RxPG News : Small Pox

Mass vaccination would not be necessary in the event of a smallpox bioterrorist attack

Tue, 17 Oct 2006 02:06:37 PST

( from http://www.rxpgnews.com ) Mass vaccination would not be necessary in the event of a large-scale smallpox bioterrorist attack in the United States, according to a study led by researchers at Fred Hutchinson Cancer Research Center that appears online in the International Journal of Infectious Diseases.

Instead, the current U.S. government policy of post-release surveillance, prompt containment of victims and vaccination of hospital workers and close contacts would be sufficient to thwart an epidemic, according to lead author Ira M. Longini Jr., Ph.D., a world leader in using mathematical and statistical methods to study the natural course of infectious diseases.

"We found that a well-prepared response of surveillance and containment, if done quickly, within a day or two of detecting the first smallpox case, would contain a large attack if up to 500 people were infected," said Longini, a member of the Public Health Sciences Division at the Hutchinson Center and a professor of biostatistics at the University of Washington School of Public Health and Community Medicine. These results apply to scenarios involving even the most virulent, fatal forms of the virus.

However, Longini emphasizes, failure to quickly isolate known smallpox cases and vaccinate their close contacts could thwart the containment of an epidemic.

These findings emerge from a committee of smallpox experts including infectious-disease modelers, epidemiologists, statisticians and clinicians who were commissioned by former Secretary of Health and Human Services Tommy Thompson to evaluate a variety of intervention strategies to determine whether the United States could contain a large-scale smallpox bioterrorist attack and, if so, how.

Specifically, the researchers were charged with determining whether surveillance and containment isolation of detected smallpox cases and vaccination of their close contacts would be sufficient to contain a large attack. They also wanted to find out whether other interventions, such as mass pre-vaccination of the general public, pre-vaccination of hospital personnel, vaccination of the target community and closure of schools after a smallpox release would help contain the spread of the disease.

Thompson's senior science adviser, Donald Ainslie (D.A.) Henderson, the physician and epidemiologist who oversaw the World Health Organization's successful campaign to eradicate smallpox from the world in the late 1970s, served as a consultant to the committee, known as the Smallpox Modeling Working Group. The group was convened by the Secretary's Advisory Council on Public Health Preparedness, a branch of the U.S. Department of Health and Human Services.

"Earlier studies recommended mass pre-vaccination of the general population to protect against a smallpox attack. None of us on the committee believed this was necessary, including D.A. Henderson, who intimately understands the natural history of the virus," Longini said. "The secretary of Health and Human Services wanted to settle such issues regarding smallpox containment once and for all, and this was our charge."

While the researchers did find that mass vaccination would slightly reduce the number of deaths from smallpox, they also found that the rate of severe illness and death caused by the vaccine itself would cancel out any benefit from mass vaccination. One person in 10,000 will have a severe reaction and one in a million will die from the vaccine, Longini said.

"Precautionary vaccination of hospital personnel and post-release vaccination of the target population would further contain the spread of smallpox, but at a cost of many more people being vaccinated," said co-author and Hutchinson Center biostatistician M. Elizabeth (Betz) Halloran, M.D., D.Sc. "The financial cost and potential illness and death related to vaccination must be weighed against the potential benefits in the event of an attack. In our opinion, pre-vaccination of the population at large is unnecessary," she said. Longini, Halloran and colleagues also found that closure of schools after a smallpox attack would have a minimal effect in preventing transmission of the disease, and that any delay in quarantining infected individuals would take a much greater toll on the community than failing to pre-vaccinate potential cases.

To conduct the study, Longini and colleagues created a computer model that calculated the spread of smallpox via aerosol dissemination the most likely choice of terrorists within a community of 50,000. Members of this virtual community interacted the way people normally do: within households, neighborhoods, preschool groups, schools, a community hospital and the community at large. The age distribution and household sizes were based on the U.S. census for 2000.

Predicting the spread of an infectious disease such as smallpox requires much more than simply connecting dots on a map. Instead Longini and colleagues rely on a tool called stochastic modeling to take into account real-world unpredictability, as well as many factors about the disease and the affected population. In constructing these models, Longini and colleagues begin with assumptions about how people interact and how the virus spreads. They also introduce and evaluate the effectiveness of various intervention strategies.

