decoy proteins or to devise new vaccines. Millions of lives depend on our finding a way to restore both aspects of our immune defense against HIV/AIDSthis study should go a long way toward that goal.

Measles vaccinations need to be repeated to protect HIV-infected children

Tue, 17 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) HIV-infected children may require repeat measles vaccination for protection, according to new research from the Johns Hopkins Bloomberg School of Public Health and other institutions. The researchers found that only half of the HIV-infected children who survived without antiretroviral therapy maintained protective antibody levels 27 months after receiving measles vaccine. By comparison, 89 percent of children without HIV maintained their immunity, as did 92 percent of the HIV-infected children who were revaccinated in a mass measles immunization campaign during the 27 months of follow-up. The study results were published online June 19, 2007, by The Journal of Infectious Diseases, and will be included in the August 1, 2007, printed issue of the journal.

Despite recent progress in measles control, measles remains an important cause of child mortality in sub-Saharan Africa, says William Moss, MD, MPH, lead author of the study and an associate professor in the Bloomberg School of Public Healths Department of Epidemiology. The measles virus needs only a small proportion of susceptible children to sustain transmission and cause an outbreak. Vaccinated children with HIV could be susceptible to measles because of their waning immunity, impeding measles elimination efforts in regions with high HIV prevalence.

The study enrolled over 690 Zambian children, 2 to 8 months of age, who came to the Chawama Clinic in Lusaka, Zambia for routine childhood vaccinations. Within six months of measles vaccination at 9 months of age, 88 percent of HIV-infected children developed protective measles antibody levels, as did 94 percent of children born to HIV-uninfected mothers and 94 percent of children who did not have HIV but were born to HIV-infected mothers. The proportion of HIV-infected children who developed protective antibody levels was comparable to those achieved by the other children. However, 27 months after vaccination, measles antibody concentrations were 75 percent lower in children infected with HIV at the time of vaccination and 72 percent lower in the children who became HIV infected after vaccination, compared with HIV-uninfected children.

The World Health Organization recommends a second opportunity for measles vaccination for all children, either through repeated immunization campaigns or a routine second dose delivered through the primary health care system. These study results suggest that this practice is especially important in regions of high HIV prevalence because of waning immunity among HIV-infected children.

Sufficient resources must be invested to maintain high levels of population immunity against measles in regions of high HIV prevalence, as well as investing in strategies to prevent HIV infection and to treat HIV-infected people, said Moss.

The study authors also recommend that additional research be conducted to determine the duration of measles immunity in HIV-infected children receiving antiretroviral therapy and their response to revaccination against measles.

Vaccine trials inject hope into koala's future

Mon, 16 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The first Australian trials of a vaccine developed by Queensland University of Technology that could save Australia's iconic koala from contracting chlamydia are planned to begin later this year.

Professor Peter Timms, from QUT's Institute of Health and Biomedical Innovation, said chlamydia was a major threat to the continued survival of koalas with almost all populations affected by the disease.

The trial is planned to begin before the end of the year and will test the vaccine's ability to induce a good immune response in the koala against chlamydia, he said.

Assuming that this first trial is successful, then future trials can determine if this immune response is able to protect the koalas against chlamydial disease.

We've been able to develop the vaccine for koalas as a result of our studies on the development of human chlamydial vaccines done in the mouse model. We have identified several novel vaccine proteins that we hope will protect koalas as well.

Professor Timms said chlamydia in koalas was a significant cause of infertility, urinary tract infections, and inflammation in the lining of the eye that often led to blindness.

The numbers of koalas with chlamydia seems to be increasing, he said.

As much as 40-50 per cent of koalas coming into care in both Queensland and NSW are showing clinical signs of the disease and it seems to be getting worse.

The vaccine will be administered to a small number of koalas via an injection either under the skin or intramuscularly.

The first phase of the trial will run for between six and 12 months, he said.

We will have initial results within the first six months but we will continue to monitor the koalas for 12 months to determine how long the vaccine stimulates an immune response in the koalas and whether or not a booster shot is required.

There is no danger that a koala without chlamydia will contract the disease from the vaccine.

Professor Timms said the vaccine trial was a significant step in the right direction in fighting the threat of chlamydia in koalas.

QUT's koala vaccine team also includes Professor Ken Beagely and PhD student Asad Sukar.

While we have funding for the initial trial we are hoping to attract additional financial support for us to be able to continue this important work, he said.

We seem to be doing good science but we need more funding. We are looking for corporate or individual support to fund further research in this area.

Professor Timms said by investing in chlamydia research, people were giving hope to the future survival of koalas.

Immune system 'escape hatch' gives cancer cells traction

Mon, 16 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists at Johns Hopkins and elsewhere say they have mapped out an escape route that cancers use to evade the bodys immune system, allowing the disease to spread unchecked.

In a report published in the July 1 issue of the journal Nature Medicine, the Hopkins team, along with researchers from Florida and Nebraska, describe how myeloid-derived suppressor cells (MDSCs), which normally keep the immune system in check and prevent it from attacking otherwise healthy tissue, can suppress the anti-tumor response to cancer.

These suppressor cells block other immune system cells, CD8 killer T cells, from binding with proteins that identify the foreign antigens on the surface of unhealthy cancer cells, marking them for destruction, the team reports.

The good news, they say, is that their experiments also suggest that the chain reactions in T-cell tolerance are reversible, raising the possibility of vaccine and drug therapies that break through the blocked immune system.

Previous research had confirmed that MDSCs, produced in the bone marrow, were attracted to tumors, but until now, scientists had not identified exactly how the cells inhibit the immune systems ability to mount an attack.

By explaining some of the precise biological workings of MDSCs in cancer the teams findings suggest why experimental cancer vaccines have to date been plagued by T-cell tolerance, a weakened rather than strengthened immune response, says Jonathan Schneck, M.D., Ph.D., one of the studys authors.

Our findings also open up a new door in drug and vaccine development that we never knew existed and provide another opportunity for drug development into autoimmune diseases, where the immune system is in overdrive and needs to be slowed down, says Schneck, a professor of medicine, pathology and oncology at The Johns Hopkins University School of Medicine and its Kimmel Cancer Center.

The teams latest report built on research initially conducted at the University of South Florida, where researchers analyzed blood samples and lymph tissue from healthy mice injected with MDSCs and found that T-cell levels remained the same, indicating that MDSCs did not destroy the immune response but apparently altered how the T cells behaved.

Using chemical tests in which individual tumor cells can be tagged with a fluorescent dye that allows them to glow when they are not bound to T cells, Florida researchers measured the immune response in mice to various foreign proteins, with and without injections of MDSCs. They found an 80 percent suppression of the immune response in the presence of MDSCs, confirming that the suppressor cells were inactivating the T cells.

The Florida team then turned to Schneck, who in 1993 developed several novel proteins to test how various antigens, such as those on cancer cells, specifically latch on to T cells.

Researchers then began experiments to determine if the MDSC T-cell interference was simply genetic or had some biochemical explanation, testing a half-dozen major reactions known to occur during infection to see if any set path was particularly active during interference.

In tissue tests from tumor-filled mice bred to lack a biochemical reaction, the scientists found that one specific pathway, the reactive-oxygen species, or ROS pathway, stood out, because when inactivated, T-cell tolerance did not develop. Researchers were surprised when subsequent tests showed that ROS actually modified the T cells, altering their structure so they could no longer bind to tumor-cell antigens.

When a known byproduct of ROS, the chemical peroxynitriate, was neutralized, T-cell tolerance failed to develop in test tube studies, pinning down peroxynitrate as the culprit prohibiting immune cell binding to and marking of foreign tumor cells.

Peroxynitrate activity is the escape hatch, and now that we have identified it, we can try to cut it off before T-cell tolerance develops, or you can reverse it, says Schneck.

Plans are underway to investigate the binding receptors of MDCSs and different anticancer drugs for their ability to lower levels of MDSCs and to explore the role of MDSCs in suppressing the immune response to stress, bacterial and viral infections, organ transplantation and autoimmune diseases. Their goal, researchers say, is to find some means of accelerating or slowing down T-cell activity gone awry.

Japan's DNAVEC and IAVI partner on novel AIDS vaccine strategy

Mon, 09 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Tsukuba City, Japan and New York, July 9, 2007The New York-based International AIDS Vaccine Initiative (IAVI) and DNAVEC Corporation today announced a collaboration to jointly develop an AIDS vaccine using DNAVEC's Sendai virus (SeV) vector technology. The candidate will be designed to be administered intra-nasally to stimulate immune responses in both the blood and mucosal tissues, the initial point of entry for HIV.

This direction in AIDS vaccine development is crucial: Today, most candidates in clinical trialsnumbering close to 30are based on a cell-mediated approach, targeting only one arm of the human immune system. Promising vectors that trigger mucosal immunity at the primary site of infection and replication could serve as a first line of defense in fending off the virus. These properties may be necessary for an efficacious vaccine.

Sendai, which serves as a basis of the vector, is a RNA virus that does not cause disease in humans, is capable of efficiently delivering genes expressing HIV proteins to the immune system, and of replicating safely in the upper airway. DNAVEC and the Japanese National Institute for Infectious Diseases (NIID) have demonstrated that monkeys can be protected against SIV, a virus that causes a disease in some non-human primates that is much like AIDS, if vaccinated intra-nasally using a recombinant SeV vaccine candidate.

One of IAVI's scientific priorities is to develop vaccines by using new and improved viral vectors that can control HIV infection, said Seth Berkley, CEO and President of IAVI. The preliminary data from DNAVEC and the Japanese NIID in monkeys makes SeV a promising candidate, and we are delighted to be working with our first Japanese industrial partner on the project. Since its inception in 1996, IAVI has tested six candidate vaccines and raised nearly a half billion dollars in new funding for AIDS vaccine research and development.

IAVI and DNAVEC will each contribute scientific and technical expertise to develop the SeV vector-based AIDS vaccine, with a goal of advancing the candidate to human clinical trials within the next three years. The agreement includes pre-clinical testing for immunogenicity and safety, process development for manufacturing, and a Phase I clinical trial for the candidate. The partners will evaluate further development after the results of early testing. DNAVEC will receive royalties from any vaccine licensed for use in developed countries, while both partners have agreed to make any successful vaccine available as quickly as possible to countries hardest hit by the epidemic. IAVI also will provide financial support for the project.

This agreement brings together IAVI's proven product development expertise and experience conducting clinical trials in North America, Europe, Africa and India with DNAVEC's promising and unique vector technology, said Mamoru Hasegawa, President and CEO of DNAVEC. We are very hopeful the partnership will bring us closer to a safe and effective AIDS vaccine, which would be a great contribution to human welfare.

Currently, there are close to 40 million people infected with HIV, most of them in developing countries, with the number of new infections worldwide topping 12,000 per day. Although the international community has made significant strides in expanding AIDS treatment and care, HIV/AIDS is outpacing the global response. For every person who begins antiretroviral treatment for AIDS, estimates suggest six more become newly infected with HIV.

We simply must do a better job of marshalling the scientific talent and resources from every corner of the globe to design effective and long-term approaches to HIV prevention,concluded Berkley. Japanese biotechnology companies such as DNAVEC, with a proven capability in developing innovative vaccine concepts, will play a large role in the global search for a vaccine to end AIDS.

To date, DNAVEC has worked with the University of Tokyo and the Beijing University of Technology to develop the Sendai vector as a viable technology for HIV/AIDS vaccines.

Novel genetics research advances possibility of HIV vaccine

Thu, 05 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A pioneering collaborative study has discovered how the HIV virus evades the human bodys immune system.

The research collaborative involving scientists from the British Columbia Centre for Excellence in HIV/AIDS, Massachusetts General Hospital (MGH), Microsoft Research and Los Alamos National Laboratory used highly computer-intensive, cutting-edge statistical research methods to investigate how the HIV virus mutates to escape the bodys immune system.

Specifically, HLA class 1 is a controlling part of the human immune response. The ability of HIV to escape recognition by HLA class 1 leaves the body incapable of finding and fighting the virus.

The study, published in the July issue of PLoS Pathogens, is the largest population-based investigation of how natural variations in HLA class 1 can influence HIV genetic sequence, as well as the first characterization of changes in multiple HIV genes in response to HLA-associated evolutionary pressure.

Researchers successfully mapped sites within particular HIV genes where variations can improve the viruss ability to escape immune recognition, showing this is predictable based upon the HIV patients individual HLA class 1 profile.

This is a novel and advanced description of how the human immune system attacks the virus, and how it responds says Dr. Richard Harrigan, Director of the Centres Research Laboratories and study co-author. While we always knew the body attacks the virus and the virus changes to dodge pressure, were now more exact in knowing how this happens in people.

While the study is valuable in helping the scientific community understand how immune pressure impacts HIV, these findings hold tremendous promise in terms of global HIV efforts, says Dr. Zabrina Brumme, the studys lead author. Achieving a more in-depth understanding of the ways in which HIV mutates to avoid the human immune system will help with the design of an HIV vaccine, says Brumme, who is now with the Partners AIDS Research Center at MGH.

Data were collected from the British Columbia HOMER cohort, a large group of chronically HIV-infected, treatment-naïve individuals for whom HLA class-1 typing and HIV RNA genotyping were performed.

Microsoft Research provided personnel and advanced software tools to perform highly sophisticated statistical analysis. Algorithms developed by David Heckerman, lead researcher of the Machine Learning and Applied Statistics Group at Microsoft Research and study co-author, and his team allowed for more in-depth analysis of the data sets. We created the software tools to help researchers exploit the power of computing to more quickly and accurately identify the crucial elements of an effective HIV vaccine, said Heckerman.

The original idea for the development of these statistical methods came from Dr. Bette Korber at Los Alamos National Laboratory. Korber and co-researchers Dr. Tanmoy Bhattacharya and Marcus Daniels worked with Heckerman in further developing the cutting-edge statistical approach.

Study results demonstrate that population-based approaches could complement smaller functional studies by providing a whole-gene or whole-virus picture of immune escape. Previous B.C. Centre research published in The Journal of Infectious Diseases investigated the role of HLA class 1 variation on response to anti-HIV therapy. Moving forward, well be expanding our genetic research to other HIV genes. Well also be investigating the role of drug therapy, says Harrigan.

Researchers discover method for identifying how cancer evades the immune system

Mon, 02 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One of the fundamental traits of a tumor how it avoids the immune system might become its greatest vulnerability, according to researchers from the University of Southern California. Their findings, demonstrated in human breast and colorectal cancers, indicate that a technique for determining a tumors immune signature, could be useful for diagnosing and treating specific cancers.

In the July 1 issue of Clinical Cancer Research, a publication of the American Association for Cancer Research, the researchers describe a means for determining which genes have been altered in a tumor to allow it to evade the bodys natural defenses. In time, the researchers believe such analysis could become a standard practice in cancer diagnosis and treatment.

The implication is that once you know the mechanism by which tumors evade the immune system, you can match that tumor to available therapies, said senior author Alan L.Epstein, M.D., Ph.D., professor of Pathology at USCs Keck School of Medicine. First, we find the genetic changes that allow a tumor to defeat the immune system, then we can apply therapies that compensate for these genetic alterations.

According to Epstein, tumors are notorious for demonstrating a broad array of genetic and biological variations. Their differences vary widely between cancer types, even between subcategories within a particular type of cancer. However, while the genetic variations that comprise an immune signature are complex, the researchers discovered that a small subset of genes is integral in explaining immunological behavior.

Using real-time PCR (rtPCR), a high-speed gene amplification technique, Epstein and his M.D./ Ph.D. student, Rebecca Sadun, screened tumors to identify 14 pro-immunity genes, which tumors downplay, and 11 key anti-immunity genes, which tumors promote. They studied the expression of these genes in five mouse tumor models for breast cancer, leukemia, colon cancer, lung cancer and renal cell carcinoma. They then compared two of these immune signatures with corresponding human tumors, eight cases of human ductal carcinoma and 11 cases of colorectal cancer.

Remarkably, the researchers found that the immune signatures of each of the human breast cancer cases nearly matched that of mice. In all cases, the researchers saw a suppression of CD83 and CD28, two genes that affect activation of immune cells, and over-production of B7-H4, a gene whose protein product inhibits immune activation. The human colorectal cancers, however, showed variations in their immune signatures, which researchers saw as an indication of the need to understand the signature for each patients individual cancer.

I see it as the beginning stages of personalized medicine, where we develop tactics for treating the unique genetic make-up of a specific tumor, Epstein said. It becomes even more necessary when we look at all the immunotherapies that are becoming available or are beginning to emerge from research.

In time, Epstein believes, it will be possible to study the immune signatures for most, if not all, forms of cancer. In addition, rtPCR technology allows for a relatively inexpensive and rapid analysis on equipment available at most medical centers, researchers said. For now, we need to better understand the immune signatures for the most common human cancers in order to identify the most important targets for immunotherapy, Epstein said.

Human antibodies that block human and animal SARS viruses identified

Mon, 02 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) An international team of investigators has identified the first human antibodies that can neutralize different strains of the virus responsible for outbreaks of severe acute respiratory syndrome (SARS). The researchers used a mouse model and in vitro assays (lab tests) to test the neutralizing activity of the antibodies. The research team was led by scientists from the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID), both parts of the National Institutes of Health, and included collaborators from the U.S. Army (USAMRIID), academic institutions in the United States, Switzerland, and Australia. The research findings appear after the July 2, 2007, early online edition of the Proceedings of the National Academy of Sciences.

SARS outbreaks occurred in humans in 2002-2003 and again in 2003-2004, and each outbreak was thought to have occurred when the virus jumped from an animal host to humans. Therefore, it appears that animal strains of the virus may be capable of triggering a future human outbreak.

This study is important because the viral strain that caused the outbreak in people in 2002 probably no longer exists in nature, explains Kanta Subbarao, M.D., NIAID, whose laboratory verified the efficacy of the anti-SARS antibodies in animal models. What we need to prove for any vaccine, therapeutic, antibody, or drug is that it is effective not only against the strain of SARS virus isolated from people, but also against a variety of animal strains, because animals will be a likely source for re-emergence of the SARS virus.

The research team was led by Dimiter S. Dimitrov, Ph.D., head of the Protein Interaction Group at NCIs Frederick, Md., campus. When the first SARS outbreak occurred in 2002, Dimitrov responded to the public health crisis by applying his laboratorys expertise in how viruses enter cells, which was gained in the study of HIV, to understand how this new virus enters and exploits human cells. Their research into the spike glycoprotein, the part of the virus that binds and allows entry into human cells, provided the knowledge needed to identify several human antibodies against the SARS virus.

Our researchers at NCI Frederick have an extraordinary breadth of expertise, ranging far beyond cancer to areas such as AIDS research, advanced biotechnology, and vaccine manufacturing, said NCI Director John E. Niederhuber, M.D. We are realizing, as never before, that cancer is a model for many diseases, and NCI's research is a rich resource to our NIH colleagues and the biomedical research community at large.

Dimitrov and his colleagues identified two human antibodies that bind to a region on the SARS virus spike glycoprotein that is called the receptor binding domain (RBD). One of the antibodies, called S230.15, was found in the blood of a patient who had been infected with SARS and later recovered. The second antibody, m396, was taken from a library of human antibodies the researchers developed from the blood of 10 healthy volunteers. Because humans already have immune cells that express antibodies that are very close to those that can effectively neutralize the SARS virus, m396 could be fished out from healthy volunteers. Dimitrovs team next determined the structure of m396 and its complex with the SARS RBD and showed that the antibody binds to the region on the RBD that allows the virus to attach to host cells.

If the antibodies were successful in binding to the SARS RBD, they would prevent the virus from attaching to the SARS coronavirus receptor, ACE2, on the outside of human cells, effectively neutralizing it. When tested in cells in the laboratory, both antibodies potently neutralized samples of the virus from both outbreaks. The antibodies also neutralized samples of the virus taken from wild civets (a cat-like mammal in which strains of the virus were found during the outbreaks), though with somewhat lower potency.

The investigators next tested the antibodies in a mouse model of SARS virus infection. Mice were given an injection of one of the two antibodies, and then were exposed 24 hours later either to samples of the SARS virus from one of the two outbreaks or to virus isolated from civets. Mice that received m396 or S230.15 were fully protected from infection by SARS from humans, the researchers found. Similar to the experiments in cells in the laboratory, mice that received either antibody were also protected against infection by SARS from civets, though not completely.

Further analysis of the structure of m396 and its interactions with experimental mutations in the SARS virus receptor binding area suggested that the antibody can successfully neutralize all known forms of the virus. This antibody neutralizes all strains of SARS we tested and is likely to neutralize all strains of the virus with known sequences, said Dimitrov. There are no other reports for such antibodies available.

This elegant research leaves us better prepared for the possible re-emergence in people of viruses similar to those that caused more than 8,000 documented SARS cases and nearly 800 deaths in 2002-2003, noted NIAID Director Anthony S. Fauci, M.D. This work, which could help inform the development of therapeutics, vaccines, and diagnostics, is a pre-emptive strike against a pathogen with the potential to re-emerge.

