RxPG News : Ebola

How Ebola and Marburg viruses cause disease

Tue, 17 Oct 2006 02:00:37 PST

( from http://www.rxpgnews.com ) Researchers in the Greene Infectious Disease Laboratory at Columbia University's Mailman School of Public Health, the Centers for Disease Control and Prevention, and the Caribbean Primate Research Center have discovered a key mechanism by which the Filoviruses, Ebola and Marburg, cause disease. The identification of an amino acid sequence in Filoviruses that results in the rapid depression of immunological response is described in the December 2006 issue of The FASEB Journal. Using this information, researchers can begin to develop new drugs to stop these devastating diseases.

Filoviruses, named for their threadlike appearance in electron microscopy (filo= thread in Latin), are associated with outbreaks of fatal hemorrhagic fever in sub-Saharan Africa. Viral hemorrhagic fevers are of specific concern because they are associated with high morbidity and mortality (up to 80% mortality rates) and the potential for rapid dissemination through human-to-human transmission. The term "viral hemorrhagic fever" characterizes a severe multisystem syndrome associated with fever, shock, and bleeding caused by infection with one of a number of viruses, including the Filoviruses Ebola and Marburg.

Both humans and apes are susceptible to viral hemorrhagic fevers, and it is speculated that filovirus infections account at least in part for the recent decline in the gorilla and chimpanzee population in central Africa. There is no cure or approved vaccine for either Marburg or Ebola virus. Immunosuppression occurs early after infection and allows the viruses to reproduce rapidly and cause disease.

"Currently, there is no way to treat most viral hemorrhagic fever outbreaks, and increased international travel, trafficking in wildlife, political instability, and terrorism have made emerging infectious diseases a global concern," stated W. Ian Lipkin, MD, director of the Greene Infectious Disease Laboratory at the Mailman School's Department of Epidemiology and professor of Epidemiology, Neurology, and Pathology at Columbia University. "The identification of this new mechanism for immunosuppression is anticipated to lead to new drugs for intervention in filoviral hemorrhagic fevers of humans and apes."

In the study, researchers describe a series of amino acids in Ebola and Marburg viruses that resemble proteins in retroviruses known to suppress the immune system. By targeting these amino acids, new drugs could disrupt the ability of these viruses to shut down immune systems and make them vulnerable to the body's natural defenses.

"This brilliant study shows that many viruses, including HIV, use a similar mechanism to disarm their victims," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. "The Columbia study has shown us new ways to fight against deadly viruses the world over."

The method for discovering this protein underscores the power of bioinformatics for addressing the challenges of emerging infectious diseases. The investigators are currently exploring whether insights derived from understanding the potency of these immunosuppressive peptides can be exploited to treat autoimmune diseases.

Simplified vaccine against Ebola virus developed

Sat, 10 Jun 2006 13:20:37 PST

( from http://www.rxpgnews.com ) Humans who get infected with Ebola virus develop an illness called Ebola hemorrhagic fever (EHV), which is one of the most deadly viral diseases known; 50%90% of all ill patients die, and there is no available treatment for EHV. Scientists think that the occasional outbreaks of the disease occur because the virus jumps from an infected animal to a person (a rare event) and then is transmitted between people by direct contact with infected blood or other body fluids or parts. Several strains or variants of the Ebola virus exist. Most outbreaks have been caused either by the Zaire strain or by the Sudan/Gulu strain (so-called because that is where the particular virus was first isolated). Scientists are working on a vaccine against Ebola that could be given to people before they get infected and then protect them when they come in contact with the virus. A number of candidate vaccines have been developed and tested in animals.