The study represents the first attempt to integrate what science knows about the natural history of smallpox how various forms of the disease manifest over time with human patterns of behavior to construct the most-comprehensive model of a smallpox epidemic to date.

"If smallpox appeared in Seattle tomorrow, which it could do, I'm absolutely confident that we could contain it if our recommendations for surveillance and containment were put into practice. I rest easier now that we've done this study," Longini said. "The process was kind of like unveiling the enemy to the point where we really understood it. This research has helped us demystify the threat a bit."

Although smallpox has been eliminated as a naturally-occurring disease, the virus still exists in two approved laboratories in the United States and Russia. The Centers for Disease Control and Prevention classifies it as a "Category A" agent, presenting the greatest potential threat for harming public health if developed and used as a bioterrorist agent.

Smallpox is caused by the variola virus, which emerged thousands of years ago. Variola major, the most common form of the virus, is divided into four subcategories: ordinary (which accounts for about 90 percent of cases and has a fatality rate of about 30 percent), modified (which occurs in people who have been vaccinated and has a death rate of about 10 percent), and flat and hemorrhagic (both very rare and uniformly fatal).

According to the CDC, exposure to the variola virus is followed by an incubation period of seven to 17 days, during which people are not contagious and feel fine. The first symptoms emerge during what is called the prodrome phase, and they include head and body aches, fatigue, a high fever and, sometimes, vomiting. This phase lasts two to four days and at this point people may or may not be contagious. Then a rash emerges all over the body and grows increasingly severe over the next 20 or so days, eventually forming scabs; during this period people are contagious, particularly during the first seven to 10 days of the rash. The disease eventually resolves and contagion ends after all of the scabs have fallen off. People who survive are then considered to be immune from smallpox.

A person can become infected by prolonged, face-to-face exposure with someone who is contagious, direct contact with infected bodily fluids or a contaminated object, such as bedding or clothing, and exposure to an aerosol release.

Routine smallpox vaccination ended in 1972, which leaves at least 43 percent of the U.S. population unvaccinated, Longini said. Research suggests that those previously vaccinated may still have substantial residual immunity although, if infected, they could still transmit the virus to others. Those most vulnerable to the virus are the very young and those whose immune systems are compromised due to HIV/AIDS, cancer or some other medical condition. An estimated 50 million Americans fall into this category, Longini said.

Research suggests therapy against serious side effects of smallpox vaccine

Wed, 22 Mar 2006 01:33:37 PST

( from http://www.rxpgnews.com ) Smallpox is considered a potential terrorist weapon, but millions of people in the United States are currently advised not to get a vaccine to the disease because they are susceptible to developing a severe adverse reaction. Researchers at National Jewish Medical and Research Center report in the March issue of Immunity that a deficiency in the innate immune response may pre-dispose patients with atopic dermatitis, or eczema, to developing the skin condition eczema vaccinatum after vaccination. The findings suggest potential therapeutic targets, which may reduce the risk of this devastating side effect.

"I believe these findings could have a significant impact on our ability to vaccinate individuals with eczema and better protect them against potential bio-terrorist attacks involving smallpox," said Michael Howell, Ph.D., first author of the report and Instructor of Pediatrics at National Jewish Medical and Research Center. "We identify potential therapies, which should be further tested to determine if they can effectively and safely protect susceptible patients against eczema vaccinatum."

Eczema vaccinatum occurs when the vaccinia virus, which is currently used for the smallpox vaccine, replicates uncontrollably and circulates through the entire body. Eczema vaccinatum kills 1 to 6 percent of those affected. Up to 30 percent of children younger than 2 years of age with the disease die. It is also possible that atopic dermatitis patients can develop eczema vaccinatum even if they don't get the vaccine, but come into close personal contact with people who recently received the vaccine.