The discovery of two effective antibodies has the advantage that a newly emergent variation of the SARS coronavirus might be insensitive to neutralization with one, but still susceptible to the other. Our results demonstrate novel potential antibody-based therapeutics against SARS that could be used alone or in combination...these human antibodies could be also used for diagnosis and as research reagents in the development of vaccines and inhibitors, summarized the authors.

LSUHSC grants fund infectious diseases research and clinical trials

Thu, 28 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Chancellor Larry Hollier, MD, announced today that the Louisiana Board of Regents voted to award LSU Health Sciences Center New Orleans a $3.3 million grant and an equal share of a $5.9 million grant from their Research Commercialization and Education Enhancement Program. We are grateful to the Louisiana Board of Regents, Commissioner of Higher Education Dr. Joseph Savoie, and the Louisiana Recovery Authority, which was instrumental in obtaining these funds, for investing in our educational and research enterprises, said Dr. Hollier. These programs will help us stabilize the supply of health care professionals in New Orleans and promote economic recovery by enhancing our efforts to recruit and, as importantly, retain current faculty.

Dr. Paul Fidel, Associate Dean for Research at the LSUHSC School of Dentistry, is the principal investigator and will lead the $3.3 million South Louisiana Institute for Infectious Disease Research. The institute will build upon research strengths in fungal diseases, HIV/SIV, sexually transmitted diseases, vaccines/vaccine development, respiratory diseases, oral diseases and biodefense-emerging infections at LSU Health Sciences Center New Orleans and Tulane Health Sciences Center.

The institute will create an educational component that will provide a technical training program for Louisiana Associate or Baccalaureate students designed to prepare them for careers in academic research laboratories and the biotechnology industry. The institute will also initiate programs for intellectual stimulation and mentoring, providing research enhancement funds, as well as salary support for postdoctoral fellows and graduate students.

The institutes commercialization component will provide pathways to efficient and effective commercialization of promising translational discoveries with the help of the schools technology transfer offices, The New Orleans BioInnovation Center (NOBIC), and area business schools.

The grant enables us to take areas of strength in infectious disease research and create a Tower of Strength' and the educational component will provide a pipeline of high quality workforce for research, notes Dr. Fidel. The commercialization component will provide a pathway to more effectively take discoveries into the marketplace. Together, we envision the ultimate reward to be the advancement of the discovery process that will provide better treatment and cures for those suffering with infectious diseases.

Dr. Steve Nelson, Professor and Chief of the Section of Pulmonary Medicine at LSU Health Sciences Center New Orleans, is the co-principal investigator of the highest ranked and highest funded grant. The $5.9 million Clinical and Translational Research Education and Commercialization Program at LSU Health Sciences Center and Tulane will support clinical and translational research. The clinical core will comprise the General Clinical Research Center (GCRC) housed at University Hospital which Dr. Nelson leads as Program Director. This unit is one of a national network of approximately 78 centers usually located in units within hospitals of academic medical centers. Their primary mission is to provide a research infrastructure for clinical investigators who receive their primary support from NIH components as well as other Federal agencies.

Current GCRC research projects include new cancer therapies, new drugs for malaria, AIDS, and asthma, among others. These projects represent about $25 million of NIH funded research.

The review panel noted that the educational component is innovative and likely to be successful in increasing the numbers of trained clinical scientists. They went on to say that the use of a navigator for clinical researchers to guide the development of a clinical research protocol from conception to patient accrual is an excellent idea and should provide the type of mentoringthat is crucial for effective faculty development. The proposed commercialization core issolid and demonstrates a good institutional track record in this area.

The reviewers concluded that this is an outstanding proposal that is absolutely essential to the future of clinical and translational research in south Louisiana. It will support the infrastructure that is the backbone of clinical research and the training of future clinical and translational scientists. Given the substantial impact of Hurricane Katrina on this program and the excellent track records of the faculty involved, support is essential and highly likely to bear fruit both in terms of an improved workforce and enhanced commercialization.

The funding provided by the Board of Regents/Louisiana Recovery Authority for this proposal is essential to the recovery and growth of both medical schools and to the future of clinical research and training in Louisiana, said Dr. Nelson. It will provide our citizens with access to the latest medical therapies, train the next generation of physician scientists and healthcare professionals, and provide a pathway for the commercialization of our new discoveries into new industries and jobs in Louisiana.

New vaccine prevents CMV infection and disease in mice

Fri, 22 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of California, San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences have patented a strategy for developing a human vaccine to prevent against Human Cytomegalovirus (hCMV) infection and disease.

CMV, a type of herpes virus, is the leading viral cause of birth defects and a serious problem in patients with compromised immune systems. The bodys natural immunity doesnt protect against infection by the virus, estimated to be present in 50 to 75 percent of all adults.

Until now, scientists havent been able to develop a vaccine to protect against CMV, said Deborah H. Spector, Ph.D., UCSD Professor of Cellular and Molecular Medicine and faculty member of the Skaggs School of Pharmacy and Pharmaceutical Sciences. Using a two-pronged approach, we successfully created and tested a vaccine in a mouse model with CMV that shows enormous promise for re-directing the bodys immune system, enabling it to fight the virus.

The mouse vaccine generates an immune response that protects against both infection and development of disease when the virus is present by completely disarming the viruss ability to replicate and establish a persistent infection. The work is currently online in advance of publication in the July issue of Journal of Virology.

Our approach generates an immune response that is different from the normal response to the virus, and we hope to have found an Achilles heel in the defenses that the virus uses to evade the immune system, said Spector. The virus has evolved to persist in the host by evading the immune responses either by hiding or by misdirecting the hosts immune responses. We found a way to teach the host immune system to not be tricked by the virus. She added that the next step is to apply this strategy to create a vaccine for use in humans.

CMV is a virus that, while carried by the majority of adults in the United States, can remain dormant for years, if not the lifetime, of a healthy individual. However, two percent of all children are born with the virus passed on by the mother in utero, and 15 percent of those children will show symptoms such as hearing loss, mental retardation, motor or learning disabilities. Because the hosts natural immune system can protect from the disease but cant rid the body of the virus, people remain infected and can become re-infected or infect others through saliva.

Children in day care settings, for example, or adults who are sexually active, can pass along the virus, explained Spector. It becomes a serious problem in developing infants during the pregnancy or in those whose immune system is compromised, such as AIDS or transplant patients.

When a persistent virus such as CMV infects an individual, it disarms the host immune system in two ways by hiding or masking the proteins that would normally provoke an immune response, or by fooling the immune system into mounting a response that doesnt work to eradicate the virus.

We needed a way to make the host defense system sit up and take notice, said Christopher S. Morello, Ph.D., first author of the study.

To do this, the researchers devised a vaccine with a one-two punch that combines a DNA immunization that targets T-cells to essential genes required for CMV replication, with a killed virus that prompts the bodys B-cells to generate an antibody response.

The vaccine contains the DNA of two essential genes that are essential for replication of the virus. These genes which are also found in other herpes viruses such as chicken pox or herpes simplex have the same or very similar sequence, structure and function whether in human or mouse viruses, and present a novel target for the hosts T-cells to muster forces and attack the virus. Secondly, the vaccine also contains a boost from an inactivated virus, which generates an antibody response. Neither approach alone would give complete protection.

In mice, the vaccine not only fought the disease, but prevented the infection from being established in the first place, Morello said.

Researchers at UCSD hope to begin pre-clinical work on development of a human vaccine. If successful, an FDA-approved, commercially licensed hCMV vaccine could be administered to specific at-risk populations, such as females prior to child-bearing years, day care providers, organ transplant recipients, or as part of regular childhood immunizations.

This approach may also be valid for a number of diseases associated with persistent or latent infections, including all types of herpes-associated diseases, AIDS, or hepatitis, said Spector. These viruses persist because immune responses generated by the viral infection are not able to eradicate the virus.

Fever after smallpox vaccination tied to individual genetic variations

Mon, 18 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) St. Louis researchers have identified common DNA variations that underlie susceptibility to fever after smallpox vaccination. Their finding is the first to link individual differences written into the genetic code with a vaccine-related complication albeit a mild one.

Most of the eight genetic alterations the scientists identified increased the likelihood of fever after smallpox vaccination. A few, however, reduced fever risk. The research, led by scientists at Washington University School of Medicine in St. Louis, will be published in the July 15 issue of The Journal of Infectious Diseases and is now available online.

The study's results raise the possibility the same genetic variations linked to fever following smallpox vaccination may also influence fever risk after other live-virus vaccines, including the one for measles, mumps and rubella. This so-called MMR vaccine is routinely administered to small children, and fever is a bothersome and common side effect.

Eventually, the authors say, it may be possible to develop a test that predicts which patients are at risk for vaccine-related fevers. Such a test also may help doctors anticipate and prevent more serious complications linked to the vaccines.

"Vaccines are extraordinarily safe and effective, but that doesn't mean we can't try to make them even more acceptable by discovering ways to further reduce the chance of adverse events, including minor ones like fever," says the study's lead author, Samuel Stanley Jr., M.D., vice chancellor of research at Washington University and a professor of medicine and microbiology. The research was funded by the National Institutes of Health through a grant to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (MRCE), which Stanley directs.

Routine smallpox vaccinations in the United States were halted in 1972, when the disease was considered eradicated in this country, but the U.S. military and other high-risk groups, including some healthcare workers, continue to get the vaccine. It is made with a live but weakened vaccinia virus that provides immunity against smallpox but which can cause complications ranging from fever and fatigue to more serious illness. About 15 percent of those being vaccinated for smallpox for the first time develop a fever over 99 degrees.

Fevers related to vaccines are not considered a serious medical issue, but in rare cases they can lead to more severe complications. Individuals who get a fever after the smallpox vaccine occasionally develop myopericarditis, a potentially life-threatening inflammation of the heart muscle or sac surrounding the heart. And a small percentage of children who get fevers after the MMR vaccine will develop seizures.

"We don't know whether the same genetic variations we identified in our study are also linked to more serious vaccine complications, but our study raises that possibility," Stanley says. "I think this study will point us in that direction in terms of looking for genetic alterations that predict more serious complications."

The Washington University scientists, working in collaboration with MRCE colleagues Robert Belshe, M.D., and Sharon Frey, M.D., at St. Louis University, studied the occurrence of fever in 346 individuals who had participated in previous smallpox vaccination clinical trials evaluating Dryvax, the vaccine given to U.S. military personnel. About 95 percent of study participants were white.

Records showed that 94 developed fever after vaccination - 61 who received the vaccine for the first time and 33 who had been vaccinated before. The 252 individuals who did not develop fevers after vaccination served as the control group.

Using blood samples donated by study participants, the scientists analyzed SNPs, sites of common genetic variation, in 19 genes linked to immune response, viral replication or inflammation. They found eight alterations associated with fever in four of the genes.

Not surprisingly, those who received the vaccine for the first time were more likely to develop fever, but Stanley says, "We were able to identify specific genetic alterations that contribute to fever even in people who had already received the vaccine before."

The research team found that variations in the IL-1 gene complex on chromosome 2 were most closely linked to an increased risk of fever. This complex of genes produces a molecule that stimulates fever and is involved in inflammation. Additionally, several variations in the IL-18 gene on chromosome 11 increased fever risk, while one decreased the likelihood of fever. That gene is involved in revving up the immune system. One variation in IL-4, a gene that dampens down the inflammatory response, also reduced fever risk.

Interestingly, studies in mice have shown that immune system molecules produced by the IL-1 and IL-18 genes are linked to tissue damage in viral myocarditis, raising the question of whether a more severe complication of smallpox vaccination might be associated with variations in these genes. Although none of the study participants developed this rare complication, it has been documented in 59 of the more than 492,000 military personnel who were vaccinated between December 2002 and September 2003.

Stanley hopes further studies will delineate whether genetic alterations linked to fever also play a role in more serious vaccine complications. About 12 percent of children who receive the MMR vaccine develop fevers over 103 degrees, and about 4 percent of them go on to develop seizures in the weeks that follow vaccination.

"There might be a real benefit if we could use this kind of screening to identify children who may be more susceptible to febrile seizures after MMR," Stanley says. "If we can find ways to identify people at risk and medicate them to reduce the possibility of fever, we might be able to reduce the incidence of seizures."

How 'memory' T cells curb the spread of viruses throughout the body

Mon, 18 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A scientific discovery by Fox Chase Cancer Center researchers helps explain how memory T cells protect the body from viral diseases. The research published today in Proceedings of the National Academy of Science Online Early Edition shows lymph nodes are not just organs where immune cells reside and proliferate, but also are the sites where a major fight against the spread of an invading virus occurs.

After becoming sick from many viruses, the body becomes immune (protected) from recurrence of the same disease. This is why before vaccines were developed, childhood diseases such as measles and mumps occurred only once in a lifetime. The immunity occurs when the immune system produces cells called lymphocytes that specifically attack and eliminate the virus at the time of infection. After the infection subsides, most of the lymphocytes die but some remain in the body as memory lymphocytes and protect the body from recurrence of the disease. Similarly, vaccines induce the production of memory lymphocytes, but without causing disease.

While scientists have long known the role of antibodies in protection, whether memory cells, known as CD8 T cells, could prevent viral diseases has been debated. The new work by Fox Chase virologist Luis J. Sigal, D.V.M., Ph.D., and his Fox Chase colleagues in the virology and pathology programs, provides the basis whereby memory CD8 T cells do, in fact, prevent viral diseases.

CD8 T cells normally reside in lymphoid organs such as the lymph nodes. It was thought that to protect from disease, memory CD8 T cells needed first to multiply in the lymph nodes and then migrate through the blood to kill infected cells at the site where the virus entered the body (most commonly the skin, the lungs or the gut). This process of lymphocyte multiplication and migration may take several days while viruses multiply and spread quicker. Sigals work shows the CD8 T cells can protect from viral disease without the need to migrate from the lymph nodes to the site of viral entry.

It was very difficult to imagine how the memory T cells could win this race, said Sigal, the lead author of the study.

The Fox Chase experiments show that memory CD8 T cells rapidly multiply and kill target cells inside the lymph node.

In fact we found that memory CD8 T cells already killed target cells in the lymph node and decreased viral spread to the liver and spleen when the virus just barely started to multiply.

Thus, memory CD8 T cells do not prevent infection; but prevent disease partly because they curb the spread of the virus from the lymph node to vital organs at very early stages of the infection.

Its like having a security check point, said Sigal. Also, many cancers, like viruses, must pass through lymph nodes to metastasize, so this research may help develop vaccines that prevent tumor metastases.

Damon Runyon renews its $2.25 million investment to support young clinical cancer investigators

Fri, 15 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) New York, NY -- The Damon Runyon Cancer Research Foundation named 5 new Damon Runyon Clinical Investigators at its May 2007 Clinical Investigator Award Committee review. The recipients of this prestigious, three-year award are outstanding early career physician-scientists conducting patient-oriented cancer research at major research centers under the mentorship of the nations leading scientists and clinicians. Each will receive $450,000 to support the development of his or her cancer research program. The Clinical Investigator Award program is specifically intended to help address the worrisome shortage of physicians capable of translating scientific discovery into new breakthroughs for cancer patients. In partnerships with founding sponsor Eli Lilly and Company, and with Siemens Medical Solutions, Novartis and Genentech, the Damon Runyon Cancer Research Foundation has committed more than $30 million to support the careers of 39 physician-scientists across the United States since 2000.

The 2007 awardees are Colleen Delaney, MD, from the Fred Hutchinson Cancer Research Center and the University of Washington; Douglas K. Graham, MD, PhD, from the University of Colorado at Denver and Health Sciences Center; Juan Carlos Ramos, MD, from the University of Miami Miller School of Medicine and Sylvester Cancer Center; Joel H. Rubenstein, MD, from the University of Michigan; and Catherine J. Wu, MD, from the Dana Farber Cancer Institute.

Dr. Colleen Delaney and mentors Dr. Irwin Berstein and Dr. Fred Appelbaum focus on improving on hematopoietic stem cell transplantation. The use of umbilical cord blood for transplantation is an attractive alternative for cancer patients who cannot identify a suitable adult donor such as minority patients or patients of mixed ethnicity. However, umbilical cord blood has fewer stem cells, decreasing the likelihood of a successful transplant. Dr. Delaney has developed novel methods for increasing the concentration of stem cells in cord blood. Her mouse studies and early patient trials show encouraging results and she plans to move this technique into larger clinical trials.

Dr. Douglas Graham investigates new treatments for childhood leukemias and lymphomas. Current therapies for acute lymphoblastic leukemia (ALL), the most common pediatric cancer, are effective but have severe short and long term side effects. More targeted and less toxic therapies are needed. Dr. Graham has identified the Mer tyrosine kinase as a critical mediator of leukemogenesis and has developed two new drugs that block Mer action. Under the mentorship of Dr. James DeGregori and Dr. S. Gail Eckhardt, Dr. Graham plans to test the activity of these new compounds in mouse models of ALL and move these promising new agents into the clinic for the treatment of this deadly childhood cancer.

Dr. Juan Carlos Ramos focuses on adult T-cell leukemia/lymphoma (ATLL), a deadly blood cancer that afflicts some of the most underserved cancer patients. ATLL is caused by the human T-cell leukemia virus and a subset of ATLL patients respond to therapy with interferon, commonly used in the treatment of a number of cancers. Little is known about how or why interferon kills cancer cells. Under the mentorship of Dr. William Harrington, Jr. and Dr. Glen Barber, Dr. Ramos works to clarify the precise mechanisms of interferon therapy in ATLL and identify the specific molecular markers associated with response and prognosis. Ultimately, his studies will provide a framework to develop tests that distinguish patients who will benefit from interferon therapy from those who are unlikely to respond.

Dr. Joel Rubenstein brings basic research to the bedside to address a growing health crisis in the United States - how obesity contributes to cancer. Using novel epidemiological analyses, he will investigate the association between lower levels of circulating adipokines, obesity and the presence of Barretts esophagus. Dr. Rubenstein holds joint appointments at the University of Michigan Medical School and the Ann Arbor Veterans Administration Medical Center. Under the mentorship of Dr. Philip Schoenfeld at the University of Michigan and Dr. John Inadomi at the University of California, San Francisco, Dr. Rubenstein plans to develop strategies for reducing deaths from esophageal cancer.

Dr. Catherine Wu is developing a new treatment schema for chronic myelogenous leukemia (CML). Current treatments for CML are effective for a short time, but patients ultimately relapse and die of their disease. Under the mentorship of Dr. Jerome Ritz, Dr. Wu studies how the immune system can be enlisted in the treatment of cancer. Specifically, she is designing a tumor-specific immunotherapy with minimal side effects that will target the leukemia stem cells and ultimately lead to a non-toxic therapy to cure CML.

American College of Preventive Medicine applauds IOM report on training public health physicians

Wed, 13 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Washington, D.C. The American College of Preventive Medicine (ACPM) today applauded the recent release of the Institute of Medicine report, Training Physicians for Public Health Careers, praising the report as a major milestone for preventive medicine and public health from one of the most prestigious voices in medicine. The report calls on Congress to stem the tide of Americas eroding preventive medicine and public health workforce.

The report reflects an in-depth examination by the Committee on Training Physicians for Public Health Careers of the role and need for public health physicians, what these physicians need to know, how to ensure an adequate supply of these physicians, and how to fund the training of these physicians.

The report recommends a doubling of the estimated 10,000 public health physicians currently in practice and specifically calls for expansion and addition of Public Health/General Preventive Medicine residency programs to graduate a minimum 400 additional residents each year. The report also recommends that Congress fund a comprehensive enumeration of the public health workforce in order to project needs for public health physicians and public health education programs.

Noting that Reliable financial support of physician education and training in public health is lacking, the IOM Committee recommends the U.S. Congress fund a comprehensive educational strategy to assure an adequate number of public health physicians. Such a strategy should include funding for residency training in preventive medicine that parallels funding streams for graduate medical education in other medical disciplines, as well as reinstatement and growth of funding health professions training programs under Title VII of the Public Health Service Act.

ACPM President Michael D. Parkinson, MD, MPH, FACPM, praised the committee for its breakthrough work, long overdue, bringing together many important pieces to a very complex puzzle. Dr. Parkinson added, Making the blue ribbon case for seeing preventive medicine residency training as an underutilized yet valued national resource in need of new emphasis and federal support has been convincingly made.

Preventive medicine physicians have unique expertise in assessing and responding to the health needs of the population, including the threats of infectious and chronic diseases, occupational and environmental health issues, and behavioral and socioeconomic determinants of community health. Preventive medicine residency training programs thus address a critical need for leadership at the local, state, and national levels across a wide spectrum of issues threatening the health of our nation.

Congress has already taken the first step toward addressing some of the IOM recommendations with the recent introduction of the Preventive Medicine and Public Health Training Act, S. 1120, by Senators Tom Harkin (D-IA), Johnny Isakson (R-GA), Joseph Lieberman (I-CT), and Jeff Bingaman (D-NM). This bill works to address the present inequity in funding by calling on the Centers for Disease Control and Prevention (CDC) to establish a competitive grant program that would provide federal support directly to preventive medicine residency training programs. The legislation further stipulates that preventive medicine residents should also rotate through community health centers to provide additional clinical and population-based services to underserved communities.