The researchers who did this study are working on a vaccine that consists of two particular parts of the virus. One part is called GP (which stands for glycoprotein) and is from the outer coat of the virus; the other, NP (nucleoprotein), is from its inside. Without the rest of the virus, GP and NP cannot cause EBV. However, the hope is that giving these parts of the virus to an individual can educate their immune system to build a response against GP and NP, which would then recognize the virus should the vaccinated person become infected with the whole virus, and destroy it before it can cause disease. To get the GP and NP parts into the body so that they can cause a strong immune response (which is what effective vaccines do), the researchers used a manmade version of another, harmless virus called recombinant adenovirus 5 (or rAd5) to carry the NP and GP. The researchers have shown previously that this strategy for introducing a vaccine works in animals. The vaccinei.e., the combination of the rAd5 virus and the two Ebola virus partscan protect animals against subsequent infection with real Ebola virus that would otherwise kill them. However, during these earlier studies, the researchers had noticed that the GP part, when present at high levels, seemed to make human cells sick. They had not seen any similar problems in the experimental animals, but to be on the safe side they decided to see whether they could change the GP part so that it would still be effective as a vaccine but no longer make human cells sick.

They changed the GP part of the vaccine in different ways so that it would no longer make human cells sick and then tested whether the resulting vaccines (combined with the original NP part and the Ad5 virus) could still protect monkeys from EHF after they were infected with Ebola virus. They found that some of the new GP versions made the vaccine less effective, but others did what they had hoped for; namely, they gave the same level of protection as when the original GP part was present. While doing these experiments, the researchers also found that the NP component seemed unnecessary and in some cases even weakened the vaccine's effect.

The researchers have now developed a simplified vaccine against Ebola virus that is effective in monkeys. This vaccine consists of only a modified GP component (which is well tolerated by human cells even at high concentrations) and the rAd5 component. This vaccine is not the only candidate currently being developed against Ebola, but it seems likely that it is one of a few that will be tested in human volunteers in the near future. The initial clinical trials will test whether the vaccine is safe in humans, and whether it can cause the immune system to produce an immune response that is specific for the Ebola virus. Assuming that the outcomes of these trials are positive, the next question is whether the vaccine can protect humans against Ebola disease. Because Ebola is so dangerous and outbreaks are relatively rare, the vaccine will likely be tested only during an actual outbreak. At that time, an experimental vaccine might be given to people at immediate risk of becoming infected, especially health-care workers who, because they take care of infected patients, are themselves at very high risk of becoming infected. In addition to trials in humans, the scientists will also explore whether this vaccine, which was developed based on the GP component of the Zaire strain, can protect monkeys against infections with other strains of the Ebola virus.

Ebola Virus Vaccine May Protect Against Sudan and Zaire Species

Sat, 11 Mar 2006 20:36:37 PST

( from http://www.rxpgnews.com ) Researchers from South Carolina and Maryland have developed a bivalent vaccine that may protect against both the Sudan and Zaire species of Ebola virus. Their findings appear in the March 2006 issue of the Journal of Virology.

Ebola virus (EBOV) causes a severe hemorrhagic fever in humans and nonhuman primates resulting in death in 90% of those infected. Two particular species, Sudan ebolavirus (SEBOV) and Zaire ebolavirus (ZEBOV), have been responsible for the deadly human outbreaks that have occurred in Africa. To date, outbreaks have been limited to this region, however increasing international travel and bioterrorist threats have reinforced the need for an effective and swift acting vaccine.

In the study researchers vaccinated mice with a bivalent vaccine, containing both SEBOV and ZEBOV genes, and found that vaccination led to efficient induction of EBOV antibody and immune responses to both species. In addition, a group of immunized mice were challenged with a lethal dose of ZEBOV and the survival rate was 100%.

"To our knowledge, this is the first demonstration of a bivalent EBOV vaccine to coexpress multiple serotype proteins in a single vaccine construct, eliciting efficient humoral and cellular immune responses to both SEBOV and ZEBOV antigens," say the researchers.

Ebola DNA vaccine produces immune responses : Phase 1 trial

Wed, 22 Feb 2006 16:18:37 PST

( from http://www.rxpgnews.com ) Vical Incorporated (Nasdaq:VICL) announced today that an Ebola vaccine candidate administered using Vical's proprietary DNA delivery technology was safe and well tolerated, and produced both antibody and T-cell Ebola-specific responses in all healthy volunteers who received the full 3 doses of vaccine.