Approximately 17 percent of children in the United States are diagnosed with atopic dermatitis, suggesting that close to 50 million people in the United States face an increased risk of eczema vaccinatum following the smallpox vaccine. The U.S. Centers for Disease Control currently recommends that individuals with atopic dermatitis, and those who come into close contact with them, do not receive the live vaccine due to potential adverse reactions. This accounts for approximately 50% of the population in the United States. In case of an actual smallpox outbreak, they would likely receive the vaccine and face the increased risk of developing eczema vaccinatum.

The National Jewish research team, led by Donald Leung, M.D., Ph.D., Edelstein Family Chair of Pediatric Allergy-Immunology, had previously reported that atopic dermatitis patients have lower levels of disease-fighting antimicrobial peptides in their skin than people without the disease. They also reported that one particular antimicrobial peptide, called LL-37, could kill vaccinia virus when it is grown in cell culture.

In their current report, the researchers found that lower levels of LL-37 in the skin of patients with atopic dermatitis did indeed allow the uncontrolled growth of vaccinia virus. Skin cells from atopic dermatitis patients failed to increase LL-37 production in response to the vaccinia virus infection, while skin cells from healthy controls and patients with the skin disease psoriasis samples did ramp up LL-37 production. When the researchers added LL-37 to the infected atopic dermatitis skin cells, vaccinia virus growth slowed significantly.

"It is becoming increasingly clear how important antimicrobial peptides are in immune defense," said Dr. Leung. "They are part of the fast-acting, innate immune response. Because atopic dermatitis patients fail to mount a vigorous innate response with antimicrobial peptides, vaccinia virus infection gets well established and the slower adaptive immune response cannot eradicate it."

Atopic dermatitis patients have high levels of signaling molecules interleukin-4 (IL-4) and interleukin-13 (IL-13) in their skin. The researchers found that IL-4 and IL-13 inhibited the production of LL-37 in atopic dermatitis patients. When they added antibodies to neutralize the two interleukins, levels of LL-37 rose in atopic dermatitis patients, and the vaccinia virus infection was controlled.

"Antibodies or other drugs that neutralize IL-4 and IL-13 are currently being developed," said Dr. Howell. "We think they should be evaluated as potential therapies that could be given at the same time as the smallpox vaccine as protection against potentially fatal side effects."

Defective immune system response to smallpox vaccine - study

Wed, 22 Mar 2006 01:28:37 PST

( from http://www.rxpgnews.com ) Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have identified a defect in the immune response of people with the skin condition atopic dermatitis that puts them at risk of developing serious complications following smallpox vaccination. Led by Donald Y.M. Leung, M.D., Ph.D., of the National Jewish Medical and Research Center in Denver, the researchers used laboratory-grown human skin cells to show that an immune system protein called LL-37 is critical in controlling replication of vaccinia virus, the live virus that is the key component in standard smallpox vaccine.

The investigators are part of NIAID's Atopic Dermatitis and Vaccinia Network, which was created in 2004 to integrate clinical and animal research aimed at reducing the risk of eczema vaccinatum, a potentially deadly complication of smallpox vaccination. Eczema vaccinatum occurs almost exclusively in people who have a history of atopic dermatitis, a common, non-contagious skin disorder also known as eczema.

"This new research, the first to be published by Atopic Dermatitis and Vaccinia Network scientists, illuminates one potential mechanism leading to eczema vaccinatum and improves our understanding of the immune responses to smallpox vaccine of people with atopic dermatitis," says NIAID Director Anthony S. Fauci, M.D.

Published in this month's issue of Immunity, the study details how the overproduction in skin cells of inflammation-promoting molecules called interleukin-4 and interleukin-13 (IL-4 and IL-13) hampers LL-37 activity in people with atopic dermatitis. LL-37, a small protein produced in skin cells, is part of the body's first line of defense against invaders. Earlier research by Dr. Leung and his colleagues suggested that LL-37 is critical in controlling the spread of vaccinia virus.

In the current study, the investigators used skin samples taken from people with atopic dermatitis (as well as samples taken from healthy volunteers without skin disease and from people with another skin condition called psoriasis) to further investigate how dysfunctions in the immune response of people with eczema set the stage for eczema vaccinatum. When exposed to vaccinia virus, the skin samples from healthy volunteers and from those with psoriasis reacted by producing more LL-37. As a result, the replication of the virus was controlled and eventually halted. In contrast, LL-37 production was minimal in skin samples from people with atopic dermatitis and vaccinia replication was poorly controlled. Next, the scientists exposed skin samples from people with atopic dermatitis to vaccinia, and then added LL-37. With the LL-37 supplement, the skin cells successfully controlled the viral replication.