The decline in the number of preventive medicine specialists is a direct function of inadequate and shrinking funding sources available to offset residency training costs. During a time of growing public health threats from emerging infectious diseases, bioterrorism, and natural disasters, the IOM should be lauded for their attempts to strengthen our nations public health infrastructure and to reverse this troubling trend, said Dr. Parkinson.

Meningitis: effectiveness of preventive vaccination demonstrated

Tue, 05 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Meningitis epidemics caused by the pathogen Nesseiria meningitis (or meningococcus) provoke high mortality in children and young people under 20 years of age in sub-Saharan Africa. They rage during periods of drought from January to April, in the area known as the Meningitis Belt (see Map)

Two types of vaccine are currently on the market: the polysaccharide vaccine and the conjugated vaccine. The polysaccharide form, elaborated from a sugar present at the surface of the meningococcus provides only partial, temporary immunity in very young children (2).

The conjugated vaccine, however, is based on a combination between this same sugar and an antigenic protein and renders an effective durable immunity. It could therefore be used in a routine preventive vaccination campaign. But it is costly. Its high price, at 11 to 22 euros per dose, means it remains inaccessible for African countries. These have available only the polysaccharide vaccine, less expensive at 0.3 to 0.5 euro, but which, because of its low immunity capacity, is generally kept only for emergency vaccinations, when epidemics occur.

IRD researchers have been running a follow-up study of the people of the Niakhar region (located 150 km from Dakar, in Senegal) for more than 40 years. They looked into the question of the ability of the polysaccharide vaccine to prevent the occurrence of meningitis cases during epidemics in the course of subsequent years. To do that, they made use of results of two vaccination campaigns conducted with this vaccine by the Senegalese health services. One of these was run in 1996 in 8 of the 30 villages that make up the Niakhar region, the other in 1999, in the whole of the study area, hit be a series of epidemics between 1998 and 2000.

Using quarterly censuses carried out since 1983, the researchers collected then analysed data on childrens state of health and vaccine status. They could therefore make comparisons between the different villages regarding the number of cases of meningitis that broke out, in particular in the years that followed the 1996 vaccination campaign (3).

Their investigation revealed that in the villages vaccinated at that date, two to three times fewer subjects were recorded as suffering from the disease. The polysaccharide vaccine could help avoid up to 72% of cases in subsequent epidemics.

These results speak in favour of adopting a strategy of routine vaccination using this vaccine whenever no other vaccine is available in order to prevent meningococcus meningitis epidemics in this region of Africa. However, a conjugated vaccine which should be sold at less than 1$ (0.80 euro) per dose, is under development. Thanks to the full, durable immunity it confers right from early childhood, it is an ideal tool for a preventive vaccination strategy. Clinical trials initiated in 2006, notably in Niakhar, are continuing for a further 2 years in order to make sure that no undesirable side-effects occur after administration.

Brain inflammation may be friend, not foe, for Alzheimer's patients

Fri, 01 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Inflammation in the brain may not be so bad after all when it comes to Alzheimers disease.

In the June 1 issue of the Journal of Clinical Investigation, a team of scientists from the University of Rochester Medical Center shows that a key inflammatory regulator, a known villain when it comes to parsing out damage after a stroke and other brain injuries, seems to do the opposite in Alzheimers disease, protecting the brain and helping get rid of clumps of material known as plaques that are a hallmark of the disease.

While many scientists have assumed that inflammation as a result of disease or injury only adds to the brains woes, the new findings show that the opposite may be true when it comes to Alzheimers disease. Perhaps inflammation is playing the role of protector and is acting more like an ambulance crew helping at the site of a road wreck, not causing the crash.

The work suggests that doctors not rush in to turn off molecular events that scientists have widely considered to be detrimental in people with the disease. The findings could also renew efforts to develop a vaccine or other strategies against Alzheimers by engaging the bodys immune system.

The team expected to see the telltale clumps of material known as amyloid plaques, made up of the peptide amyloid beta, worsen. Instead, to the teams surprise, the brains of the mice with IL-1beta stuck in overdrive had only about half

This work provides evidence that blocking all inflammatory responses in Alzheimers disease is not an ideal therapy, added Shaftel. This might hinder processes that are beneficial and part of the bodys adaptive response to fight plaques.

The new findings hinge on a very special mouse that Shaftel spent three years creating with the guidance of his adviser, M. Kerry OBanion, M.D., Ph.D., associate professor of Neurobiology and Anatomy. Shaftel genetically engineered a one-of-a-kind mouse that gives him pinpoint control over brain levels of a human molecule known as interleukin-1beta, a well-recognized molecular kingpin in the realm of inflammation.

IL-1 beta, a signaling molecule that promotes brain inflammation, was one of the first molecules that scientists found in higher levels in the brains of people with Alzheimers disease compared to healthy people. Its recognized as a critical player in bringing about much of the brain damage that follows a stroke and brain injury, so its no surprise that its presence in the brains of Alzheimers patients would be assumed to be part of the problem.

In the original development of his mouse, Shaftel worked closely with Stephanos Kyrkanides, D.D.S., Ph.D., associate professor in the Eastman Department of Dentistry and an expert on using a class of viruses known as lentiviruses for use in gene therapy. The team used a lentivirus to boost levels of IL-1 beta in select brain regions of its engineered mouse, then applied the technology in mice specially designed to develop Alzheimers disease.

The mice developed normally for six months. Then Shaftel raised the level of IL-1beta in one part of the brain the hippocampus, an area of the brain that specializes in memory and one of the first parts of the brain to be affected by the disease and followed the mice for an additional month, watching for effects in the brain regions that were awash in higher-than-normal levels of IL-1beta. Its the first use of an organism where scientists can boost IL-1beta in select areas and then watch what happens as the process unfolds.

The team expected to see the telltale clumps of material known as amyloid plaques, made up of the peptide amyloid beta, worsen. Instead, to the teams surprise, the brains of the mice with IL-1beta stuck in overdrive had only about half as many plaques as mice without the over-active IL-1beta.

Through extensive experiments, the team showed that the mice simply werent making fewer plaques, but rather that the body was better at getting rid of the plaques. The team suspects the involvement of brain cells called microglia, the major immune cell that rushes to injury sites and helps repair and clean up wounds in the brain.

The work is the latest in a growing body of research that is trying to determine the exact role of inflammation in Alzheimers disease. OBanion notes that some studies have found that taking medications to squelch inflammation, such non-steroidal anti-inflammatory drugs or NSAIDs, might help reduce a persons chances of getting Alzheimers disease, while other studies, including a study of more than 2,100 people published in April, refute that notion.

There is a great deal of evidence that inflammation plays a potentially negative role in Alzheimers disease, said OBanion. But much of the evidence comes from experiments with cells in a dish or postmortem human tissue, not from living organisms in which disease progression is closely monitored.

People have talked for a long time about a balance of good guys and bad guys within the inflammatory process, either causing harm or alleviating the disease. The current work reinforces the idea that inflammation is not simply the bad guy that many people think it is.

The work could have ramifications for the development of a vaccine or other strategy to protect against or fight off Alzheimers. Work on an Alzheimers vaccine has at times been promising, reducing the number of plaques in the brains of animals and a few people with the disease, but its also been fraught with difficulty, producing side effects such as encephalitis or severe brain inflammation in people with Alzheimers.

The potential to treat Alzheimers disease by modulating the immune system is tremendous and is an area that has not been fully explored, said OBanion. That said, people have to remember that the current findings are in mice, not people. We need to be cautious about how to interpret the results.

Vaxfectin-formulated measles DNA vaccine elicits long-term protection in nonhuman primates

Thu, 31 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Vical Incorporated (Nasdaq:VICL) today announced that a measles DNA vaccine formulated with the company's Vaxfectin? adjuvant elicited protective levels of neutralizing antibodies in juvenile (1 ? 2 year old) nonhuman primates confirmed by complete protection following challenge more than one year after vaccination, and sterilizing immunity as evidenced by no clinical signs of disease and no detectable virus after challenge. In a separate study, the same vaccine elicited protective levels of neutralizing antibodies in infant (6 ? 10 weeks old) nonhuman primates with no vaccine-related adverse events. The studies were conducted in collaboration with Diane E. Griffin, M.D., Ph.D., Alfred and Jill Sommer Professor and Chair of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, under a grant from the Bill and Melinda Gates Foundation.

Sterilizing immunity is a rarely achieved ultimate goal in vaccination, said Vijay B. Samant, Vical's President and Chief Executive Officer. The ability to provide such complete immunity with no adverse events offers proof of concept for Vaxfectin?-formulated DNA vaccines. We look forward to continued development of the measles vaccine program by our collaborators at Johns Hopkins.

We have tested a number of measles DNA vaccines, and the data relating to Vical's Vaxfectin?-formulated DNA vaccine showed marked differences both in terms of disease resistance after exposure and antibody levels over the other vaccines, without significant side effects, said Dr. Griffin. These data are exciting because of the potential of providing safety and efficacy suitable for infants and young children in the developing world, and continued development could result in a major impact on global measles disease and death rates.

The study in juvenile rhesus macaques tested the protective efficacy of a bivalent DNA vaccine encoding measles hemagglutinin and fusion glycoproteins. Vaccine was delivered by intradermal needle-and-syringe injection of two 0.5 mg doses or by intramuscular needle-and-syringe injection of two 1.0 mg doses at four-week intervals. All vaccines were formulated with Vical's patented Vaxfectin? adjuvant. Neutralizing antibody levels exceeded the accepted protection threshold prior to the second injection at Week 4, peaked at Week 5, and remained well above the accepted protection threshold for more than one year, with no difference noted between routes of administration. Animals were challenged by intratracheal inoculation at Week 55, resulting in complete protection of all vaccinated animals against disease symptoms. None of the vaccinated animals had detectable levels of measles virus at any time point tested, in contrast to negative control animals which all had detectable virus. Measles-specific T-cell responses were also detected after vaccination. The vaccines were well-tolerated in all animals.

The study in infant rhesus macaques tested only intradermal needle-and-syringe delivery of vaccine at the same 0.5 mg dose used in the juvenile animals. Neutralizing antibody levels exceeded the accepted protection threshold prior to the second injection at Week 4, peaked at Week 8, and remained above the accepted protective level throughout the 20-week follow-up period. No adverse events related to the vaccination were observed. Data were presented by Adriá® Vilalta, Ph.D., Vical's Senior Scientific Manager of Immunogen Discovery, at the annual meeting of the American Society of Gene Therapy (Seattle, May 30 ? June 3).

International studies show high efficacy for HPV vaccine

Thu, 31 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new vaccine aimed at preventing cervical cancer is nearly 100 percent effective against the two types of the human papillomavirus (HPV) responsible for most cases of cervical cancerÑstrains 16 and 18. Results of an international meta-analysis study of the vaccine are published in the June 1 issue of the journal Lancet.

In the current and largest study to date, researchers combined and analyzed the data from four randomized trials that involved 20,583 women ages 15 to 26 from more than two dozen countries across Europe, North America, Latin America and Asia. Participants were randomly assigned to receive the HPV vaccine or placebo and followed for an average of three years.

Researchers found that the prophylactic administration of the vaccine was highly effective in preventing pre-malignant changes of the cervix, also known as cervical dysplasia.

This is a much larger combined study that shows 99 percent efficacy, a clear reduction of pre-cancerous cervical lesions. We demonstrated significant protection against serious HPV-related diseases, including high-grade cervical pre-cancers, in women not previously exposed to the relevant HPV types targeted by the vaccine, says Kevin Ault, MD, associate professor of obstetrics and gynecology at Emory University School of Medicine, one of the authors of the study and a key researcher in the development of the vaccine.

HPV strains 16 and 18 are responsible for about 70 percent of all cases of cervical cancer. In clinical trials the vaccine, manufactured by Merck under the name Gardasil, also demonstrated a high efficacy rate in protection from HPV types 6 and 11, which together cause about 90 percent of all cases of genital warts. All four types cause a large number of abnormal Pap test results and low-grade cervical lesions.

Cervical cancer is the second most common cause of cancer deaths in women worldwide, accounting for about 240,000 deaths each year. In 2007 experts predict cervical cancer will strike an estimated 11,000 women in the United States and nearly half a million women worldwide. Every day in the United States ten women die from cervical cancer, says Dr. Ault.

Thanks to the results of this meta-analysis and a previous publication in Lancet, we now have data on three more rare cancers -- adenocarcinomas in situ of the cervix, as well as vulvar and vaginal cancer. All these female cancers are caused by HPV and can be successfully prevented with the HPV vaccine.

According to estimates from the Centers for Disease Control and Prevention (CDC) more than 20 million men and women in the United States are infected with HPV, and more than six million new infections are reported each year, making it the most common sexually transmitted disease in the nation.

Nearly all sexually active people are going to get exposed to the virus sometime during their lives, says Dr. Ault. For most people, HPV causes no complications and goes away on its own. However, in some cases, if left untreated, certain high-risk types of HPV can lead to cervical cancer.

The goal of the study was to see if we could prevent precancerous cases and the results of this combined analysis show near 99 percent effectiveness. Everyone who gets cancer goes through a pre-cancerous stage, says Dr. Ault. There are about 50 to 60 million pap smears performed each year in the United States, and about seven percent are abnormal. We spend about 3 billion dollars each year to find and treat these pre-cancerous stages caused by some type of HPV.

Gardasil was approved by the U.S. Food and Drug Administration last year for use in females 9 to 26 years of age. While controversy has been raised about giving pre-adolescent girls a vaccine for a sexually transmitted disease, Dr. Ault argues, young women, young girls make very good immune responses to this vaccine, so that will enhance their protection. Widespread immunization with the HPV vaccine along with continued screening will help decrease the burden of cervical cancer and other HPV-related diseases, he says.

Human antibodies protect mice from avian flu

Mon, 28 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) An international team of scientists, including researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, report using antibodies derived from immune cells from recent human survivors of H5N1 avian influenza to successfully treat H5N1-infected mice as well as protect them from an otherwise lethal dose of the virus.

The possibility of an influenza pandemic, whether sparked by H5N1 or another influenza virus to which humans have no natural immunity, is of serious concern to the global health community, says NIAID Director Anthony S. Fauci, M.D. If the success of this initial study is confirmed through further laboratory and clinical trials, human monoclonal antibodies could prove to be valuable therapeutic and prophylactic public health interventions for pandemic influenza.

The research, to be published May 29 in PLoS Medicine, represents a three-way collaboration among Kanta Subbarao, M.D., and her coworkers at NIAID; Antonio Lanzavecchia, M.D., and colleagues from the Institute for Research in Biomedicine, Bellinzona, Switzerland; and Cameron Simmons, Ph.D., from the Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

Four Vietnamese adults diagnosed with H5N1 influenza infection between January 2004 and February 2005 agreed to donate blood soon after they had recovered from their illness. In Switzerland, Dr. Lanzavecchia extracted antibody-producing white blood cells, called memory B cells, from the Vietnamese samples and treated them with a process he developed so that they rapidly and continuously produced large amounts of antibody. Next, researchers in Dr. Subbarao's lab screened 11,000 antibody-containing samples provided by the Swiss team and found a handful able to neutralize H5N1 influenza virus. Based on these results, Dr. Lanzavecchia purified the B cells and ultimately created four monoclonal antibodies (mAbs) that secrete H5N1-specific neutralizing antibodies.

Dr. Subbarao and her coworkers first tested whether the human H5N1 mAbs could protect mice from severe H5N1 infection. Groups of five mice received either of two human H5N1 mAbs at one of three dosages or human mAbs against diphtheria or anthrax. One day later, the mice were exposed through their noses to lethal doses of H5N1 influenza virus.

All the control micethose receiving non-H5N1 mAbsrapidly developed severe illness and died within a week. In contrast, all the mice that received the first H5N1 mAb testedregardless of dosesurvived, while 80 percent of mice receiving the highest dose of the second H5N1 mAb survived. Additional tests showed that mice receiving either of the two protective H5N1 mAbs had levels of virus in the lungs that were 10 to 100 times lower than those in control mice, and little or no virus moved beyond the lungs.

The investigators also tested the therapeutic potential of the human H5N1 mAbs. Using blood products from influenza survivors is an old idea, the researchers note. During the flu pandemic of 1918-19, for example, physicians took serum from recovered flu patients and gave it to new victims; recent historical research indicates that those blood transfusions, when given early in the illness, sometimes saved recipients' lives.

In their study, Dr. Subbarao and her colleagues infected groups of mice with a lethal dose of an H5N1 virus that had circulated in Vietnam in 2004. A total of 60 mice were given one of the four H5N1 mAbs at 24, 48 or 72 hours after infection while a control group received non-influenza mAbs. All the mice in the control group died within 10 days of infection, while 58 of the 60 treated mice survived. All four H5N1 mAbs conferred robust protection. Most surprisingly, says Dr. Subbarao, the survival rate was excellent even when treatment was delayed for three days.

Spurred by these results, the NIAID investigators next tested whether the H5N1 mAbs might be used to treat mice infected with a related but distinct H5N1 virus. Although the four mAbs used in the experiment originated after infection with the 2004 H5N1 virus, three of them nevertheless prevented the mice from dying when given 24 hours after they were infected with a 2005 H5N1 virus. This suggests, the researchers say, that human mAbs may provide broad protection against variant H5N1 virusesa desirable quality in any therapeutic aimed at the constantly evolving flu virus.

Taken together, the findings from this international collaboration are encouraging, says Dr. Subbarao. They show that fully human mAbs with potent H5N1 influenza virus neutralizing ability can be rapidly generated from the blood of convalescent patients and that these mAbs work well to both treat H5N1 infection and prevent death from such infection in a mouse model. The authors plan to take the research forward by scaling up the production of H5N1 mAbs and, if the technique proves safe and effective in additional animal tests, to evaluate these human mAbs in clinical trials in humans.

Vaccine hope for malaria

Wed, 23 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One person dies of it every 30 seconds, it rivals HIV and tuberculosis as the worlds most deadly infection and the vast majority of its victims are under five years old. Now, just over 100 years since Britains Sir Ronald Ross was awarded the Nobel Prize for finally proving that malaria is transmitted by mosquitoes, researchers at The University of Nottingham believe they have made a significant breakthrough in the search for an effective vaccine.

Malaria infects around 400 million people every year and kills between one and three million, mostly children.

Dr Richard Pleass, from the Institute of Genetics, said: Our results are very, very significant. We have made the best possible animal model you can get in the absence of working on humans or higher primates, as well as developing a novel therapeutic entity.

Using blood from a group of people with natural immunity to the disease, a team from the School of Biology refined and strengthened the antibodies using a new animal testing system which, for the first time, mimics in mice the way malaria infects humans. When injected into mice, these antibodies protected them against the disease.

The World Health Organisation (WHO) says malaria is a public health problem in more than 90 countries and describes it as by far the world's most important tropical parasitic disease. It kills more people than any other communicable disease except tuberculosis and more than 90 per cent of all malaria cases are in sub-Saharan Africa. According to WHO, the dream of the global eradication of malaria is beginning to fade with the growing number of cases, rapid spread of drug resistance in people and increasing insecticide resistance in mosquitoes.

Until now there has been no reliable animal model for human malaria. Mice do not get sick when infected with the blood-borne parasite that causes malaria in people. And the immune system of mice shows a different response to humans when it comes into contact with the parasite.

This meant that despite making a promising antibody vaccine that worked against the parasite in a lab dish, the team could not test it in a living animal.

In a new study published in the journal PLoS Pathogens an open access journal published by the Public Library of Science Dr Pleass and his collaborators in London, Australia and The Netherlands describe how they got around the problem by creating a mouse model of the human malaria infection. They took a closely related mouse parasite and genetically modified it to produce an antigen that the human immune system recognises.

Next, they genetically altered the mouses immune system to produce a human molecule on its white blood cells that recognises the parasite and, together with antibodies, destroys it. In trials the team showed that human antibodies given to the mice protected them from the parasite.

The team, who were funded by the Medical Research Council and the European Union, are now hoping to refine the model with a view to starting the first phase of clinical trials in humans.

Landmark study details demographic, ecological and genetic spread of rabies in raccoon outbreak

Thu, 17 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Analyzing 30 years of data detailing a large rabies virus outbreak among North American raccoons, researchers at Emory University have revealed how initial demographic, ecological and genetic processes simultaneously shaped the virus's geographic spread over time. The study appears online in the Proceedings of The National Academy of Sciences.

Our study demonstrates the combined evolutionary and population dynamic processes characterizing the spread of a pathogen after its introduction into a susceptible host population, says Leslie Real, PhD, Emory University Asa G. Candler professor of biology. During invasion, emerging pathogens, such as rabies, ebola and hantavirus, undergo rapid evolution while expanding their numbers and geographic range; yet, it is difficult to demonstrate how these processes interact, says Dr. Real.

However, this particular outbreak, which went largely unchecked until relatively recently, was unusually well documented both spatially and temporally. Data were methodically collected and stored since the outbreak began in the mid-1970s. In addition, the Centers for Disease Control and Prevention (CDC) had been stockpiling viral samples from the outbreak since 1982, giving scientists a treasure trove of genetic data ripe for analysis.