The Phase 1, randomized, placebo-controlled, dose-escalation study, the first human trial for any Ebola vaccine, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and conducted at the NIH Clinical Center. The data were presented at the American Society for Microbiology (ASM) 2006 Biodefense Research Meeting in Washington, D.C., by Julie E. Martin, D.O., a trial investigator and research scientist at NIAID's Dale and Betty Bumpers Vaccine Research Center (VRC), which developed the vaccine. The DNA vaccine used in the Phase 1 trial incorporates genetic material encoding core and surface proteins from two strains of Ebola. Vical has secured a nonexclusive license from the NIH to proprietary gene sequences used in the vaccine.

"The high rates of immune responses at all dose levels in this initial human Ebola vaccine study support continued development of this vaccine and further evaluation of our technology for potential additional biodefense and emerging disease applications," said David C. Kaslow, M.D., Vical's Chief Scientific Officer, "particularly where antibody responses may be protective. Our processes allow rapid development and manufacturing of vaccines without handling potentially dangerous pathogens."

The vaccine used in the Phase 1 trial vaccine included three plasmids (closed loops of DNA), one each encoding the surface glycoprotein (GP) from the Zaire strain of Ebola, GP from the Sudan/Gulu strain, and the internal nucleoprotein (NP) from the Zaire strain. Subjects received three doses of vaccine or placebo at one-month intervals via intramuscular needleless injection. Three cohorts tested progressively higher doses of the vaccine at 2 mg (5 subjects), 4 mg (8 subjects), or 8 mg (8 subjects with 6 receiving the full three doses). Each cohort included two additional subjects who received placebo instead of active vaccine.

The vaccine was well tolerated, with no severe adverse reactions to the vaccine reported at any of the doses tested. Ebola-specific antibody responses against at least one of the encoded antigens were detected in all vaccine recipients. GP-specific antibody and T-cell responses were detected in all recipients who received the full three doses at all dose levels.

Charting the Path of the Deadly Ebola (ZEBOV) Virus

Wed, 26 Oct 2005 15:39:38 PST

( from http://www.rxpgnews.com ) Thanks to sensationalized accounts of patients with liquefying flesh and spouting blood, the Ebola virus may well be the most feared disease on the planet. But the reality of the virus, which strikes humans and other primates, is grim enough, with patients experiencing sudden onset of fever, headache, intense weakness, and muscle pain, followed by diarrhea, vomiting, severe rash, organ failure, and massive hemorrhaging, sometimes external, within two to 21 days of exposure. The first human Ebola outbreaks occurred between 1976 and 1979 in Sudan and Zaire (now the Democratic Republic of Congo), where 88% of the 318 infected persons diedâa typical mortality rate for this strain, called the Zaire strain of Ebola virus (ZEBOV). It's thought that humans acquired the virus after handling infected gorilla and chimp carcasses.

Over the past ten years, separate outbreaks of the deadly Zaire strain have killed hundreds of humans and tens of thousands of great apes in Gabon and the Republic of Congoâwhich harbor roughly 80% of the last remaining wild gorilla and chimpanzee populations. Between 1983 and 2000, poaching and logging precipitated catastrophic declines in these great apes, but scientists fear that Ebola may pose an equally deadly threat. Any efforts to contain the next epidemic depend on understanding the dynamics of the virus's spread.

In a new study, Peter Walsh, Roman Biek, and Leslie Real combined genetic data with information on the timing and location of past ZEBOV outbreaks to determine the merits of two competing hypotheses to explain the emergence and spread of the virus. In the prevailing view, ZEBOV arose from long-persistent local strains after increased contact between humans or great apes and an unidentified reservoir host. But Walsh et al. found support for the alternative hypothesis: that ZEBOV had recently spread to the outbreak regions. This is good news because a virus that spreads at a predictable rate in a predictable direction is far easier to control than one that emerges by chance or at the hands of an unknown trigger.