Dr. Leung and his group then looked more closely at why vaccinia infection fails to induce LL-37 production in atopic dermatitis skin. Comparing immune responses of skin cells grown in the lab from healthy volunteers and from people with atopic dermatitis, the researchers found that the latter skin samples produced excessive amounts of IL-4 and IL-13. Adding IL-4 and IL-13 to skin cells from healthy volunteers prior to vaccinia exposure reduced levels of LL-37 production. Conversely, when the scientists applied IL-4- and IL-13-neutralizing antibodies to skin samples from people with atopic dermatitis, LL-37 production increased significantly.

Together, these findings suggest a rationale for new treatment approaches to eczema vaccinatum, notes Dr. Leung. One approach involves developing drugs to mimic the action of LL-37 or developing LL-37-containing creams that could be applied to the skin in order to boost its ability to contain vaccinia virus infection. Another approach could be to develop agents to neutralize IL-4 and IL-13. Although no such drugs are currently marketed, compounds that can neutralize IL-4 and IL-13 are under study as possible asthma and allergy treatments, Dr. Leung says, and might also be applied to eczema vaccinatum treatment.

Smallpox vaccine, which is made with live vaccinia virus (a close relative of the virus that causes smallpox), has not been routinely given in the United States since the early 1970s. But recent concerns about the possibility of a bioterrorist attack using smallpox virus prompted authorities to reinstate voluntary smallpox vaccination for specific groups, such as military personnel. In the first five months of 2003, the U.S. Department of Defense vaccinated more than 450,000 personnel against smallpox. During this period, the majority of those who deferred vaccination cited atopic dermatitis or other skin conditions as the main reason.

Secret of smallpox's success may lead to bioterror cure

Sun, 22 May 2005 14:32:38 PST

( from http://www.rxpgnews.com ) In disease, as in war, offensive strategies can become weaknesses, if the defenders see the enemy coming and compensate for its weapons.

By manipulating what is perhaps the most devastating trick in cellular weaponry of pox viruses like smallpox, Arizona State University virologist and Biodesign Institute researcher Bertram Jacobs believes that he can turn the biochemical machinery of the pox viruses against themselves and protect the public against catastrophic bioterror attacks.

And if he is correct, Jacobs may not only be able to create a vaccine that can cure smallpox infections in their early stages, but he may also have a powerful tool for fighting a host of other viral pathogens, including HIV.

Jacobs has received a $1 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), to develop an effective post-exposure vaccine for smallpox. The research is one of ten projects funded under Project Bioshield, which gives federal agencies new tools to accelerate research on medical countermeasures to safeguard Americans against chemical, biological, radiological or nuclear attack.

The idea for the vaccine comes from Jacobs and his team's discovery of a gene that gives pox viruses uncanny ability to camouflage themselves from mammalian immune systems. The ability to stay hidden allows the smallpox virus, in particular, time to grow and multiply to the point of causing devastating disease before the immune system detects it and attempts to mount a counter-attack.

Jacobs notes that there have been clues to this property of the virus present in historical results from using vaccinia, or cowpox, to immunize against smallpox. In most people, exposure to vaccinia generally only causes a mild infection in humans before the immune system responds and eliminates the virus, also leaving immunity to smallpox and other pox viruses in its wake.

"And there has been anecdotal evidence that if you get exposed to smallpox and get vaccinated within 4 days of exposure, the vaccine will protect you," Jacobs said. The immune system is apparently better able to detect the vaccinia virus than it is smallpox, and thus vaccinia alerts the immune system in time to counteract the smallpox infection.

Jacobs' idea for a post-exposure vaccine is to strengthen the immune response to the vaccinia virus by completely eliminating the viral gene that allows pox viruses to hide. The more visible the vaccinia virus is to the immune system, the stronger the immune response should be and the better the body should be able to fight off a smallpox infection.