Together these data offer a rare chance to examine how the demographic and spatial processes of spread and population expansion over 30 years have shaped viral evolution on a geographic scale, says Dr. Real. Landscape features, such as rivers and mountains, can have a pronounced effect on the rate of rabies' spread and may therefore affect viral dynamics on a large scale, he says.

The study, for example, showed that because mountain ranges make for a poor raccoon habitat especially at higher elevations, raccoons did not cross the Appalachian mountain chain during the first part of the outbreak, which clearly limited the virus's westward expansion, says Dr. Real. Likewise, it was found that the Allegheny Mountains appear to have slowed the virus's expansion to the north. The study area ranged from North Carolina to Vermont, as far east as Chesapeake Bay, and westward into Tennessee and Ohio.

These results provide important insights into the geographic scale of rabies persistence and will be increasingly important in understanding the epidemiology of rabies and other emerging zoonotic diseases, those diseases that can be transmitted between animals and people, in a geographic context, says Dr. Real. We can then use these insights to predict where and when zoonotic disease outbreaks will occur so we can target surveillance and intervention, he says.

For example, in the United States, the western expansion of rabies is currently controlled through the distribution of an oral rabies vaccine stretching from Ontario, Canada, down to Alabama. But should the rabies breech this barrier, there are no natural settings to keep the virus from spreading across the entire Midwest. However, we can now model what the spread of the virus would look like and then intervene, says Dr. Real.

Although raccoons are common throughout North America, their impact as a rabies host before the 1970s was limited to the southeastern United States, particularly Florida. However, this situation changed dramatically in 1977 when a raccoon-specific rabies virus variant (RRV) was detected in West Virginia. The RRV later spread quickly along the mid-Atlantic coast, and by 1999 infiltrated thousands of square kilometers.

It is estimated that rabies causes more than 50,000 human deaths annually worldwide, and roughly $30 million is spent each year to treat patients exposed to rabies in the United States. The estimated public health costs associated with rabies detection, prevention and control exceed $300 million annually in the United States, according to the CDC. These costs include vaccination of companion animals, animal control programs, maintenance of rabies laboratories and medical costs.

The quest for an effective HIV vaccine presents new possibilities, challenges

Wed, 16 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A vaccine that prevents HIV infection remains an important goal in the fight against AIDS, but the current top HIV vaccine candidates may not work in this way, say scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Rather, the first successful preventive HIV vaccines, if administered prior to HIV infection, may reduce HIV levels in the body, thereby delaying the progression to AIDS and the need to start antiretroviral drugs. These vaccines may also reduce the chance that a person infected with HIV would pass the virus on to other people, according to NIAID Director Anthony S. Fauci, M.D., and Margaret I. Johnston, Ph.D., director of NIAIDs Vaccine Research Program in the Division of AIDS.

In a review article in the May 17 issue of the New England Journal of Medicine, Drs. Johnston and Fauci examine the daunting challenges posed by HIV, the evolution of HIV vaccine research, the role T cells may play in HIV vaccine effectiveness, and how the first successful HIV vaccine may fit into a comprehensive HIV/AIDS prevention effort.

Vaccines typically work by mimicking the effects of natural exposure to a specific microbe. Because of initial exposure, the immune system develops the ability to recognize the specific microbe and can protect the human body against it if it reappears. HIV, however, has thwarted scientists efforts thus far to develop a classic preventive vaccine for the virus because of its ability to integrate into target cells and evade clearance by the immune system. The interaction between HIV and the immune system is complex, and how different HIV-specific immune responses help to control infection is only partially understood.

The development of an HIV vaccine is a complex research challenge because the virus is unusually well-equipped to elude immune defenses, says Dr. Fauci. Much progress has been made; however, we must continue research efforts to improve our understanding of HIV and how it evades the immune system, to design new vaccine candidates and to assess the most promising ones in clinical trials.

Dr. Johnston adds, An important research challenge is to determine if these so-called T-cell vaccines that primarily induce a cellular immune response can have a beneficial effect by reducing viral levels and preserving critical cells needed to control infection. There will be a tremendous public health challenge as well, in an HIV vaccine that does not completely prevent the virus from establishing itself in the body.

Once HIV enters the body, it infects crucial CD4+ T cells, replicates, spreads throughout the body and establishes HIV reservoirs in lymphatic tissues. Within weeks of exposure, virus levels peak and then decline to levels that may remain low for months or years. It is believed that CD8+ T cells--so-called killer T-cells--are responsible for this reduction in HIV levels; however, their ability to continue to suppress the virus declines over time as the virus mutates and the immune system is progressively destroyed.

The infection of CD4+ T cells occurs very early in HIV disease, and virus persists indefinitely. Other viruses also replicate robustly but, unlike HIV, most do not establish a permanent reservoir of infected cells in the body. The window of opportunity to prevent long-term HIV infection may close permanently once a pool of latently infected cells is in place, Drs. Johnston and Fauci note. Neutralizing antibodies, which can attach to and eliminate free virus, only appear after HIV levels have declined substantially. Further, the effectiveness of these antibodies is stymied because of the rapid genetic changes that occur in HIVs outer envelope protein, which allow the virus to escape detection.

While early efforts to develop an HIV vaccine focused on the viral envelope, an improved understanding of how HIV causes disease has brought increased attention to the role that T cells could play in an HIV vaccine by spurring cellular immunity. Numerous animal and human studies have confirmed how important cellular immunity is in the early and later stages of HIV infection, even though the virus is never completely eliminated. Vaccines that induce strong cellular immune responses may have some benefits, say the authors. In non-human primate models of HIV infection, T-cell vaccines have reportedly decreased the total amount of virus produced during early infection, caused a reduction in virus levels following the acute stage of infection, or produced some combination of these effects. In many of these animals, disease progression was also delayed.

Based on the scientific evidence, several questions remain, say Drs. Johnston and Fauci: Can a vaccine that does not prevent HIV infection but reduces virus levels and preserves a segment of uninfected CD4+ T cells from destruction benefit the immunized individual Might people immunized with T-cell vaccines before HIV exposure remain disease-free for a prolonged period once they are infected

Additionally, T-cell vaccines may reduce secondary HIV transmission if they can help the immune system keep viral replication at a very low level for a long time. Studies have suggested that people with high levels of virus--namely those in the early and late stages of infection--are most likely to infect their sexual partners. A preventive vaccine given before exposure to HIV might stifle the initial burst of virus, better control virus levels and potentially reduce that persons ability to infect other people, Drs. Johnston and Fauci assert.

Vaccines of this type present several complications, however. T-cell-mediated control of HIV infection may not stave off disease forever. Additional human studies would be needed to determine if the vaccine also reduces the spread of HIV. Finally, an HIV vaccine that delays but does not completely prevent disease could not stand alone as a preventive measure; the public health community would need to include it as part of a broader HIV prevention program, so that recipients would minimize, or ideally, not engage in high-risk behaviors, according to the authors.

Currently, several vaccines that induce primarily T-cell responses are in or will soon enter expanded human clinical trials to determine if they impact HIV infection. Researchers also continue to give high priority to creating an HIV vaccine that induces broadly neutralizing antibodies, which might prevent the establishment of HIV infection. Although rare, such antibodies do exist, giving hope to scientists that a vaccine to induce such antibodies can be designed.

Drs. Johnston and Fauci conclude that a vaccine that prevents HIV infection by clearing the virus before cells become latently infected remains the goal. In addition, they believe that even a vaccine that does not prevent infection could prove beneficial if it prolongs the disease-free period and possibly even reduces virus transmission. If such a vaccine is shown to be successful and is eventually licensed, it would need to be delivered as part of a comprehensive, multifaceted HIV prevention program.

Study finds no link between autism and thimerosal in vaccines

Wed, 16 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBIA, Mo. -- The increase in the number of diagnosed cases of autism in recent years has sparked concern that environmental toxins may cause this complex disorder. However, a new University of Missouri-Columbia study concludes that exposure to Rh immune globulin preserved with mercury-containing thimerosal before birth was no higher for children with autism.

This study adds to the evidence that there is no casual association between thimerosal and childhood autism, said Judith Miles, who is the William S. Thomson Endowed Chair of Autism and professor of pediatrics and pathology in the MU School of Medicine. We conclude that there is no indication that pregnancies resulting in children with autism were more likely to be complicated by Rh immune globulin/thimerosal exposure.

The study investigated thimerosal exposure during pregnancies that resulted in the birth of a child subsequently diagnosed with autism. Although experts anticipate that autism will be the first behavioral/psychiatric disorder for which major genes will be identified, there is still fierce debate that thimerosal, a preservative commonly used in vaccines and is almost 50 percent ethylmercury, is responsible for the rise in the disorder. Rh negative women are routinely treated with Rh immune globulin (RhIg) during the third trimester to prevent hemolytic disease, in which the mothers immune system attacks fetal blood cells. Like many vaccines, RhIg manufactured in the United States contained thimerosal prior to 2001. Since young fetal brains are more susceptible to neurotoxic effects, researchers led by Miles, of the MU Thompson Center for Autism and Neurodevelopmental Disorders, assessed Rh status and thimerosal exposure of mothers of children with autism.

The study included 214 mothers of 230 children diagnosed with an autism spectrum disorder. Rh status, RhIg with thimerosal exposure and Rh incompatibility (in which the mothers Rh status is different than the fetuss) were established by reviewing medical records. The results showed that in children with autism, Rh negative status was no higher in their mothers than in the general population, that exposure to RhIg (preserved with thimerosal) before birth was no higher and that pregnancies were not more likely to be Rh incompatible.

We hope this report of no association between autism, Rh negativity and thimerosal exposure during pregnancy will offset some of the decreased compliance with immunization recommendations which is known to increase morbidity and mortality from childhood infectious diseases, Miles said.

Autism diagnoses have increased significantly during the past two decades, which coincides temporally with the addition of five pediatric vaccines to the immunization schedule, exposing children to increasing doses of ethylmercury, a known toxin. Though the vast majority of studies indicate no association between vaccines and autism, the FDA, CDC and American Academy of Pediatrics recommended that thimerosal be removed from all routinely recommended early childhood vaccines; this was accomplished by 2002.

Miles points out that even though RhIg and childhood vaccines are now free of thimerosal in the United States, it is important to analyze questions of safety since thimerosal continues to be used in many places around the world to preserve vaccines to help make them affordable.

Miles said that few studies have focused on pregnancies of Rh negative mothers who received RhIg during pregnancy, probably because the thimerosal is diluted before reaching the fetus and has been assumed to be innocuous. Nevertheless, there is a concern that even very small doses delivered when the brain is especially sensitive can be toxic. Numerous Internet sites and one research study assert that RhIg causes autism and that a high percentage of mothers of children with autism are Rh negative, neither of which was shown to be true in the current study. In addition, a recent study hypothesized that Rh incompatibility itself could disrupt fetal neurodevelopment, thus playing a role in autism, but the current study found no increase in the proportion of Rh incompatibility in mothers of autistic children. In response to the claim that only certain groups of children are at risk, the authors also analyzed specific autism spectrum disorder subgroups and found that none had significant increases in either Rh negativity or thimerosal exposure during pregnancy.

The study Lack of Association Between Rh Status, Rh Immune Globulin in Pregnancy and Autism was published in the May 2007 issue of the American Journal of Medical Genetics.

Herpes infection may be symbiotic, help beat back some bacteria

Wed, 16 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Mice with chronic herpes virus infections can better resist the bacterium that causes plague and a bacterium that causes one kind of food poisoning, researchers report in this week's Nature.

Scientists at Washington University School of Medicine in St. Louis attributed the surprising finding to changes in the immune system triggered by the long-term presence of a latent herpes virus infection. In latent viral infections, the virus is present for the lifetime of the host in a relatively quiescent form that does not cause overt symptoms.

While presenting their results, researchers stressed that they did not want to minimize or in any way disregard the human suffering and health risks caused by disease-causing herpes infections. But they noted that several strains of herpes viruses found in much of the human population remain symptom-free throughout the host's lifetime.

Our results suggest that we should look at whether humans receive similar advantages from these and other chronic infections that do not cause active disease, says senior author Herbert W. Skip Virgin, M.D., Ph.D., head of the Department of Pathology and Immunology. If so, that has public health implications because we would want to very carefully weigh the risks and benefits of eliminating a virus that our bodies have established a symbiotic relationship with.

Scientists previously used vaccination to eliminate the deadly and highly contagious smallpox virus. Vaccines are currently in use or in clinical trials for several disease-causing strains of herpes.

Human herpes viruses include oral and genital herpes, the chickenpox virus, cytomegalovirus, Epstein-Barr virus and Kaposi's sarcoma-associated herpes virus. During an initial period of acute infection, many of these viruses cause symptoms, such as fever, cold sores or blisters. They then enter periods of latency. Sometimes symptoms never recur; sometimes they flare up periodically before becoming quiescent again. In addition, less infamous herpes viruses like HHV6 and HHV7 permanently infect most humans without ever producing any significant symptoms.

The results have potentially wide-reaching implications for immune research. Humans and other mammals have spent millions of years living and evolving with latent viral infections, Virgin notes, and the new results imply that infections may have altered our immune systems at a fundamental level. This could mean the virus-free animal models scientists use to study vaccines, autoimmune diseases, and other immune system issues have the potential to produce misleading results.

Chronic virus infections may in part define what a normal human immune response is, says Virgin, who is the Edward Mallinckrodt Professor of Pathology and Immunology. We may need to think about that as we consider the implications animal model results hold for human diseases.

Scientists have recognized for years that many types of bacteria and other microorganisms live in the human gut to the advantage of both the microbes and their human hosts. The results from the Virgin lab are among the first to suggest the potential for symbiotic benefits from viral infections that live in areas beyond epithelial surfaces like the skin, throat or intestines.

For the new research, Virgin's group worked with strains of mouse herpes virus closely related to human Epstein-Barr virus, Kaposi's sarcoma-associated herpes virus and cytomegalovirus. During studies of how mouse herpes viruses transition from acute to latent infections, Virgin made a discovery that piqued his interest in the possibility that latent infections might confer unrecognized benefits.

We found evidence that the mouse immune system controls latent herpes infections in part by increasing production of a protein hormone called interferon gamma, Virgin says. This is a signaling hormone that in effect puts some immune system soldiers on yellow alert, causing them to patrol for invaders with their eyes wide open and defense weapons ready.

Other scientists previously had shown that interferon gamma helps the immune system fight off some strains of bacteria. This led Virgin and his colleagues to test herpes-infected mice with exposure to the bacteria Yersinia pestis, which causes plague, and Listeria monocytogenes, which is a minor cause of food poisoning and can infect the central nervous system. Many aspects of Listeria infection in mice are also similar to those that occur in humans infected with tuberculsis. They found that when mice had a latent herpes infection, the bacteria replicated more slowly and were less likely to kill the mice.

When herpes was still in the acute phase of infection, no protective effect was present. When scientists exposed the mice to a mutant herpes virus that can infect but cannot establish latency, the herpes infection did not confer resistance. The protective effect could be produced by two different mouse herpes viruses.

We have a good feel for who the main players are in this protective effect, but we need further research to better understand the exact mechanisms that underlie the process, Virgin says.

He suspects that the virus may be prompting the immune system to produce more interferon gamma to keep itself from emerging from latency. If the virus stays latent, it prevents itself from seriously endangering the host and can continue to spread to new hosts from its current perch.

We need to explore whether there are additional costs and benefits to the host from this, Virgin says. Are there additional pathogens that find it harder to come in as a secondary infection after herpes becomes latent Do other latent infections convey similar protective effects These are not the kinds of questions we're accustomed to asking about such infections, but our findings suggest that we need to start.

Virgin notes that human and mouse herpes viruses are genetically very closely related. The similarity strongly suggests that modern herpes viruses are likely descended from herpes viruses that infected evolutionary ancestors common to both mice and humans.

That means that for as long as we've been human, these viruses have been with us, he says. In that respectgiven the millions and millions of years that mammalian immune systems have had to adapt to these virusesperhaps these results are not as surprising as they might seem at first.

Getting to the core of an emergent public health threat

Tue, 15 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The outbreak of severe acute respiratory syndrome (SARS) in 2002 was a loud wake-up call for researchers studying infectious diseases. SARS infected over 8,000 people, killed 10 percent of those infected, and weakened most with pneumonia.

The SARS outbreak was a strong reminder that new viruses can emerge, and whether new or old, pathogens can cause not only significant disease and death, but they can also have a global socioeconomic impact, said Brenda Hogue, an associate professor in the Biodesign Institutes Center for Infectious Diseases and Vaccinology and School of Life Sciences. Hogue has been involved in a big push to uncover some of the key clues behind coronavirus illness.

When SARS emerged, no one could have predicted that a new coronavirus, usually the culprit of nothing more than a common cold in humans, could become so harmful and spread so quickly through health systems from China to Canada.

Coronaviruses routinely cause about 30 percent of the common colds in humans, and infect a large number of animals where they cause significantly more severe diseases.

We expect that some of what we learn about coronaviruses will no doubt be applicable to other viruses too, Hogue said. Our long-term goals are to make use of this basic research to design better vaccines and develop new targets for antiviral treatments.

One of the well known characteristics of viruses is their uncanny ability to hijack the resources of its host. What made SARS such an alarming threat was that the symptoms were much more severe than had been seen before in human coronavirus infections. Even though the SARS virus has not reappeared in humans since the 2003 outbreak, Hogue remains cautious. Epidemiologists and those of us who work with these viruses think that it will reappear, she said.

As with other emergent threats, Hogue said that the outbreak of the SARS virus in Asia was linked to animals that live close to humans, including bats and cat-like animals called civets. So, while SARS may have been mitigated for now, Hogue and researchers hope that their efforts studying the basic science behind viral infection will apply to a variety of diseases, including the looming specter of pandemic flu.

Hogue and her Biodesign Institute colleagues have produced several insights into coronavirus biology that may also help pinpoint future weaknesses in the viral armament. In a recent paper published in the Journal of Virology (March 2007), Mouse Hepatitis Coronavirus A59 Nucleocapsid Protein Is a Type I Interferon Antagonist, lead authors Ye Ye and Kevin Hauns, graduate students in the Center for Infectious Diseases and Vaccinology, discovered a viral protein that may allow the virus to evade the immune system.

The suspected molecular cause is a nucleocapsid protein, whose primary role is to help assemble the viral genome into the virus particle that can readily infect the body. The nucleocapsid protein has been found to circumvent type I interferons, natural proteins that help mount the bodys initial immune response against viruses.

Hogue and colleagues plan to focus their efforts on determining how the coronavirus nucleocapsid protein is able to act as an interferon antagonist, and will also continue to look for other viral proteins that may act as immune response antagonists. Based on what we know about the nucleocapsid protein and how it interferes, there must be at least one other virus protein acting as an antagonist, Hogue said.

Coronaviruses invade cells in the human body like spiny cockleburs by first attaching to cells with their spike proteins that stick out from the viral envelope. The spikes not only help cause infection, but appear under the microscope as a halo or crown around the coat that gives coronaviruses their name. After it attaches, the virus then enters the cell and quickly uses the cells machinery to make copies of itself to spread an infection.

Hogue is collaborating with Zhong Huang, an assistant research professor also in Biodesigns Center for Infectious Diseases and Vaccinology, to express parts of the spike protein in plants. The scientists hope to develop a vaccine that can block the interaction of the spike protein with the host receptor and consequently prevent infection.

Another important viral target of Hogues research is the role of the coronavirus envelope protein (E protein), described in Role of the Coronavirus E Viroporin Protein Transmembrane Domain in Virus Assembly, Journal of Virology (April 2007). By creating mutants of the E protein in a mouse coronavirus model that infects the liver and other organs, Ye and Hogue found that the virus lost some of its ability to assemble and be released from cells.

Proteins similar to the E protein that can form channels in membranes are present in other viruses too, which would make the development of an antiviral that blocks the function of the E protein potentially applicable to a wide variety of diseases, Hogue said.

Teasing apart the cycle of coronavirus infection has helped Hogues group identify new molecular targets and provided some exciting avenues to pursue. By continuing their fundamental research on viruses, the Biodesign team hopes to refine their understanding of virus-host interactions. Our basic research is an essential foundation for translational research directed at dealing with the diseases caused by these viruses, Hogue said.

Students devise oral quick-dissolve strips for rotavirus vaccine

Mon, 14 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A thin strip that dissolves in the mouth like a popular breath-freshener could someday provide life-saving rotavirus vaccine to infants in impoverished areas. The innovative drug-delivery system was developed by Johns Hopkins undergraduate biomedical engineering students.

During a two-semester course, the seven-student team fabricated a thin film that should melt quickly in a babys mouth, prompting the child to swallow the vaccine. The dissolved medication is coated with a material to protect it in the childs stomach. This coating is also designed to release the vaccine in the small intestine, where it should trigger an immune response to prevent a rotavirus infection.

The novel drug-delivery system is needed because rotavirus is a common cause of severe diarrhea and vomiting in children, leading to about 600,000 deaths annually. Most of these occur in developing nations, where medical services to treat intestinal distress are not widely available. Rotavirus vaccine to prevent this illness is currently produced in a liquid or freeze-dried form that must be chilled for transport and storage, making it very expensive for use in impoverished areas. In addition, newborns sometimes spit out the liquid, a problem that is less likely to occur with a strip that sticks to and dissolves on the tongue in less than a minute.