The authors modeled the virus's spread based on assumptions of a long-persistent virus versus a recently emerged virus, and tested the predictions of these competing hypotheses using genetic dataâgathered from gene sequences taken from human samples at the different outbreak sitesâand information on the spatiotemporal dynamics of the outbreaks. Charting the evolutionary relationships of the viral genotypes identified one major lineage with a most recent common ancestor consistent with the 1976 outbreak. Comparing the path of descent with outbreak localities mirrored the timing of the outbreaks, with new outbreaks directly descending from those preceding.

Analyzing the spatiotemporal pattern of outbreaks revealed a spread at the rate of about 50 kilometers/yearâa predictable path not likely for a persistent virusâwith the first epidemic in Yambuku, then spreading south to Kikwit and west to BoouÃ©, Gabon. Plotting the geographic distribution of genotypes revealed a clear spatial structure at both local and regional scales: the genotypes from the 2001â2003 Gabon/Congo outbreaks, for example, decreased in genetic similarity as distance increased. Again, this finding is consistent with the recently emerged hypothesis, which predicts a correlation between genotype and geography at different distances. Simulations of viral evolution in a spreading epidemic also showed a consistent spread pattern and a strong correlation between genetic divergence and spatial separation. Though the authors can't say how the virus was transmitted, the simulations showed that a âsimple nearest neighbor contact processâ could produce the linear, uniform spread rates found here.

Though the strength of the individual lines of evidenceâtiming of origin, spatial spread, and genetic/distance ratioâis not conclusive when considered separately, taken together, they support the hypothesis that a âconsistently moving wave of ZEBOV infectionâ recently spread to outbreak sites in Gabon and Congo. Following its current course, ZEBOV may hit populated areas east of Odzala National Park within 1â2 years and reach most parks containing large populations of western gorillas in 3â6 years. Two Ebola outbreaks have already hit human populations west of Odzala, and over the past two years, the largest gorilla and chimp populations in the world, found in Odzala, have been devastatedâthe disease is spreading to the last unaffected sector of the park right now. These findings suggest that strategies to protect villagers and some of the last remaining wild apes from future outbreaks would do best to concentrate efforts at the front of the advancing waveâand start acting now. âLiza Gross

Scientists discover how Ebola virus infects cells

Fri, 15 Apr 2005 18:55:38 PST

( from http://www.rxpgnews.com ) Ebola virus reproduction in laboratory-grown cells is severely hampered by enzyme-inhibiting chemicals, and these chemicals deserve further study as possible treatments for Ebola virus infections in humans, report scientists supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH).

The researchers, whose paper is published online today in Science Express, identified two cellular enzymes Ebola virus must have to reproduce. When those enzymes are blocked, the virus loses most of its infectivity, the scientists found.

Ebola virus, like the Marburg virus now alarming Angola, is a filovirus, a family of viruses that cause severe and frequently fatal hemorrhagic fevers. "Finding medical countermeasures for viral hemorrhagic fevers is a global public health priority because not only do these diseases occur naturally but they also have the potential to be unleashed by bioterrorists," says NIH Director Elias A. Zerhouni, M.D.

"This new research sheds light on the mechanism Ebola virus uses to enter cells," notes NIAID Director Anthony S. Fauci, M.D. "These findings raise the possibility of a broad-spectrum antiviral therapy that could be effective against multiple hemorrhagic fever viruses."

Senior author James M. Cunningham, M.D., of Brigham and Women's Hospital and Harvard Medical School in Boston, and his colleagues discovered two cellular enzymes that the Ebola virus co-opts and uses to cut up one of the virus' surface proteins. Once this protein is snipped apart, the virus is free to begin multiplying. The scientists applied broad-spectrum enzyme inhibitors to mammalian cells before exposing them to Ebola virus. When one specific cellular enzyme, cathepsin B, was inhibited, the infectivity of Ebola virus dropped to near zero. An accessory role is played by another cellular enzyme, cathepsin L, the scientists determined.

Inhibitors of cathepsins are already under clinical development as anti-cancer drugs. The authors write, "Further investigation of the antiviral efficacy of [enzyme] inhibitors maybe warranted. The wealth of existing knowledge regarding the design and in vivo pharmacology of these inhibitors may facilitate development of an anti-Ebola-virus therapy."