Over the past 15 years, Jacobs has developed a variety of mutant vaccinia viruses that lack the camouflage gene, and have proved harmless to mice that otherwise get sick from vaccinia. Currently, he is testing these strains for their ability to protect mice that have already been exposed to a particularly lethal strain of vaccinia, or to mouse pox, another pox virus.

"We want to look at all of our mutants and see which ones work best in this post-exposure prophylaxis," explained Jacobs. Though results are preliminary, several strains look promising.

Jacobs' experimental results verify that the de-cloaked viruses not only do not cause disease, but improve disease resistance when they are present. When a mouse has been exposed to a lethal vaccinia virus and then is vaccinated with a very low dose of the mutant virus only 100 virus particles the mouse gets sick but eventually recovers. The more mutant virus the mice are given, the less sick they become.

"If you give them a million particles, they don't even get sick -- the animals stay healthy," notes Jacobs.

"The body reacts and it fights off both the mutant, and also the normal virus that normally would hide itself," said Jacobs. "The more you put in, the more likely it is for the immune system to say 'Hey, wait a minute! There is something going on here! I need to start fighting a virus infection!' and so it fights the mutant virus and a normal pathogenic virus as well."

The gene that Jacobs has isolated and eliminated from the mutants is a special adaptation of pox viruses that appears to help the viruses hide double-stranded RNA, a form of RNA that only viruses produce and that animal immune systems have learned to recognize.

"It's what we call a 'pathogen associated molecular pattern' a biomarker that is only present in your body when you are infected with a virus and that the body knows to look for and respond to," said Jacobs. "The body responds in a lot of different ways, but the main way is it starts producing an immune response double-stranded RNA is very powerful in eliciting this.

"What this gene in pox viruses does is make a protein that binds up all the double-stranded RNA like a little sponge, and this is how the viruses hide infection from your cells," he explained. "Take the gene out and now we have a vaccinia virus that can no longer hide itself it can't camouflage its signature anymore from the cells in its body."

Once the virus calls attention to itself, the immune system begins a complex immune response, including developing antigens that specifically target the virus. Because the virus's double-stranded RNA signal is very clear, the immune response tends to be very strong when the quantity of the uncloaked virus is high.

According to Jacobs, the uncloaked vaccinia virus has the potential to be useful for developing novel post-exposure vaccines for other dangerous viruses as well, making available a who new arsenal of weapons against disease. Antigen-eliciting genes from hard-to-treat viruses such as HIV could potentially be added to the mutant vaccinia virus, which would draw the immune system's attention to the target virus's proteins, thus creating a strong immune response to the target virus. Though perhaps controversial, such a method could ultimately provide effective protection from some of humankind's most challenging viral enemies.

Jacob's current attempt to develop a post-exposure smallpox vaccine is also not with its challenges. Because of the extreme dangerousness of the smallpox virus, the effectiveness of the vaccine cannot actually be tested through clinical trials on humans. Instead, the vaccine is tested on mice and other animal models, using viruses closely related to smallpox that are lethal to those animals.

"We're testing with vaccinia and mousepox in lab mice, and in dormice with monkeypox. These are good model systems if we can protect against mousepox in mice, then we have a high level of certainty that the vaccine will be able to protect against smallpox in humans," Jacobs said.

"Since you can't test in people, the FDA's animal efficacy rule applies. If you can show efficacy in several animal models, then you can presume efficacy in humans, if it is for a disease that you can't ethically expose people to in trial. The vaccine will go through safety studies in humans, though."

Because of the importance of the research for national security, Jacob's work is on a fast-track, with the studies projected to yield a usable vaccine virus within eighteen months. At that point, the virus will go to a commercial manufacturer, who will be responsible for developing and then producing a complete nasal-delivery vaccine. If all is successful, a large number of doses will then be produced and put into storage for possible use in case of emergency, in accordance with the procedures of Project Bioshield.

Though the final product may take a while to be produced and, one hopes, may never have to be used, Jacobs has a feeling now of years of research coming to fruition.

"This is the result of work that we have been doing for 15 years now and I think we are really very close to producing some really important findings, especially now that we are engaged in these fast-track projects," Jacobs said. "It's really exciting."