To address the drawbacks of the liquid vaccine, the Johns Hopkins students developed a thin film delivery system that would be easy to store and transport and would not require refrigeration. Although further refinement is needed to maintain the viability of the vaccine, the delivery system itself appears sound, and the Johns Hopkins Technology Transfer staff has applied for a provisional patent. The thin film vaccine system was among the undergraduate projects introduced to the public this month at the universitys annual Biomedical Engineering Design Day showcase.

The idea is that you would place one of these dissolving strips on the infants tongue, said Hai-Quan Mao, the teams Johns Hopkins faculty advisor. Because the strips are in a solid form, they would cost much less to store and transport than the liquid vaccine. We wanted this to be as simple and as inexpensive as possible.

The idea originated last year at Aridis Pharmaceuticals, a San Jose, Calif., firm that possesses vaccine stabilization technologies and a rotavirus vaccine that is made stable at room temperatures. Seeking a product resembling breath-freshening strips to deliver the vaccine, Vu Truong, cofounder and chief scientific officer at Aridis, contacted Mao. Truong earned a doctorate in pharmacology and molecular science from the Johns Hopkins School of Medicine and knew of Maos expertise in biomaterials. Mao, an assistant professor of materials science and engineering in the university's Whiting School of Engineering, described the vaccine challenge to one of his undergraduate lab assistants, senior Christopher Yu, who became co-leader of the team that tackled the project.

Initially, the students confronted several obstacles. They were unable to copy the manufacturing process used to make breath strips because the harsh solvent and high temperatures used would destroy the vaccine. They also had to devise a protective coating that would remain intact when exposed to stomach acid but would dissolve in the chemically neutral environment of the small intestine.

Through extensive research and testing, the students solved these problems. They refined a room-temperature production and drying process to make the strips and identified an FDA-approved biocompatible polymer coating that would protect the vaccine from stomach acid but release the medicine in the small intestine. The coating is pH-responsive, meaning it delivers its medical payload only when the acid-alkaline level in its environment is appropriate.

What the students have accomplished is a way to incorporate a pH-responsive polymer system that works with an oral quick-dissolving thin film, Truong said. Its still very early in the process, but the pieces theyve come up with have been very encouraging. We have the delivery vehicle prototype. Im optimistic that we can make this work with our vaccine.

Truong added, I was pleasantly surprised. Professor Mao entrusted this project to some cream-of-the-crop students. They have delivered the kind of results that even seasoned professionals might not have delivered.

Truong said his company is in talks to fund further research in Maos lab to refine the strips so that they can dispense the Aridis rotavirus vaccine. Animal testing could begin later this year, he said. This is probably the second-most important childhood vaccine needed in the developing world, right behind a malaria vaccine, he said. The mortality rate is high.

The student inventors are pleased about the potential public health benefits. They also found the hands-on assignment to be a valuable part of their engineering education. This was a really good experience, said Yu, the student co-team leader. When you run into problems in a project like this, you have to think hard about how to solve them or work around them. Its much more rewarding than a basic textbook problem, where theres an expected answer and you dont necessarily have to think as broadly or as creatively.

Dealing deadly cancers a knockout punch

Thu, 10 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) New scientific evidence is helping to build a compelling case for oncolytic viruses as a first-line and adjunctive treatment for many cancers.

Reovirus, a non-pathogenic virus under development at Calgary, Alberta-based Oncolytics Biotech, has shown powerful anti-cancer activity against cultured tumor cells, in animal models, and in human clinical trials. Oncolytics' proprietary reovirus formulation, Reolysin®, is active against numerous cancers, including intractable sarcomas and melanomas.

Recent studies also indicate that Reolysin works synergistically with standard anti-cancer drugs, providing significantly stronger responses than either agent alone.

In addition, other studies completed in the past year have shown Reolysin has the ability to prime patients' immune systems against their particular cancer, leading to additional cancer cell killing. It is through this second inflammatory mechanism that researchers hope Reolysin will bring about long-term remissions of once-untreatable cancers.

At the Fourth International Conference on Oncolytic Viruses as Cancer Therapeutics in March 2007 in Scottsdale, Arizona, several presentations focused on reovirus efficacy alone or in combination with standard chemotherapies.

In one study, investigators examined the tumor-killing ability of reovirus plus cisplatin, a standard chemotherapy agent, in a mouse melanoma model that included both cultured cells and live animals. The results of the preclinical study showed that the combination of reovirus and cisplatin was significantly more effective than cisplatin or reovirus alone at killing melanoma cancer cells in a mouse model. The investigators intend to explore the mechanism of this promising synergistic action in further detail in future preclinical work.

Another presentation at the Arizona conference reported on the use of Reolysin plus the cancer drug cyclophosphamide in an animal model of melanoma. When treated with both agents, test animals experienced enhanced tumor regression compared with either agent alone, and without additional toxicity. Oncolytics has permission from the U.K. regulatory authorities to test Reolysin in three separate human trials in combination with the cancer drugs gemcitabine, paclitaxel/carboplatin and docetaxel.

Perhaps the most exciting findings of Reolysin combination therapy were reported at the American Association for Cancer Research Annual Meeting in April, 2007. In mice transplanted with a human colon cancer, Reolysin plus gemcitabine completely eradicated the tumors in four of five test animals. It is rare to see the virtual elimination of tumours as well as the long-lasting therapeutic effect that was observed in this study.

Combination therapy results for reovirus in animals are particularly encouraging because they suggest that Reolysin can improve the anti-tumor activity of standard chemotherapy agents in advanced cancer patients without causing additional toxicity, said Dr. Karl Mettinger, Chief Medical Officer of Oncolytics.

Physicians often prefer to treat cancer with multiple agents, but toxicity limits these approaches. Since reovirus typically is not pathogenic in humans nor associated with severe toxicity in clinical studies, its co-administration is not expected to increase a treatment's overall toxicity.

Study shows continued success for new HPV vaccine against virus responsible for cervical cancer

Wed, 09 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new vaccine aimed at preventing cervical cancer is nearly 100 percent effective against the two types of the human papillomavirus (HPV) responsible for most cases of cervical cancer. Results of a nationwide study of the vaccine will be published in the May 9 issue of the New England Journal of Medicine.

Cervical cancer is the second most common cause of cancer deaths in women worldwide, resulting in nearly half a million diagnoses and 240,000 deaths each year. Every day in the United States ten women die from cervical cancer, according to Kevin Ault MD, associate professor of obstetrics and gynecology at Emory University School of Medicine, and one of the study authors.

But for the next generation of young women, a series of three shots of a new HPV vaccine marketed by Merck under the name Gardasil could make the difference in preventing cervical cancer. The vaccine targets HPV types 16 and 18, which cause about 70 percent of all cases of cervical cancer. It also targets HPV types 6 and 11, which together cause about 90 percent of all cases of genital warts.

Researchers at more than a dozen international medical centers evaluated the efficacy of quadrivalent vaccine targeting HPV types 6, 11, 16, 18 in more than 12,000 women ages 15 to 26 in 13 countries for nearly three years. They found a near 100 percent efficacy rate in prevention of HPV types 16 and 18.

It's the first vaccine designed specifically to prevent cancer, says Dr. Ault, one of the authors of the study and a key researcher in the development of the vaccine. The two main things to emphasize are the vaccine efficacy and the safety. These clinical trials have consistent efficacy around 98 percent. And severe reactions to the vaccine appear to be rare.

According to estimates from the Centers for Disease Control and Prevention (CDC) more than 20 million men and women in the US are infected with HPV, and more than six million new infections are reported each year, making it the most common sexually transmitted disease in the nation.

Nearly all sexually active people are going to get exposed to the virus sometime during their lives, says Dr. Ault. For most people, HPV causes no complications and goes away on its own. However, in some cases, if left untreated, certain high-risk types of HPV can lead to cervical cancer.

The goal of the study was to see if we could prevent precancerous cases and we were 98 percent effective. Everyone who gets cancer goes through a pre-cancerous stage, says Ault. There are about 50 to 60 million pap smears performed each year in the US, and about seven percent are abnormal. We spend about 3 billion dollars each year to find and treat these pre-cancerous stages caused by some type of HPV.

To date there is no vaccine specifically designed to treat disease that is already established. Dr. Ault explains the current HPV vaccine is meant to be a preventive or prophylactic vaccine Ð that's why it is given to adolescents.

Gardasil was approved by the U.S. Food and Drug Administration last year for use in females 9 to 26 years of age. While controversy has been raised about giving pre-adolescent girls a vaccine for a sexually transmitted disease, Dr. Ault argues, young women, young girls make very good immune responses to this vaccine, so that will enhance their protection.

Researchers believe the vaccine will be effective in lowering a girl's lifetime risk of cervical cancer. To that end Merck launched the national One Less campaign last year, which encourages females eligible for the vaccine to begin their vaccination series of three shots over six months and to continue seeing their doctor for regular checkups and screenings.

Health officials renew Indo-US Vaccine Action Program

Tue, 08 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) U.S. and Indian health officials have renewed the Indo-U.S. Vaccine Action Program (VAP), a 20-year-old bilateral collaboration supporting research on vaccines, immunology and related biomedical issues. The VAP aims to reduce the burden of vaccine-preventable diseases of public health significance in India, the United States and other parts of the world, and to promote vaccines as one of the most cost-effective health technologies.

National Institutes of Health (NIH) Director Elias A. Zerhouni, M.D., and Secretary of the Department of Biotechnology in India, Maharaj K. Bhan, M.D., signed the Joint Statement on May 3, 2007, renewing this historic program for another five-year period.

The Indo-U.S. Vaccine Action Program continues to demonstrate that international cooperation focused on outstanding research and the development of critically important public health tools can save millions of lives, says Dr. Zerhouni. The U.S. government remains steadfast in its commitment to this program and its scientific vision.

Dr. Bhan, a former VAP grantee who currently oversees the government department that implements the program, says that the VAP has been one of Indias most important and successful international scientific collaborations since the program began in 1987. A total of 35 collaborative research projects have been funded over the last two decades, and many talented young scientists have been trained through relationships fostered by this program, he notes.

VAPs research priorities include acute respiratory illnesses, hepatitis, rotavirus diarrhea, cholera, leishmaniasis, typhoid, rabies, HIV/AIDS, tuberculosis, malaria and emerging and re-emerging infectious diseases.

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), and Roger Glass M.D., Ph.D., NIH associate director for international research and director, Fogarty International Center, also attended the event and welcomed continuation of the program. On behalf of the U.S. government, NIAID manages the VAP and has provided scientific guidance since its inception.

The widespread use of existing vaccines and the development of new vaccines are essential as we confront vaccine-preventable diseases globally, says Dr. Fauci.

Based on the success of VAP, several other NIH institutes and another agency of the U.S. Department of Health and Human Services, the Centers for Disease Control and Prevention, have signed similar bilateral agreements with the government of India.

These collaborations clearly benefit both countries and the global biomedical and public health research community more broadly, notes Dr. Glass.

Many VAP-supported research projects have directly addressed critical health problems. Rotavirus is responsible for about 20 percent of diarrhea-related hospitalizations and 100,000 deaths in India each year. With VAP funding, Indian and American scientists discovered novel strains of rotavirus in Indian newborns. Further research confirmed that when these strains are used as a basis for candidate vaccines, the vaccines might protect against the disease. Drs. Bhan and Glass developed the candidate vaccine, which is being tested in large-scale clinical trials in India.

Other successful collaborations include the development of a new hepatitis C diagnostic test for Indian patients. As a demonstration of the programs commitment to move from discovery to public health impact, VAP also will assist the commercial development of these diagnostic measures. This is especially important because currently available diagnostic methods that are reasonably effective in the United States have shown low specificity in India.

Recently, three VAP scientific missions to India discussed cooperation on HIV/AIDS, rabies and malaria. Since rabid animal bites and rabies-related human deaths are common in India, U.S. experts helped review the status of rabies prevention and recommended actions that might reduce the number of people who die. Efforts also are under way to develop collaboration on malaria vaccine research.

Smallpox outbreak: How long would it take for vaccines to protect people? Would it work?

Mon, 30 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) ST. LOUIS -- In the event of a smallpox outbreak in the United States, how long would it take for a vaccinSLU scientist leads national studye to start protecting Americans by stimulating an immune response?

A new national study led by Saint Louis University School of Medicine will attempt to answer this question.

General routine vaccinations for smallpox were stopped in the United States in 1971, and the world was declared free of smallpox in 1980. But because of the recent concern about biowarfare and bioterrorism throughout the world, the U.S. government is making efforts to improve its ability to protect its citizens in the event of a bioterrorist attack involving the smallpox virus (Variola major virus).

This study at Saint Louis University will look at the ability of an investigational vaccine made by Bavarian Nordic to stimulate the immune system against smallpox.

Vaccines prevent disease by giving the body a jump-start at recognizing the infecting virus or bacteria, said Sharon Frey, M.D., the principal investigator for the study at Saint Louis University. After successful vaccination, the body experiences a quicker fighting response to the infection, which lessens or completely avoids the symptoms of illness.

Unlike some other diseases, getting vaccinated following exposure to smallpox could provide protective effects. For example, for the flu vaccine to work, people need to get vaccinated before being exposed to influenza. The currently licensed smallpox vaccine, however, provides benefits post-exposure, and may be useful in further preventing the spread of the disease.

If there were a release of the smallpox virus, we would vaccinate people immediately after the release, Frey said. We'd move in and vaccinate people to prevent the spread.

Frey said this research compares the ability of a new investigational smallpox vaccine called IMVAMUNE® to produce a strong immune response against smallpox disease with another vaccine called Dryvax®, the currently licensed vaccine. The new vaccine will be given either alone or in combination with Dryvax.

Another purpose of the study is to see how quickly people can be protected against smallpox after a release of smallpox into the environment, Frey said.

Dryvax® vaccine is the original Food and Drug Administration (FDA) licensed vaccine that was used to protect humans against smallpox disease. In this study, the Dryvax® vaccine is being used as a research vaccine because its use in this study is different than the FDA approved current recommended use of this licensed vaccine.

The Dryvax® vaccine is made from a live virus called vaccinia. The only people who presently receive this vaccine are people who work with viruses associated the risk of similar pox diseases; these are called by names like vaccinia, orthopox and monkeypox virus. (This group includes some government employees, some emergency workers military personnel and researchers).

Increase seen in pneumococcal infections not covered by childhood vaccine

Tue, 24 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Alaska Native children are experiencing increased rates of serious infections caused by strains of pneumococcal bacteria that are not covered by the current childhood pneumococcal vaccine, indicating the importance of ongoing surveillance of vaccine effectiveness, according to a study in the April 25 issue of JAMA.

Before introduction of 7-valent pneumococcal conjugate vaccine (PCV7), Alaska Native children and adults experienced high rates of invasive pneumococcal disease (IPD) compared with nonNative Alaskans. Introduction of PCV7 into the routine childhood vaccination schedule in 2001 resulted in decreases in vaccine-type IPD and consequent decreases in all IPD among U.S. children, according to background information in the article. With the introduction of PCV7, one concern has been the potential for nonvaccine serotypes to emerge and diminish the disease prevention gains made through the use of PCV7.

Rosalyn J. Singleton, M.D., M.P.H., of the Centers for Disease Control and Prevention, Anchorage, and colleagues evaluated IPD in Alaska children for evidence of the emergence of nonvaccine serotype disease. The researchers conducted a statewide population-based laboratory surveillance of invasive Streptococcus pneumoniae infections (such as pneumonia, meningitis, or bacteremia [bacteria in the blood stream]) from January 1, 1995, through December 31, 2006.

The authors found that in the three years after introduction of PCV7 (2001-2003), IPD decreased 67 percent among Alaska Native children younger than 2 years and 61 percent in nonNative Alaska children in the same age group. Between 2001-2003 and 2004-2006, IPD rates did not change for nonNative Alaska children younger than 2 years but increased 82 percent among Alaska Native children so that the overall IPD reduction in these children was only 39 percent during 2004-2006 compared to before vaccine introduction. Since 2004, the invasive pneumococcal disease rate caused by nonvaccine serotypes has increased 140 percent compared with the prevaccine period (from 95.1 per 100,000 in 1995-2000 to 228.6 in 2004-2006). During the same period, there was a 96 percent decrease in heptavalent vaccine serotype disease.

The rapid success of PCV7 in Alaska has led to the near elimination of PCV7-serotype disease and elimination of a health disparity for types covered by the vaccine. However, for Alaska Native children there now exists a substantially elevated risk for IPD from serotypes not contained in PCV7. The demonstration of replacement IPD in Alaska Native children may signify a limit to the usefulness of the currently available vaccine and emphasizes the importance of development of extended valency vaccines or vaccines not dependent on serotype-specific prevention. These data also highlight the value of continued surveillance and other epidemiological investigations to monitor the effects of pneumococcal vaccines, the authors conclude.

(JAMA. 2007;297:1784-1792. Available pre-embargo to the media at

New research shows that flu is a trigger of heart attacks

Tue, 17 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Doctors need to take concerted action to ensure that people who are at risk of heart disease receive the influenza vaccine every autumn, according to the authors of a new report published today (Wednesday 18 April) in the European Heart Journal. Their research shows that influenza epidemics are associated with a rise in deaths from heart disease and that flu can actually trigger the heart attacks that result in death.

However, only about 60% of people in the USA who ought to have a flu jab actually have one and this percentage is even smaller in Europe, said Professor Mohammad Madjid, the lead author of the report.

Our research has shown that influenza epidemics are associated with a rise in coronary deaths. This calls for more intensive efforts to increase the vaccination rate in people at risk of coronary heart disease. This may be especially important in an influenza pandemic when we would expect to see high mortality amongst the elderly and those suffering from heart problems or who have multiple coronary risk factors, he said. Between 10 and 20% of people catch flu every year, and I have estimated that we can prevent up to 90,000 coronary deaths a year in the USA if every high risk patient received an annual flu vaccination.

Prof Madjid, who is assistant professor of medicine at the University of Texas-Houston, and a senior research scientist at the Texas Heart Institute in Houston, USA, worked with colleagues in the US and in St Petersburg in the Russian Federation to investigate deaths between 1993 and 2000 in St Petersburg that had been shown by autopsy reports to be due to coronary heart disease.

This was a population where only a small minority were receiving flu vaccines or statin drugs, so this enabled us to see what happened naturally in the absence of these medicines, said Prof Madjid. Relying on autopsy reports rather than death certificates enabled us to be much more accurate about the cause of death, because doctors often neglect to list flu on a death certificate if their patients have died from a heart attack and, conversely, heart attack symptoms can be missed in patients suffering from flu and pneumonia.

They found that 11,892 people died from acute myocardial infarction (AMI) (47.8% men and 52.2% women), and 23,000 died from chronic ischaemic heart disease (IHD) (40.1% men and 59.9% women). The peaks in deaths from both AMI and IHD coincided with the times when influenza epidemics and acute respiratory disease (ARD), which often accompanies flu, were at their height. They found that the chances of dying from AMI increased by a third in epidemic weeks, compared to non-epidemic weeks, and the chances of dying from IHD increased by a tenth. This was the same for both men and women and in different age groups.

Researchers believe that flu causes an acute and severe inflammation in the body, which, in some patients, can destabilise atherosclerotic plaques [2] in coronary arteries and cause heart attacks.

Prof Madjid said: Most people develop atherosclerotic lesions in their coronary arteries in early childhood and these lesions grow over time. Inflammation plays a pivotal role in development and growth of these lesions. Most people in Western countries live with different stages of atherosclerosis and many will never show any clinical manifestations of the atherosclerosis. However, in some patients the quiescent, stable atherosclerotic plaques undergo sudden changes, mainly due to exaggerated inflammation, leading to rupture of these vulnerable plaques and subsequent formation of clots resulting in heart attacks.

This study shows that flu is an important trigger of heart attacks because flu is a severe infection, with high incidence rates and is readily preventable. Therefore, our results give us a new tool for preventing heart attacks.

My public health message is that flu is an important killer in cardiac patients. If people can recognise that the flu vaccine has specific cardioprotective effects, then high-risk people will be more likely to make sure that they receive the influenza vaccine every year. We know from our other research that one in three people with heart disease do not consider themselves at high risk for heart-related complications from influenza and therefore do not receive the annual flu shots. Currently, people are not practising as we preach, and doctors need to work to change this.

He urged the European Society of Cardiology to follow the lead set in the USA by the American Heart Association and American College of Cardiology and recommend that all at-risk people should be given flu vaccines. The vaccine may be even more beneficial for those from deprived socio-economic groups or under-developed countries who are not taking all the recommended cardioprotective medications due to their high cost or lack of access to proper medical care. In contrast, the flu vaccine is inexpensive, easy to administer and could save thousands of lives every year.

Prof Madjid who directs a research lab dedicated to the effect of flu on the cardiovascular system pointed out that the implications of the research were even more important with a looming flu pandemic when a much higher percentage of the population could be expected to catch the illness.

