Aug. 19, 2003 Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) have created a promising vaccine against West Nile virus by replacing parts of a distantly related virus with proteins from the West Nile virus. The NIAID research team replaced proteins in a virus known as dengue type 4 with the corresponding West Nile virus proteins, creating a hybrid virus vaccine that protects monkeys from West Nile infection, they report in a paper to be published in the September issue of the journal Virology and currently available online.
"The Department of Health and Human Services has responded vigorously to emerging infectious diseases, including West Nile Virus, and we aim for the earliest and best possible protection for Americans," says HHS Secretary Tommy G. Thompson. "We will continue aggressive research and development steps, and we will continue to work with our public health partners toward preventing mosquito-borne disease and ensuring effective prevention and treatment."
"West Nile is one of the emerging infectious diseases for which we are developing novel preventive and therapeutic tactics," says NIAID Director Anthony S. Fauci, M.D. "Because our researchers have more than a decade of experience working with this class of virus, they could respond very quickly to the urgent public health need for a promising West Nile virus vaccine."
Human clinical trials of the vaccine are expected to begin before the end of 2003. "We're optimistic that our engineered virus vaccine will provide long-term immunity to West Nile virus, but the human clinical trials will give us the definitive data," says Brian Murphy, M.D., of the NIAID Laboratory of Infectious Diseases.
West Nile virus is spread to people by mosquitoes. It usually produces mild, flu-like symptoms but can cause a deadly encephalitis, or inflammation of the brain. The virus was first detected in the United States in 1999. Since then, it has spread rapidly from the northeastern United States throughout North America. Centers for Disease Control and Prevention statistics show that West Nile cases this year are quickly outpacing those for the same period in 2002. The disease is most severe among the elderly and has sickened 470 and claimed 10 lives in the United States this year.
The potential West Nile vaccine is a live but weakened virus. To create it, scientists took the dengue 4 virus and replaced its outer shell proteins with corresponding proteins from West Nile virus, explains Alexander Pletnev, Ph.D., lead investigator and NIAID molecular biologist.
Dr. Pletnev and colleagues at NIAID developed the strategy of mixing parts of one virus with another to form chimeric viruses for use as vaccines in 1991. They found that this approach could cripple the disease-causing virus but still trigger a strong immune response against it.
To ensure the safety of the chimeric virus in humans, the scientists further weakened the West Nile/dengue 4 virus by deleting some of the genetic material, RNA in this case, from the dengue virus. With this deletion, the chimeric virus was less able to replicate itself when injected into the monkeys. Even though it was further weakened in its ability to replicate in the monkeys, the monkey immune system was still able to produce protective antibodies against the West Nile virus proteins.
The scientists tested two versions of the West Nile/dengue 4 virus in rhesus monkeys, one with the entire dengue virus RNA and one with some of the dengue RNA deleted. By doing so, they proved that deleting some of the dengue RNA weakened it even further.
NIAID scientists gave one or the other of the two chimeric virus vaccines to 12 monkeys and then measured the monkeys' antibodies to both West Nile and dengue 4 virus. They also simultaneously injected eight other monkeys with either West Nile virus or dengue 4 virus for comparison.
After six weeks, the scientists injected West Nile virus into all 20 monkeys. The 12 monkeys that received a version of the West Nile/dengue 4 virus developed high levels of neutralizing antibodies that successfully fought the West Nile virus.
Because it was less able to replicate, the West Nile/dengue 4 virus with the RNA deletion will be the first one used in the planned clinical trials in humans. Scientists favor this virus as a vaccine because it triggered high levels of West Nile antibodies and did not produce measurable levels of virus in monkeys. It could provide life-long immunity against West Nile virus and would be highly unlikely to mutate into a disease-causing virus. It is also not likely to be passed via mosquitoes to birds or other animals.
NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Reference: A Pletnev et al. Molecularly engineered live-attenuated chimeric West Nile/dengue virus vaccines protect rhesus monkeys from West Nile virus. Virology, in press. Available online at http://www.sciencedirect.com. doi:10.1016/S0042-6822(03)00450-1.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
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