In the majority of influenza epidemics (except for the 1918 Spanish flu pandemic) cardiovascular deaths surpassed any other causes of mortality, including pneumonia. During influenza pandemics, heart disease patients may be considered among the priority groups to receive the vaccine or antiviral drugs. Meticulous use of plaque-stabilising agents such as statins, beta-blockers, aspirin and angiotensin-converting enzyme inhibitors should offer additional protection during an influenza outbreak, he said.

Prof Madjid said that a number of new vaccines were being developed against avian flu virus (the most likely cause of the next flu pandemic), In addition, we are rapidly stockpiling antiviral drugs (such as Tamiflu), so I think we are likely to have the means of preventing or combating the virus, if nature doesnt take us by surprise this year, he concluded.

Promising Flu Vaccine from Insects

Sat, 14 Apr 2007 11:39:34 PST

EXPERIMENTAL FLU VACCINE APPEARS PROMISING IN EARLY TESTS

âThe use of recombinant DNA techniques to express proteins in cell culture has been a successful approach for generation of highly effective vaccines for the prevention of hepatitis B virus and human papillomavirus. Among the available expression technologies, recombinant baculovirus is especially well suited for production of influenza vaccine because the rapidity with which genes can be cloned and inserted into this vector facilitates updating the vaccine at regular intervals.

In addition, the extraordinarily high yields of protein possible in this system provide the opportunity to use much higher and potentially more effective doses of vaccine. Expression of the HA protein in insect cells using recombinant baculovirus also avoids the need to work with potentially pathogenic live influenza viruses and the attendant biocontainment issues that would be a particular concern for generation of pandemic vaccines. The preliminary demonstration of protective efficacy in adults provides further support for the development of this promising approach for prevention of seasonal and pandemic influenza,â the authors conclude.

LSU professors monkey around with the Rhesus Macaque genome

Thu, 12 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) BATON ROUGE -- Since the 2001 launch of the Human Genome Project, which released a first draft of the entire sequence of human DNA, many researchers have dedicated themselves to creating a library of comprehensive, species-specific genetic sequence maps available for study. Scientists at LSU recently took part in the International Rhesus Macaque Sequence and Analysis Consortium, which successfully detailed the full DNA sequence of the rhesus macaque, the third primate including humans to undergo sequencing. The results will be published in the journal Science on Friday, April 13.

The rhesus macaque, a primate species that had a common ancestor with humans and chimps but diverged from the human-chimp lineage approximately 25 million years ago, still shares about 93 percent of its genome sequence with humans. This makes the macaque an integral part of primate evolutionary studies and could allow researchers to gain a better understanding of HIV/AIDS in humans.

Mapping the macaque genome is a significant achievement for many reasons, said Mark Batzer, Andrew C. Pereboom Alumni Departmental Professor of Biological Sciences at LSU and leader of two of the sequence analysis units of the consortium. It provides additional insight into the pathways involved in the infection and spread of pathogens in primates, which could potentially lead to the development of new and improved treatment options, vaccines and other preventative measures in humans.

Mobile elements, an integral part of this study and one of Batzers specialties, are selfish DNA sequences that duplicate themselves many times and integrate throughout the genomes in which they reside. These elements exist at copy numbers of 100,000 elements or more, make up about 50 percent of primate genomes and were generally thought to have no function. However, these elements have an impact on genome structure and are even involved in shaping genomes. Mobile elements have also been shown to cause many diseases in humans such as breast cancer, familial hypercholesterolemia and Tay-Sachs and can also be involved in the creation of new genes and gene families. As a consequence, the impact of mobile elements on genomes in general, and on primate genomes in particular, is multifaceted.

Genetic and physiological similarities with humans make rhesus macaques the most commonly used nonhuman primate in biomedical research. Their response to infectious diseases such as SIV, or simian immunodeficiency virus, is similar enough to the human reaction to HIV, or human immunodeficiency virus, that these primates serve as a dominant model for disease studies and vaccine development. Because of this, access to the complete macaque sequence offers scientists even more in-depth research avenues into current and pressing health issues affecting society today.

Experimental flu vaccine appears promising in early tests

Tue, 10 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) An influenza vaccine produced with the use of insect cells appeared safe and produced an immunogenic response in healthy adults, suggesting promise as an alternative to using embryonated eggs for the development of influenza vaccine, according to a preliminary study in the April 11 issue of JAMA.

All currently licensed influenza vaccines in the United States are produced in embryonated hen's eggs. There are several well-recognized disadvantages to the use of eggs as the substrate [the base on which an organism lives or grows] for influenza vaccine. Eggs require specialized manufacturing facilities and could be difficult to scale up rapidly in response to an emerging need such as a pandemic, the authors write. They add that development of alternative substrates for influenza vaccine production has been identified as a high-priority. One potential alternative is use of the influenza virus hemagglutinin (HA; an antibody that causes red blood cells to clump together) using recombinant (genetic recombination) DNA techniques.

John J. Treanor, M.D., of the University of Rochester, N.Y., and colleagues evaluated an experimental influenza vaccine consisting of recombinant HA expressed in insect cells by a recombinant baculovirus (rHA0). The clinical trial was conducted at three U.S. academic medical centers during the 2004-2005 influenza season and included 460 healthy adults. Participants were randomly assigned to receive a single injection of saline placebo (n = 154); 75 µg of an rHA0 vaccine containing 15 µg of hemagglutinin from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus and 45 µg of hemagglutinin from influenza A/Wyoming/3/03 (H3N2) virus (n = 153); or 135 µg of rHA0 containing 45 µg of hemagglutinin each from all 3 components (n = 153). Serum samples were taken before and 30 days following immunization.

The researchers found: We have shown that the rHA0 vaccine is well tolerated in healthy adults and immunogenic at both doses evaluated, and we obtained preliminary evidence of protection against influenza infection and disease. The safety data generated in this study are consistent with the safety profile observed in previous studies of rHA0 vaccine. These vaccines have been well tolerated at all doses administered and are associated with low rates of local reactions.

The use of recombinant DNA techniques to express proteins in cell culture has been a successful approach for generation of highly effective vaccines for the prevention of hepatitis B virus and human papillomavirus. Among the available expression technologies, recombinant baculovirus is especially well suited for production of influenza vaccine because the rapidity with which genes can be cloned and inserted into this vector facilitates updating the vaccine at regular intervals. In addition, the extraordinarily high yields of protein possible in this system provide the opportunity to use much higher and potentially more effective doses of vaccine. Expression of the HA protein in insect cells using recombinant baculovirus also avoids the need to work with potentially pathogenic live influenza viruses and the attendant biocontainment issues that would be a particular concern for generation of pandemic vaccines. The preliminary demonstration of protective efficacy in adults provides further support for the development of this promising approach for prevention of seasonal and pandemic influenza, the authors conclude.

St. Jude named a Center of Excellence in flu research

Mon, 02 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) St. Jude Children's Research Hospital has been designated one of six Centers of Excellence for Influenza Research and Surveillance funded by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health.

NIAID will award $23 million per year for seven years to establish the consortium of centers, which includes St. Jude, according to Robert Webster, Ph.D., a member of the Infectious Diseases department and holder of the Rose Marie Thomas Chair at St. Jude. Webster, the principal investigator for the NIAID contract at St. Jude, also directs the WHO Collaborating Center for Studies on the Ecology of Influenza Viruses in Lower Animals and Birds, one of only five such collaborating centers in the world.

The mission of the centers is to expand NIAIDs influenza surveillance program in the United States and internationally to determine how these viruses cause disease as well as how the human immune system responds to them. The goal is to help the federal government prepare for and respond to seasonal influenza as well as outbreaks of animal influenza that might cause pandemics, or worldwide epidemics, in humans.

St. Jude will perform both surveillance of influenza viruses and basic research under the new contract. There are a variety of viruses to monitor besides the well-known H5N1, Webster said. For example, H7N7 infected chicken industry workers in the Netherlands; and H9N2, which circulates in many global avian populations, also sporadically appears in humans.

The establishment of the six Centers of Excellence is an extension of work done by St. Jude under a contract NIAID awarded the institution in 1999, two years after the 1997 outbreak of H5N1 in Hong Kong. That program established surveillance in aquatic birds and in live bird markets in Hong Kong and supported the study of the natural history of influenza viruses that have the potential to cause a pandemic. The St. Jude team also trained investigators in animal influenza surveillance techniques, developed tests to detect these viruses and provided seed vaccines to NIAID.

The aim of the surveillance in the new contract is to track outbreaks of influenza virus infections in animals that routinely come into close contact with people and that have the potential to cause a pandemic. The investigators will monitor viruses in several U.S. states and in more than a dozen countries. In addition, through its collaborators in Hong Kong, St. Jude will monitor children admitted to hospitals in China for influenza and maintain a surveillance program for severe acute respiratory syndrome (SARS) in Southeast Asia.

The basic research efforts are aimed at determining the molecular, ecological and/or environmental factors that influence how these viruses cause disease, how they spread and evolve and how the immune system responds to infection with these viruses. The Center of Excellence designation will also help St. Jude evaluate antiviral drug treatments and factors that cause drug resistance.

This award recognizes both the enormous contribution that St. Jude has made over the last several decades in the study of animal influenza viruses, as well as our leadership role in this area, said Richard Webby, Ph.D., assistant member in the Division of Virology in the Infectious Diseases department at St. Jude and a co-principal investigator for the St. Jude Center of Excellence research program.

The other five Centers of Excellence and their principal investigators are the University of California at Los Angeles (Scott Lane); University of Minnesota, Minneapolis (Marguerite Pappaioanou); Emory University, Atlanta (Richard Compans); Mount Sinai School of Medicine, New York (Adolfo Garcia-Sastre) and the University of Rochester, Rochester, N.Y. (John Treanor).

Immune response to cancer stem cells may dictate cancer's course

Mon, 26 Mar 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Although stem cells hold incredible promise in the fight against certain diseases, in cancer they're anything but helpful. In fact, mounting evidence is showing that a tumor's growth and spread may depend on cancer stem cells, which comprise only a very small subset of the tumor. Now, a new study by Rockefeller University scientists shows that immunity to cancer stem cells may help protect people with a precancerous condition from developing the full-blown disease, and that these cells could be an important target for cancer vaccines.

About three percent of adults over 40 test positive for a condition known as monoclonal gammopathy of undetermined significance, or MGUS. MGUS itself is relatively benign, but in a small number of cases it progresses into multiple myeloma, a cancer of blood plasma cells. Yet despite the fact that MGUS and myeloma cells are genetically quite similar, researchers had been unable to figure out why most MGUS patients never develop the cancer. In research published in the March 26 issue of the Journal of Experimental Medicine, Madhav Dhodapkar, associate professor and head of Rockefeller's Laboratory of Tumor Immunology and Immunotherapy, shows that MGUS patients who naturally develop an immune response to an embryonic stem cell protein, called SOX2, appear to be protected against the development of myeloma.

Dhodapkar and his colleagues tracked patients with early plasma cell tumors which are present in both MGUS and early myeloma for as long as three years, then filtered their results depending on whether the subjects had an immune reaction against SOX2. Thirteen patients showed immunity to the protein and, by the end of the study, none of the 13 had tumors that progressed. But of the 18 patients who did not have an immune reaction to SOX2, 70 percent developed progressive myeloma. So a person's immunity to this antigen, SOX2 which is thought to be very important to embryonal stem cells and is also expressed in cancer appears to predict the outcome in people with premalignancy or early myeloma, Dhodapkar says. This shows that the biology of stem cell genes is going to be very important in the context of cancer biology. Because when you get an immune response against these genes the outcome is quite different than when you don't.

This immune response, which correlates so closely with clinical outcome, appears to be targeting the cancer stem cells rather than the bulk tumor cells in myeloma something that gives researchers hope for a completely new approach. In immunology for the longest time, we've tried to focus on targeting bulk tumors. But maybe we should be targeting stem cells, Dhodapkar says. You need to target the roots to really kill the tree, but what we've been doing is trimming the branches and it hasn't worked.

Not only does this study give Dhodapkar a potential target for cancer vaccines, it also shows him that the immune systems of the people with the precancerous MGUS didn't just react to SOX2; they reacted to a completely different set of antigens than did the immune systems of patients with the fully developed cancer. Scientists have known for decades that cancer cells carry antigens, mutant proteins that can be recognized by the immune system. So they've concentrated on trying to identify tumor antigens and induce the immune system to attack them. The new research, however, also implies that researchers might be better off studying which antigens the immune system attacks before the cancer takes hold. It's becoming clearer that the immune system in cancer is really a two-edged sword, Dhodapkar says. Certain aspects, particularly inflammation, can promote cancer. But it's really important for us to figure out what parts of the immune system help prevent, or help target, cancer in a beneficial manner.

Because the immune systems of MGUS and myeloma patients respond to such different antigens, Dhodapkar also envisions these differences being used to screen for onset of disease in people who otherwise show no sign of disease. And this method could be used not just for myeloma but also for any tumor preceded by precancerous lesions. You could use immune response as a way of screening for all kinds of cancers, because it recognizes cancer at a stage where it can't be seen by any other method, he says.

Dhodapkar notes that the study is preliminary and must be confirmed in larger numbers of patients. This raises more questions than it answers right now, he says, but these studies provide new targets which we can develop vaccines and drugs against.

New test for most virulent HPV strains under study

Mon, 19 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) A test for the two strains of human papillomavirus responsible for most cervical cancers is under study.

The molecular assay uses a cervical scraping, like that for a liquid-based Pap smear, to test for HPV types 16 and 18, responsible for 70 percent of cervical cancers, says Dr. Daron G. Ferris, family medicine physician and director of the Gynecologic Cancer Prevention Center at the Medical College of Georgia.

Data from a National Cancer Institute trial shows that if you have a genital infection with HPV types 16 or 18, your chance of getting moderate to severe precancerous cervical changes or cancer is much higher than if you have one of the other types, says Dr. Ferris, a principal investigator on the national study evaluating the assay.

The NCI study followed women infected with different types of the typically slow-acting virus over 10 years. It found women infected with type 18 had a 15 percent risk of cancerous or pre-cancerous changes after 10 years, those with type 16 had a 20 percent increased risk while those with the 11 other strains had a collective risk of 1-2 percent.

Clearly, there is a big difference between HPV types 16 and 18 and all the other cancer-causing strains of HPV, says Dr. Ferris.

The type-specific assay, developed by Third Wave Technologies, Inc., in Madison, Wis., is being tested along with an assay that looks for the presence of 14 types of cancer-causing HPV. A test that detects 13 types of HPV already is commercially available, so the new test could become the second non-type-specific HPV test on the market.

Dr. Ferris, who was involved in early studies of the HPV vaccines, hopes the new tests will one day provide better options for screening for the most common sexually transmitted disease.

The current national study is giving the new HPV test and the type-specific assay to 1,500 women age 30 and older with a negative Pap test and to 1,000 women age 18 and older with cervical cell changes of undetermined significance pathologists call this most common abnormal result ASC-US or higher-grade abnormalities.

These are the two ways to use HPV testing, says Dr. Ferris. One is as a primary screening adjunct test with a Pap test for women age 30 and older and the other is as a triage test when women have an abnormal Pap smear result.

An HPV test typically follows an ASC-US Pap smear which at best, is about 80 percent accurate, he says.

However, the HPV test, which is more accurate, has not become widely accepted as a primary screening tool for women age 30 and older, he says, citing cost and the tradition of Pap smears as likely factors.

This new HPV test could lengthen the interval of screening for cervical cancer. If the new test is as good as the old one and if the HPV test is negative, there is only a 1 percent chance you actually have something wrong, he says, noting that Pap smears really dont add much to the equation.

Still, when he lectures around the country and asks for a show of hands of physicians using HPV tests in women over 30, few go up; he hopes that will change.

I think its a possibility in the future that we wont be doing Pap smears on women over 30; it might just be screening with an HPV test. A lot of experts are suggesting maybe that is the way we should go, he says.

In fact, the American College of Obstetricians and Gynecologists and American Society for Colposcopy and Cervical Pathology already recommend HPV testing in all women over 30.

Women under 30 are another matter. Ages 15 to 25 are peak sexual activity years and peak years for HPV infection, says Dr. Ferris. Fortunately, the vast majority of the infections are cleared; ones that persist to age 40 are most likely to cause problems. Seventy percent of patients clear the infection. The 30 percent who dont, if they still have it by the time they are age 40, are heading down the wrong path, he says. Less expensive Pap smears likely would continue to be used in the under-30 group to catch the few infections that become problematic in this age group.

Currently, there are not FDA-approved drugs to cure cervical pre-cancers and cancers caused by HPV, although centers such as MCG are evaluating potential therapies. Resulting cervical changes may be followed with frequent Pap smears or colposcopy, in which physicians can view the cervix and freeze, excise or vaporize significant cellular changes.

For more information about the study, call Study Coordinator Ansley Dennis in Dr. Ferris office at 706-721-2535.

Scientists unveil piece of HIV protein that may be key to AIDS vaccine development

Wed, 14 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) In a finding that could have profound implications for AIDS vaccine design, researchers led by a team at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have generated an atomic-level picture of a key portion of an HIV surface protein as it looks when bound to an infection-fighting antibody. Unlike much of the constantly mutating virus, this protein component is stable andmore importantly, say the researchersappears vulnerable to attack from this specific antibody, known as b12, that can broadly neutralize HIV.

Creating an HIV vaccine is one of the great scientific challenges of our time, says NIH Director Elias A. Zerhouni, M.D. NIH researchers and their colleagues have revealed a gap in HIV's armor and have thereby opened a new avenue to meeting that challenge.

The research team was led by Peter Kwong, Ph.D., of NIAID's Vaccine Research Center (VRC). His collaborators included other scientists from NIAID and the National Cancer Institute, NIH, as well as investigators from the Dana-Farber Cancer Institute, Boston, and The Scripps Research Institute in La Jolla, CA. Their paper appears in the February 15 issue of Nature and is now available online.

This elegant work by Dr. Kwong and his colleagues provides us with a long-sought picture of the precise interaction between the HIV gp120 surface protein and this neutralizing antibody, says NIAID Director Anthony S. Fauci, M.D. This finding could help in the development of an HIV vaccine capable of eliciting a robust antibody response.

For years, AIDS vaccine developers have been stymied by the seemingly unlimited ways HIV eludes natural and vaccine-induced immune defenses. Notes Dr. Kwong, The more we learned about HIV, the more we realized just how many levels of defense the virus has against attacks by the immune system. For example, not only does HIV mutate rapidly and continuouslydefeating attempts by the immune system to identify and destroy itthe virus is also swathed by sugary molecules. This nearly impenetrable sugar cloak prevents antibodies from slipping in and blocking the proteins the virus uses to latch onto a cell and infect it.

In 1998, Dr. Kwong and colleagues published the first X-ray snapshot of the core of HIV gp120 as it attaches to a cellular receptor known as CD4. That image gave researchers a glimpse of some sites on the virus that could be targets of drugs or vaccines, but it also revealed the extent of HIV's overlapping defenses. For example, scientists subsequently learned that CD4-gp120 contact causes gp120 to change shape, a viral feint known as conformational masking, which acts to further shield HIV from immune system attack.

While the earlier study provided a picture of the CD4-gp120 complex, the new finding delineates the precise stepwise engagement between gp120 and CD4. The researchers found that the gp120-CD4 encounter starts with a highly focused contact and then expands to a broader surface that stabilizes the interaction.

The first contact is like a cautious handshake, which then becomes a hearty bear hug, says Gary Nabel, M.D., Ph.D., director of NIAID's VRC and co-author of the new paper.

An effective HIV vaccine likely needs to induce antibodies that can sense and destroy multiple HIV strains. Scientists have sought such broadly neutralizing antibodies by studying the blood of people whose immune systems appear to hold the virus at bay for long periods of timeb12 is one of these rare, broadly neutralizing antibodies.

Until now, no one had succeeded in determining the detailed structure of b12 in complex with gp120. It was extremely difficult to crystallize b12 bound to gp120, says Dr. Kwong, in part due to the inherently flexible nature of the chemical bonds in gp120. To overcome the problem, the investigators created a variety of gp120s and eventually made the protein stiff enough to capture a picture of it in complex with b12. They saw that b12 binds gp120 at the same point where gp120 initially attaches to CD4. Unlike the gp120-CD4 interactions, however, b12 can latch onto the site of CD4's first contact without requiring a shape change in gp120 to create a stable bond between the two molecules. Essentially, the scientists found that the initial point of CD4 contact is a site of gp120 weakness because it is the site of recognitioncalled an epitopefor b12.

One of our primary goals is to develop HIV vaccines that can stimulate broadly neutralizing antibodies, says Dr. Nabel. The structure of this gp120 epitope, and its susceptibility to attack by a broadly neutralizing antibody, shows us a critical area of vulnerability on the virus that we may be able to target with vaccines. This is certainly one of the best leads to come along in recent years.

Peptide vaccine fights off breast tumors with aid of bacteria-mimicking agents

Thu, 01 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) PHILADELPHIA -- With the help of immune system-stimulating molecules that mimic bacterial components, researchers have used a type of cancer vaccine to both delay and prevent breast tumors in mice. The strategy, they say, holds promise for the future use of peptide vaccines in women who are at high risk for developing breast cancer.

Researchers from the Mayo Clinic, University of South Florida, and University of Torino employed substances called toll-like receptor agonists to help a synthetic peptide vaccine raise the immune system response against breast cancer tumors. Simultaneously, they used antibodies to blunt other aspects of the immune system that might interfere with a strong killer T cell response, improving the effectiveness of the vaccine.

In the February 1 issue of Cancer Research, the researchers report that their strategy was effective in preventing spontaneous tumors in transgenic mouse models for breast cancer, even when the vaccine was given when the mice already had early stage cancer.

The challenge is to get a foreign peptide recognized by the immune system as a threat so it can react and produce anti-tumor immune cells, said Esteban Celis, M.D., Ph.D., professor in the department of interdisciplinary oncology at the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida in Tampa. We've shown that stimulating the immune system using toll-like receptor agonists is very important to alerting it and producing lymphocytes that will have an anti-tumor effect.

According to Celis, the immune system usually doesn't react as strongly to a synthetic peptide in a vaccine as it does against an infectious agent, which is why immune system boosters such as toll-like receptor agonists, which mimic bacterial DNA, help. They also used anti-CD25 antibodies to tie up immune system T regulatory cells, which often serve as brakes that can reduce responses to the vaccine.

The researchers studied both normal mice and transgenic mice carrying an activated HER2/neu oncogene, which has been linked to breast cancer in humans. In order to get a protective immune response, the transgenic mice were repeatedly given vaccine in combination with the toll-like receptor agonist or were given antibodies that blocked their protective T regulatory cells. Celis and his colleagues found that the peptide vaccine administered this way could prevent or slow the growth of injected tumor cells, and showed some benefit against early stage spontaneous breast tumors.

The vaccine was most effective in preventing spontaneous tumors when it was given once at week eight along with anti-CD25 antibodies -- when most mice have excessive and often precancerous breast tissue growth called hyperplasia. It completely prevented spontaneous tumors in HER2/neu mice up to 35 weeks of age. Even without the antibody, tumors took much longer to develop, and when they did, they grew more slowly.

This kind of therapy could be applied to women who have a high likelihood of developing cancer -- women with pre-malignant hyperplasia or who have a genetic predisposition or make-up that makes them at high risk, Celis said.

Although the peptide vaccine was effective in preventing spontaneous tumors in the HER2/neu mice, Celis cautions that the mice had to be vaccinated prior to the appearance of measurable tumors and that the animals had to receive repeated immunizations.

Once tumors appear, only certain mice respond and there is only a delay in tumor growth, he said. It extends survival but does not cure the mice. We know that the immune response in these mice is much lower than in the animals that are younger, and it's likely that the tumor is making something that is inhibiting the immune response.

Flu experts call for mandatory shots for health care workers

Thu, 25 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) ALEXANDRIA, VA -- The top professional society of infectious diseases experts is insisting that all physicians, nurses, and other health workers caring for patients be vaccinated against influenza each year or decline in writing. It is the strongest call yet to plug a critical weakness in the nation's flu preparations.

The Infectious Diseases Society of America (IDSA) is issuing the call to Congress and the Administration as part of a new set of recommendations to better prepare the nation and the world for an inevitable influenza pandemic, as well to improve responses to the perennial threat of seasonal influenza.

The document is one of the most complete assessments to date on the major outstanding issues surrounding flu preparations. IDSA intends its principles to complement Congress' and the Administration's efforts in enacting the Pandemic and All-Hazards Preparedness Act in December 2006. IDSA's principles support many of the concepts found in the new law, but provide additional direction and a level of specificity not found in the Act.

The Centers for Disease Control and Prevention estimates that about 226,000 people are hospitalized with influenza and 36,000 people die from it every year in the United States alone. Even a mild influenza pandemic is expected to kill 100,000 to 250,000 Americans, and a severe pandemic could kill 2 million.

Health care workers caring for sick patients are routinely exposed to influenza virus and often spread it around. Yet each year fewer than two in five health care workers get a flu shot.

It's our professional duty to first do no harm, said Andrew T. Pavia, MD, chair of IDSA's National and Global Public Health Committee. Voluntary systems haven't brought immunization rates up far enough. For the sake of our patients, all health care workers must get a flu shot every year or they must be required to opt out in writing.

Responding to the perennial threat of seasonal flu will help us prepare for an influenza pandemic, and vice versa, said Kathleen Maletic Neuzil, MD, chair of IDSA's Pandemic Influenza Task Force. For example, she said, the yearly supply of influenza vaccine fluctuates widely because there are very few pharmaceutical companies interested in manufacturing it. A bigger and more stable market for vaccine would lure more companies into the field, improving the capacity to quickly develop a pandemic vaccine.

IDSA applauds the federal government for making a great deal of progress on pandemic influenza preparedness over the past two years, particularly with the passage last year of the Pandemic and All-Hazards Preparedness Act. But the bulk of the work remains ahead, and Dr. Neuzil noted there is a looming risk of flu fatigue as attention drifts elsewhere.

Attention to pandemic flu is not what it was at this time last year, but pandemic flu is not last year's story, she said. The threat has always been with us, and it will likely always be with us. If we hope to be ready the next time a killer virus emerges, we need a serious, sustained, long-term commitment.

As part of its own continuing commitment to assist in preparing for this serious threat, IDSA has compiled 12 principles for action on pandemic and seasonal influenza:

Billions of dollars saved in US by polio vaccination

Fri, 19 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Boston, MA -- A new study by researchers at the Harvard School of Public Health (HSPH) finds that polio vaccination in the United States has resulted in a net savings of over $180 billion, even without including the large, intangible benefits associated with avoided fear and suffering. This first study to retrospectively demonstrate the enormous benefits of polio vaccination appears as part of a special issue on polio in the December 2006 issue of Risk Analysis.

The history of polio vaccination in the U.S. spans over 50 years and includes different phases of the disease, multiple vaccines, and a sustained significant commitment of financial resources. Lead author of the study, Kimberly Thompson, associate professor of risk analysis and decision science at HSPH, emphasized that this study should help people understand and better appreciate the huge economic savings that can come from investments in public health interventions.

The researchers, Professor Thompson and Dr. Radboud Duintjer Tebbens, a research associate at HSPH, estimated the costs and the effectiveness of historical polio vaccination strategies. They found that the U.S. invested over $35 billion between 1955 and 2005 and will continue to invest billions into the future to pay for polio vaccination. They estimated that these historical and future investments translate into over 1.7 billion vaccinations that prevent approximately 1.1 million cases of paralytic polio and over 160,000 deaths, thus saving Americans hundreds of billions of dollars in treatment costs.

Dr. Stephen Cochi, U.S. Centers for Disease Control and Prevention Global Immunization Division Senior Advisor and an expert on polio said, This study documents the extraordinary power of vaccines not only as highly effective tools to prevent disease, disability, and death, but to provide enormous economic savings to society.

Although the last case of paralytic polio from wild poliovirus occurred in the U.S. in 1979, poliovirus outbreaks currently still occur around the world and American children continue to receive polio vaccinations. Dr. Bruce Aylward, Director of the Global Polio Eradication Initiative at the World Health Organization, stated that, as we stand on the brink of eliminating wild polioviruses around the world, these results provide a glimpse of the massive economic benefits of global polio eradication. To date, the Global Polio Eradication Initiative has succeeded in reducing the annual cases of paralytic polio from an estimated 350,000 cases in 1988 to less than 2,000 cases in 2006. The only remaining areas of the world that have not yet disrupted transmission include regions in four countries (Afghanistan, India, Nigeria, and Pakistan).

NIAID DNA vaccine for H5N1 avian influenza enters human trial

Wed, 03 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) The first human trial of a DNA vaccine designed to prevent H5N1 avian influenza infection began on December 21, 2006, when the vaccine was administered to the first volunteer at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD. Scientists from the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), one of the NIH Institutes, designed the vaccine. The vaccine does not contain any infectious material from the influenza virus.

Unlike conventional flu vaccines, which are developed by growing the influenza virus in hens' eggs and then administered as a weakened or killed form of the virus, DNA-based vaccines contain only portions of the influenza virus' genetic material. Once inside the body, the DNA instructs human cells to make proteins that act as a vaccine against the virus.

VRC Director Gary Nabel, M.D., Ph.D., together with a team of scientists from the VRC recognized the potential for employing new vaccine technology against influenza, a disease for which effective vaccines have long been made, but for which the reliability of supply and manufacturing capacity has been problematic. Dr. Nabel and his colleagues previously have shown the DNA vaccine approach to be effective against influenza viruses in animal models, including highly pathogenic viruses such as the H5N1 strain and the H1N1 virus that caused the deadly 1918 pandemic. The DNA vaccine used in this study is similar to other investigational vaccines evaluated by the VRC that hold promise for controlling other viruses, such as HIV, Ebola, SARS and West Nile.

An effective H5N1 influenza vaccine would provide a potentially life-saving advance against a global health threat, notes NIAID Director Anthony S. Fauci, M.D. More broadly, development of this DNA vaccine technology has the potential to improve our production capacity for vaccines to prevent seasonal influenza and other diseases.

This influenza vaccine trial is further evidence of the ability of the NIAID Vaccine Research Center to rapidly translate basic research into potential products, he adds. Our accelerated effort to understand and find new solutions to pandemic influenza is part of the NIAID commitment to respond to new emerging infectious disease threats and to improve public health preparedness.

Highly pathogenic avian influenza A viruses, specifically H5N1, have emerged in the past decade, causing widespread sickness and death in domestic and wild bird populations. As of December 27, 2006, 261 laboratory-confirmed human cases of H5N1 had been reported to the World Health Organization, resulting in death of more than half of infected individuals. While human cases remain relatively rare and are largely the result of direct virus transmission from infected birds, a few cases of human-to-human transmission have been reported. The severity of disease and the potential for human-to-human spread has provided a major incentive to accelerate developing a human vaccine for avian influenza.

With the spread of avian influenza virus, new strains have emerged, including clade II viruses in Indonesia and elsewhere that have drifted genetically from the initial strains detected in Southeast Asia. With this study, the investigators hope to learn whether new technologies, such as DNA vaccines, can provide protection against such viruses.

This vaccine is aimed at newer strains of the H5N1 virus that currently pose a threat in Indonesia and represents an example of our ability to respond to shifting viruses with modern technology, says Dr. Nabel.

The study will enroll 45 volunteers between the ages of 18 and 60. Fifteen will receive placebo injections and 30 will receive three injections of the investigational vaccine over 2 months and will be followed for 1 year. Volunteers will not be exposed to influenza virus.

The vaccine contains no infectious material, and the virus was not present during any stage of the manufacturing process, notes Julie E. Martin, D.O., principal investigator of the study. It is impossible for the vaccine to cause infection, she adds, because it employs new technology known to safely stimulate broad immune responses. NIAID researchers will measure immune responses to the vaccine, assess its safety, and compare its potency to more traditional vaccine approaches.

New details on how the immune system recognizes influenza

Mon, 01 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Drawing upon a massive database established with funds from the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), scientists have completed the most comprehensive analysis to date of published influenza A virus epitopes--the critical sites on the virus that are recognized by the immune system. The findings, reported by researchers at the La Jolla Institute for Allergy and Immunology (LIAI), are being published online this week by the journal Proceedings of the National Academy of Sciences.

The study should help scientists who are designing new vaccines, diagnostics and immune-based therapies against seasonal and pandemic influenza because it reveals in molecular detail exactly where the immune system focuses on the viruses. Although the complete molecular structures of essentially all major strains of influenza viruses are known, immune responses concentrate on limited regions of certain parts of the virus, and these regions must be identified as immune epitopes by research studies. The LIAI team found that while there were hundreds of shared epitopes among different virus strains, including the avian H5N1 virus, only one has been published that appears ideal for multi-strain vaccines. Information on shared protective epitopes is important for developing influenza vaccines that can provide broad protection against multiple strains of the virus.

This study is interesting for what it shows we know and do not know, says NIAID Director Anthony S. Fauci, M.D. It reveals many gaps in our knowledge of influenza viruses and indicates where we need to focus our attention.

The analysis drew upon a much larger effort called the Immune Epitope Database and Analysis Resources Program, which began in 2004 after NIAID awarded LIAI a $25 million contract to create a single repository of immune epitopes from critical disease-causing microbes, including agents that might be used in a bioterrorist attack. Influenza epitopes comprise only a portion of the extensive database, which has become the largest single collection of such information anywhere in the world. It includes data from thousands of separate articles published over several decades, providing extensive dossiers on dozens of pathogens.

The purpose of the database is to provide a catalog of molecules and structures that scientists around the world can quickly access and use to understand the immune response to a variety of epitopes, or methodically predict responses to as-yet untested targets, says Alessandro Sette, Ph.D., who heads the Vaccine Discovery division at LIAI and is the lead investigator on the project.

For the current study, Dr. Sette and his colleagues examined 600 different epitopes from 58 different strains of influenza A virus. One of their main goals was to determine how conserved, or similar, epitopes are between different strains of bird and human influenza viruses. Knowing this is important because the virus rapidly mutates and can swap gene segments between strains, which could increase the ability of an avian virus to be transmissible to humans.

In addition, only a handful of the epitopes are known to be associated with protective immunity. Most of the influenza virus epitopes in the database are those recognized by a type of immune cell known as a T cell; far fewer are recognized by B cells, a type of white blood cell that produces infection-fighting antibodies. Antibodies induced by seasonal and pandemic flu viruses or vaccines are a major component of immunity that protects against these viruses.

Strains of influenza virus can vary enough in their neutralizing B cell epitopes that a vaccine against one strain may not protect against another strain. But if epitopes are conserved between virus strains, the immunity a person has developed towards one strain might provide at least some protection against the other strain.

Using a software tool they developed, the LIAI team found hundreds of conserved influenza virus epitopes in the database, including those between avian H5N1 and strains of human influenza viruses. But what is less clear from the analysis is how cross-reactive an immune response would be to most of these conserved epitopes. Further analyses may assist scientists in identifying vaccine targets that might offer broader protection and in predicting how effective a new vaccine will be.

Other analyses revealed major gaps in scientists' knowledge about influenza viruses. Of the 600 epitopes in the database, for instance, very few were from strains of H5N1 avian influenza. And even though the database contains epitopes from all the influenza virus' proteins, the vast majority of the data relates to just two influenza proteins, the hemagglutinin (HA) and nucleoprotein (NP).

Most of the influenza virus data comes from analyses of immune responses obtained with mice; some comes from rabbits, ferrets and monkeys, and very little comes from humans or birds. In fact, only one antibody epitope came from a human. The LIAI researchers say more studies should be focused on identifying human T and B cell epitopes from human and avian strains of influenza virus--especially those associated with protective immunity.

The bottom line is that this study shows us where we need to go, says project director Stephen Wilson, Ph.D., chief technology officer at LIAI. Hundreds of flu epitopes have already been published and are now in the database, but critical gaps become apparent when one looks for human antibody targets.

Plans for the future include adding data on epitopes that are involved in autoimmune diseases and epitopes that trigger allergic and asthmatic reactions. Dr. Sette and his colleagues have also built numerous tools for analyzing and visualizing the data and for predicting immunity against different pathogens--all of which is publicly accessible on their Web site (see

Arrest deters kerb crawlers from further prostitution activity

Sun, 24 Dec 2006 19:24:15 PST

( from http://www.rxpgnews.com ) New research indicates that men arrested for buying sex from prostitutes are much less likely to continue their prostitution activity than clients of prostitutes not arrested for such behavior.

The study, published in the scientific journal PLoS ONE, was carried out by a team of researchers led by Devon D. Brewer, director of the research firm Interdisciplinary Scientific Research. "Our findings are unexpected, because previous studies of youth indicated that arrest had no effect on, or even increased, their delinquent and criminal behavior," Brewer said.

The researchers analyzed police records of clients, or "johns", arrested for prostitution in Colorado Springs, USA, and information on clients who sought HIV testing at the local health department or were involved in a large health department study of prostitutes and their sex partners. Arrested clients were usually caught in stings where female police officers posed as prostitutes in high-prostitution areas, and nearly all arrested clients were convicted. Clients first identified by arrest were similar to those first identified by the health department in terms of their demographic characteristics and prostitution activity. The researchers also examined records from several states in the USA and found that clients, after being arrested, did not appear to seek prostitutes in other communities or prostitutes who work in off-street settings.

"These results suggest that simply arresting and prosecuting clients of prostitutes may be enough of a deterrent that additional interventions, such as sending clients to 'john schools' or educational programs that emphasize the harms of prostitution, may be unnecessary to lower recidivism," Brewer noted. "However, because only a very small percentage of clients in a community are arrested, other strategies and increased enforcement may be necessary to reduce the demand for prostitution further."

The research was funded by a grant from the National Institute of Justice, U.S. Department of Justice.

Cellular pathway yields potential new weapon in vaccine arsenal

Fri, 22 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) When a cell has to destroy any of its organelles or protein aggregates, it envelops them in a membrane, forming an autophagosome, and then moves them to another compartment, the lysosome, for digestion. Two years ago, Rockefeller University assistant professor Christian Münz showed that this process, called autophagy, sensitizes cells for recognition by the immune system's helper T cells. But he didn't know how often this pathway is used or how efficient it is. Now, a new study published online today in the journal Immunity goes a long way toward addressing these questions and shows that the pathway is so common that it could be a valuable new way of boosting vaccine efficacy.

There are two types of T cells: Helper T cells encourage their counterpart, killer T cells, to hunt down and attack invading pathogens. T cells typically recognize antigens only once they're presented to them by major histocompatibility compex (MHC) scaffolding molecules on a cell's surface. Antigens on MHC class I molecules are recognized by killer T cells and had originally been thought to come only from sources inside a cell (proteins from the nucleus or other cellular part); those on MHC class II molecules are recognized by helper T cells and had been thought to come from sources outside the cell, such as fragments of dead, infected cells. But as Münz discovered two years ago, an autophagy pathway allows intracellular antigens to be presented on MHC class II molecules.

Now Münz, head of Rockefeller's Laboratory of Viral Immunobiology, and Dorothee Schmid, a graduate student in the lab, have shown that the autophagy pathway is far more widespread than they thought: They found that a surprising number of cells with MHC class II molecules on their surfaces used the autophagy pathway. In skin (epithelial) cells and two other types of immune cells (dendritic and B cells), 50 to 80 percent of the autophagosomes moved into the loading compartment for MHC class II molecules. For types of cells that upregulate MHC class II upon inflammation -- epithelial cells of infected organs, for instance -- one could assume that they might actually use the autophagy pathway fairly frequently, Münz says.

Then, to test the pathway's effectiveness, the researchers targeted an influenza antigen directly to autophagosomes. They found that they were able to increase antigen presentation by MHC class II molecules, subsequently boosting helper T cell recognition of viral antigens. This targeting pathway could be very efficient for vaccine development, Münz says, especially for recombinant viral vaccines like those against HIV. Killer T cell responses are usually short-lived. But if you can increase recognition by helper T cells, then you'll be more likely to maintain the killer T cell response and establish immunological memory.

Effective HIV control may depend on viral protein targeted by immune cells

Sun, 17 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) An effective response of the immune systems killer T cells against infection with HIV may depend on exactly which viral protein is targeted, according to an international group of researchers. A new study finds that HIV-infected individuals in whom virus-specific CD8 T cells are targeted against the Gag protein have lower viral levels than do those with CD8 responses directed against other viral proteins. The report from the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH), the University of Oxford and University of KwaZulu-Natal in South Africa is receiving early online release in Nature Medicine.

Understanding which immune responses are effective in control of HIV is of critical importance in vaccine development, says Philip Goulder, MD, PhD, of PARC-MGH and Oxford, the senior author of the study. Previous approaches have focused on a more is better approach, seeking to generate responses against a broad range of viral proteins, but these results challenge that dogma.

While many strategies for developing a vaccine to control HIV focus on the activity of the CD8 T lymphocytes that recognize and destroy virus-infected CD4 T cells, the fact that even patients in the last stages of AIDS can have measurable CD8 responses indicates that those responses are not always effective. To investigate how variations in CD8 response alter the ability to control HIV, the research team enrolled almost 600 South African patients who had not yet been treated for their HIV infections.

The researchers comprehensively mapped the CD8 responses against all viral proteins and also investigated whether the versions of HLA Class I molecules involved in the immune systems recognition of HIV protein fragments made a difference. When new viruses are produced within an infected cell, Class I molecules grab viral fragments and display them at the cell surface, thereby alerting CD8 cells that the cell has been infected and should be destroyed. Earlier studies, including a 2004 Nature report from the same group, showed that the genetically determined version of an individuals HLA Class I molecules could strongly influence immune control of HIV.

The current study found that only CD8 responses against the Gag protein were associated with significantly reduced viral levels and that individuals with responses against several different Gag fragments had even lower viral loads. In contrast, those with stronger responses against other HIV proteins including Env, a protein that is the focus of several vaccine studies had higher viral levels indicating poorer control of HIV.

In people receiving no antiretroviral treatment, the improved HIV control associated with Gag-specific CD8 response would probably translate into asymptomatic infection for more than a decade, compared with progression to AIDS within two to three years of infection in those with no Gag responses. The reason why patients particular HLA Class I molecules are linked to different HIV disease outcomes now appears to be related to the number of Gag fragments displayed by different versions of the Class I molecule.

Mechanisms underlying the different effects of the protein-specific immune responses are unknown and require further investigation. The researchers suggest that responses against proteins like Env might be inherently less effective or might only be generated in response to elevated viral loads. Therefore, the findings of this study, which reflect chronic HIV infection, might not apply in situations in which vaccination generates an immune response before infection occurs.

The possibility that there may be fundamental differences between the impact of Gag and non-Gag CD8 responses on the ability to control HIV has clear relevance to vaccine development, says Goulder, who is an associate professor of Medicine at Harvard Medical School.

Quality not quantity important for immune response to HIV

Sun, 17 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) When it comes to an immune response against HIV, research funded by the Wellcome Trust in the UK and the National Institutes of Health in the US has found that bigger is not necessarily better, contrary to conventional medical wisdom. The research may have a profound impact on the development of a vaccine against the disease.

Conventional medical wisdom tells us that the bigger the immune response, the more effective it will be in controlling HIV, says Professor Philip Goulder, a Wellcome Trust Senior Research Fellow in Clinical Science at the University of Oxford. However, our study suggests that this might not be the case. While most of the immune responses generated against HIV appear to be ineffective, responses targeting one particular HIV protein can bring about control of the virus.

About 40 million people are thought to be living with HIV worldwide. The virus, which causes AIDS, is thought to kill 3 million people each year. Despite being first identified in 1981, a vaccine to prevent infection has so far proved elusive.

When HIV infects the body, it hides out in so-called helper T-cells. T cells play an important role in the immune response generated by the body to fight infection. There are a number of different types of T cells, each playing a different role in this battle. Helper T-cells (HTCs) regulate the body's immune response and it is the loss of these cells that leads to the development of AIDS.

Another type of T cell, the cytotoxic T cell (CTC), recognises and attacks infected HTCs. It was previously thought that the bigger the CTC response, the more effective it would be. It is this dogma that has influenced development of HIV vaccines, with the vaccines attempting to stimulate a large response.

However, Professor Goulder and colleagues found that the type of CTC response is crucial and that some types of response may have a negative effect and could actually hinder the immune response. The research, a population-based study involving investigators at the University of Oxford in the UK, Partners AIDS Research Center at Massachusetts General Hospital in the US and the University of KwaZulu-Natal, South Africa, investigated the immune responses against HIV in nearly 580 HIV-infected people in KwaZulu-Natal. It is published online today in the journal Nature Medicine.

Some of the CTCs attack so-called 'Gag' proteins within the HIV virus, whilst others attack proteins such as the 'Env' protein on its surface, explains Professor Goulder. In our study group, it seems that the higher the response to the Gag proteins, the more effective the immune system was at fighting infection. However, for reasons that are unclear, the opposite was true for responses to the Env proteins, where a stronger response was associated with a higher viral load in other words, worse control of HIV.

Professor Goulder believes these findings may have implications for the development of a HIV vaccine.

There seems to be clear evidence that 'Gag is good', says Professor Goulder. This means that rather than developing a vaccine with a spectrum of CTC responses, we may need to look at a more targeted vaccine.

Could the ability to expel worms lead to a future asthma treatment?

Thu, 14 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Based on experiments with worms similar to those that infest millions of children in the tropics, researchers see potential for a new way to treat asthma. Parasitic infections and asthma may cause the human immune system to react in some of the same ways, and may one day be cured by manipulating some of the same proteins, according to research published today in the journal Science.

To be effective, the immune system must decide which cells and chemicals need to be ramped up to best destroy the invader at hand, be it bacterium, virus or worm. In 1986, Tim Mosmann, Ph.D., now director of the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, led a team that first described a new concept for how the immune system might make such choices: the Th1/Th2 Model. A landmark in immunology, it was a major step toward unraveling the systems complexities. Todays study results show how the model continues to define new players in the immune system and to suggest new treatment approaches.

The point of the study is that each new detail in our understanding of the immune system creates opportunities to make changes that counter disease, said Mosmann. These results, while early, suggest that helping the body make more of a newly defined immune chemical may prevent roundworm infection, and that shutting it down may reduce lung damage in asthma.

Part of the immune system is adaptive, pumping out vast numbers of immune cells on the hope that one will be the right shape to link up with, and become activated by, any invader encountered. When one of those immune cells recognizes an invader, it expands into an army of clones specifically selected to attack that organism. One workhorse of the adaptive system is the helper T cell, a white blood cell that secretes protein messengers called cytokines to accelerate the immune response.

According to Mosmanns model, T cells differentiate into two major sets of helper T cells, Type 1 (Th1) and Type 2 (Th2), each defined by the cytokines they produce. Each profile is more effective at attacking certain invaders, with Th1 responses, for example, better against bacteria that live inside cells. Th2 cytokines include interleukin-4 (IL-4), interleukin-5 (IL-5) and interleukin-13 (IL-13), all of which are useful in immune responses against worms. In a clue to the worm/asthma link, IL-4, IL-5 and IL-13 also trigger mechanisms that cause irreversible damage to the lungs of asthmatic patients.

Flu shot effective against drifted influenza, nasal spray vaccine less so

Wed, 13 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) ANN ARBOR, Mich.--- During a year in which the circulating strains of influenza showed genetic differences from the strains in vaccines, the traditional killed-virus flu shot was found to be effective in preventing influenza in healthy adults. The live attenuated-virus nasal spray vaccine also prevented illnesses but was less effective.

Both outcomes were determined by laboratory confirmation of flu infection, a University of Michigan study found.

Earlier studies had suggested that the nasal spray, sold by MedImmune as FluMist, might offer better protection against drifted viruses that had genetically changed between vaccine formulation and annual influenza activity. The nasal spray, which is based on a live but weakened virus, was 86 percent protective in one study conducted in children during a major drift year. However, FluMist had not previously been studied head-to-head against the shot in adults with laboratory confirmation.

The killed-virus flu shot is usually billed as 70 to 90 percent effective against circulating strains that are well matched to vaccine strains. During the 2004-2005 flu season, a University of Michigan team found that the killed-virus flu shot was 75 percent effective against a moderately-drifted type A virus and two types of B virus. The standard formulation of both the flu shot and the nasal spray vaccine includes two types of A influenza and one B, but in the 2004-05 season, there were two B strains circulating and one type A.

On the other hand, FluMist was 48 percent effective. These results may only apply to the 2004-05 flu season, said Dr. Arnold S. Monto, professor of epidemiology. In other years the results may be different. We need a more specific understanding of which viral changes matter and which don't. There are many things about vaccine protectiveness that we still don't completely understand.

It may be that the difference in effectiveness between the shot and the spray can be attributed to poorer protection against type B infections in participants given FluMist, Monto said, but that's not clear from this study.

The live attenuated vaccine marketed as FluMist was developed at the University of Michigan by Hunein John Massaab, professor emeritus of epidemiology. MedImmune produces it under a license with the University.

Monto's research team is conducting a randomized, double-blind, placebo-controlled three-year trial with National Institutes of Health funding in which the two vaccines are being compared head-to-head and against a placebo. Prior to the 2004-05 flu season, they vaccinated 1,247 people aged 18 to 46 in four Michigan communities.

A source of confusion about vaccine effectiveness against drifted viruses may stem from study design. Many vaccine evaluation studies rely on a clinical diagnosis of influenza-like illness, or measures of the immune response to infection in the blood. For the present study, Monto and lead author Suzanne Ohmit, assistant research scientist in epidemiology, took throat swab specimens from participants experiencing flu symptoms and analyzed them, using virus isolation and PCR techniques, to determine if influenza virus was causing the illness.

Monto and Ohmit suspect that the adult participants in their study in 2004-05 had enough prior experience with influenza that the live attenuated virus may have failed to infect their nasal passages and initiate an immune response as it is intended to do. However, both still believe that the nasal spray is very effective in children and may be more effective than the killed vaccine in the young.

FluMist works very well in children with naive immune systems, Ohmit said. The FDA approval of FluMist limits its use to people between age 5 and 49 years.

In another paper in the same edition of the New England Journal of Medicine, FluMist was administered to school children and the children were followed to see if they and their families had been protected against flu. The study's authors conclude that vaccinating children had some protective effect on the children and their families, confirming a notion of herd immunity first tested by Arnold Monto in a 1970 influenza vaccine study.

Without having children in their study, Monto and Ohmit can't tell whether the two vaccines would have conferred different protection in 2004-05 in that age group. However, data from a study conducted in 2004-05 in children aged 6 to 59 months by MedImmune, suggested that FluMist offered significantly greater protection than the flu shot. A MedImmune study discussed in October at a Toronto conference also found that FluMist was more successful at initiating antibody response than the traditional shot in young children.

Monto and Ohmit will continue to follow study participants vaccinated in Fall 2005 , without vaccinating them this year, to see whether the shot or the spray offer long-term protection.

Cancer immunoresistance linked to loss of tumor suppressor gene

Sun, 10 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Cancer immunoresistance may be partially due to loss of a well-known tumor suppressor gene, according to new research led by Andrew T. Parsa, MD, PhD, assistant professor of neurological surgery at the University of California, San Francisco.

The findings are reported today (December 10) online and are scheduled to appear in the January issue of Nature Medicine.

It has been known for a long time that cancer cells have many different ways to avoid the immune system, including the common strategies of hiding proteins that are normally expressed on the cell surface or making proteins that act to suppress immune responses, according to Parsa. Some researchers believe that immunoresistance may contribute to cancer progression and development, he added.

Over the past four years, Parsas lab has focused on trying to understand how specific mutations associated with high grade glioma correlate with immunoresistance. Malignant glioma is among the deadliest types of brain cancer for which there currently is no effective treatment.

My colleague James Waldron and I began screening different cell lines for mutations and trying to match these mutations up with proteins that suppress the immune system, Parsa said.

The researchers began to see an interesting trend. Glioma cells with mutation in a specific gene called the phosphatase and tensin homolog gene, or PTEN, seemed more resistant to the immune system than glioma cells with normal PTEN function. Determining the mechanism responsible for the immunoresistance proved more difficult.

Fortunately, Russ Piepers lab here at UCSF had developed a model that took normal human astrocytes and made them act like a malignant glioma. This allowed us to study the effects of PTEN mutation in a very well controlled manner, Parsa said.

In glioma patients who have lost PTEN function, the tumor cells were found to express high levels of B7-H1, a protein that contributes to immunoresistance. According to Parsa, high levels of B7-H1 on a cancer cell can be thought of as a protective barrier, and T-cells that come in contact with B7-H1 positive cancer cells are ineffective.

Many types of genetic mutation can give rise to a brain tumor, he explained, but with this particular type of mutationthe loss of PTEN function and the expression of B7-H1-- the immune system will have a harder time killing the cancer.

The results of Parsas work may have implications beyond brain tumors. Loss of PTEN function is found in many types of cancers, including prostate and breast. Emerging therapies that rely on the immune system to fight cancer could potentially be more or less effective based on PTEN function.

Immunotherapy for cancer has been effective in some patients but not in others. Its possible that this link between PTEN loss and B7-H1 expression is responsible. We need to look at this further, said Parsa.

New approach to BSE successful in lab

Fri, 01 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) A new method of treatment can appreciably slow down the progress of the fatal brain disease scrapie in mice. This has been established by researchers from the Universities of Munich and Bonn together with their colleagues at the Max Planck Institute in Martinsried. To do this they used an effect discovered by the US researchers Craig Mello and Andrew Fire, for which they were awarded this years Nobel Prize for Medicine. Scrapie is a variant of the cattle disease BSE and the human equivalent Creutzfeld-Jakob disease. However, it will take years for the method to be introduced to medicine, the researchers warn. Their findings are published in the next issue of the Journal of Clinical Investigation (Vol. 116, No. 12, December 2006).

Scrapie, Creutzfeld-Jakob and BSE are among the most unusual diseases known to medical research. Unusual because the pathogens are apparently neither viruses nor bacteria, being simply protein molecules known as protein prions. What is even more peculiar: exactly the same prion proteins occur in healthy animals. The only difference is that they have a different shape. When there is contact with their diseased twins they change their shape, also becoming diseased. The result is an irresistible chain reaction. The malformed prion proteins can be deposited in the brain, thereby destroying brain tissue. Prion diseases are always fatal, often, however, not until months after the outbreak of the disease. As yet there is no cure.

In mice suffering from scrapie the pathogenic prion protein is known as PrP-Scr, whereas the normal variant is PrP-C. PrP-C seems to have a protective effect in diseases like a stroke. Interestingly, mice which cannot produce any PrP-C appear to be completely healthy. This has become the starting point for a new therapeutic approach which for some years now has been current in research circles: can we not simply switch off the production of healthy PrP-C in infected animals, thereby depriving the diseased PrP-Scr of its ability to spread In this way the chain reaction would be interrupted.

New therapeutic approach

Scientists from Munichs Ludwig Maximilian University and the University of Bonn, in conjunction with colleagues from the Max Planck Institute in Martinsried, have been testing whether this approach works. In doing so they cut back the production of PrP-C in mice by means of an ingenious procedure. The researchers used a special RNA molecule for this purpose. RNA is related to the genetic molecule DNA. There are types of RNA known as siRNAs which can attach themselves to specific genes, thereby preventing these from being read. The production of the appropriate protein is thus shut down. This effect is known as RNA interference; its discovery was rewarded with this years Nobel Prize for Medicine. We modified the brain cells of mice in such a way that they were able to produce siRNAs in place of the healthy PrP-C protein, explains Professor Alexander Pfeifer, director of the Institute of Pharmacology of the University of Bonn. In cell cultures the production of PrP-C was thereby cut back by up to 97 per cent.

The researchers then tested what effect these siRNAs had on mice which had scrapie. If brain cells are to produce siRNAs, you have to smuggle in the corresponding gene, says Professor Kretschmar, director of the Prion Centre of Munichs Ludwig Maximilian University. But presumably well never manage to equip all the cells in the brain with this gene. This is why the researchers also wanted to find out how many cells they have to revamp genetically to treat scrapie or similar diseases successfully. For this purpose they bred mice that only had some brain cells which could produce siRNAs. Whereas the untreated mice died on average after 165 days, the mice which had been treated lived appreciably longer, is how Professor Kretschmar summarises the results.

BSE-resistant cattle

It varied how much longer they lived: if only a few cells could produce siRNAs, the mice died at almost the same time as the control mice, i.e. on average after 170 days. However, if the majority of the brain cells were protected by siRNA, the mice survived the prion disease for up to 230 days, in other words about a third longer.

Basically siRNAs seem to be a promising therapeutic option for scrapie, CJD or BSE, Professor Pfeifer emphasises. However, it will take years before the method can be used on human beings. The method is also relevant for animal breeding: in principle it can be used to breed cattle which cannot produce any PrP-C. They would then be resistant to BSE.

Painkillers may reduce effectiveness of vaccines

Thu, 30 Nov 2006 14:38:23 PST

( from http://www.rxpgnews.com ) New York, Nov 30 - The intake of painkillers at the time of vaccination may reduce the effectiveness of the vaccine, suggests a new study.

When a person is vaccinated, the goal is to produce as many antibodies as possible to effectively neutralise the infection, reported science portal EurekAlert.

To do this, white blood cells - that form a component of the blood and help defend the body against infections spring into action to produce the antibodies.

B cells also serve as the immune system's memory for future protection against the illness.

But Richard P. Phipps and colleagues at University of Rochester discovered that when a person took painkillers, the drug also reduces the ability of B cells to make antibodies.

Their findings were based on laboratory studies of blood samples from people who participated in early clinical trials for the human papillomaviruses - vaccine. HPV is a common cause of various sexually transmitted infections.

New vaccine stimulates colorectal cancer patient's immune systems to fight cancerous cells

Wed, 15 Nov 2006 04:59:37 PST

( from http://www.rxpgnews.com ) British researchers have developed a vaccine that stimulates colorectal cancer patients' immune systems to fight cancerous cells.

In a clinical trial of 67 patients, researchers at the University of Nottingham observed that when the vaccines were administered before and after surgery to remove cancerous tumors, they helped stimulated immune cell production in up to 70 percent of patients. These results are published in the November 15 issue of Clinical Cancer Research.

This is the first vaccine shown to stimulate TNF-alpha an immune-system protein that is very effective at killing cancer cells, said Lindy Durrant, senior author of the study and professor of cancer immunotherapy at the university.

The vaccine works by stimulating the patients' immune response to generate infection-fighting white blood cells called T cells, which in turn produce immune system proteins called cytokines that destroy cancer cells. The antibody contained in the vaccine, called 105AD7, was cloned from a patient who survived seven years with liver metastases from colorectal cancer, Durrant explained.

This is very unusual as most patients die within one year of getting liver metastases, she said. I thought if this antibody had helped this patient, if we could clone it, it might help others.

105AD7 is structurally similar to CD55, a protein that attaches to sugar molecules and is overexpressed in colorectal cancer cells, protecting them from attack by the body's immune system. While low levels of CD55 occur in all cells exposed to the immune system, increased expression of the protein has been observed in multiple types of tumors, including up to 80 percent of colorectal cancers.

During the trial -- the largest to date looking at 105AD7 plus surgery -- 67 patients with colorectal cancer who were scheduled for surgery to remove their primary tumor were randomly assigned to receive either 100 micrograms of 105AD7 with a powder to help absorb the vaccine, 105AD7 along with BCG (a bacteria used to stimulate the immune system in cancer patients) during the first immunization and the powder in subsequent vaccinations, or no treatment.

The patients, who had varying degrees of disease, averaged age 66. Twenty-eight patients had colon cancer while in 39 patients the primary tumor was located in the rectum.

Patients were immunized before surgery on the day they were recruited for the study, and again two weeks later if surgery had not yet been performed. The vaccines were continued three, six and 12 weeks after surgery, and then at three monthly intervals up to a maximum of 24 months after surgery. Blood samples were collected from the patients during recruitment, at surgery, and at the time of the three-, six- and 12-week post-operative immunizations. Additional blood samples were acquired one month after each subsequent immunization.

Laboratory tests of the blood samples indicated that a T-cell response against the vaccine was recorded in the majority of patients. The responses tended to have two peaks: one following the start of the immunization schedule and another several months later, after additional immunizations. About 70 percent of patients produced both TNF-alpha and GM-CSF a protein that stimulates white blood cell production in response to both the vaccine and to CD55.

The immune responses to both the vaccine and CD55 were measurable, adding support to the use of CD55 as a target in cancer treatment, Durrant said.

Nineteen of the patients died during the follow-up period. Durrant and colleagues noted that the trial was not designed to study the effect of the vaccines on survival.

U of S Vaccine and Infectious Disease Organization team discovers key step in flu virus replication

Wed, 15 Nov 2006 04:59:37 PST

( from http://www.rxpgnews.com ) As public health officials around the world keep a nervous eye on the spread of avian influenza, the University of Saskatchewan's Vaccine and Infectious Disease Organization (VIDO) has uncovered a key step in how the influenza virus causes infection.

Yan Zhou and her team have discovered how a crucial pathway that supports the influenza A virus's ability to reproduce itself is activated, a finding that could pave the way for new drugs and vaccines.

The paper will appear in the January 2007 issue of the Journal of General Virology and recently has been given advance on-line publication.

The work we are doing will be applicable to all influenza viruses, including influenza A virus subtype H5N1, said VIDO Director Lorne Babiuk.

Zhou says that although years of research remain to be done, this work provides novel insights for developing live vaccines and antiviral drugs for influenza epidemics and pandemics. A provisional patent has been filed on the findings.

Given the health, economic and social consequences of influenza epidemics, the work of Dr. Zhou and her team demonstrates the importance of building influenza research capacity in Canada, said Dr. Bhagirath Singh, Scientific Director of the CIHR Institute of Infection and Immunity.

Their research findings may help to develop new influenza treatments and prevent the disease, as well as add to global pandemic preparedness research.

To survive, the influenza virus hijacks the host animal or human's cellular machinery and forces it to make more copies of the virus. The researchers believe that the cellular events involved in this process are an excellent target for interventions against influenza.

The study revealed novel characteristics of a protein, called NS1, that activates a key pathway in the virus's reproduction. This information will help the researchers learn how to create harmless influenza viruses that can be used as live vaccines.

The pathway can be thought of as an assembly line with a switch to turn it on, says Zhou. If the switch is turned on, the pathway enables efficient production of more viruses. But only the NS1 protein can turn on the switch.

The researchers are investigating genes and proteins of the influenza viruses of swine, horses and birds to see how they activate downstream cellular signalling pathways. To do this, they are using reverse genetics technology, where researchers begin with a gene and figure out its function.

These studies will allow the team to identify the genes that enable the virus to cause disease, laying the groundwork for antiviral drug development.

Increasingly, new diseases involve both humans and animals, said Andrew Potter,VIDO's Associate Director (Research). VIDO's background in veterinary research means that when diseases like avian influenza develop, we have the resources to begin studying the disease fairly quickly.