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Research on West Nile Virus
West Nile virus belongs to a group of disease-causing viruses known as flaviviruses, which are spread by insects, usually mosquitoes. Other flaviviruses include yellow fever virus, Japanese encephalitis virus, dengue virus, and Saint Louis encephalitis virus. West Nile virus is the most familiar flavivirus and represents an emerging infectious disease in the United States. Most human infections are mild, causing fever, headache and body aches, often accompanied by a skin rash and swollen lymph glands. If the virus crosses the blood-brain barrier, however, it can cause life-threatening encephalitis (inflammation of the brain) or meningitis (inflammation of the lining of the brain and spinal cord). The virus is not contagious and cannot be spread among humans.
The first step in the transmission cycle of West Nile virus occurs when a mosquito bites an infected bird. Although the virus primarily cycles between mosquitoes and birds, infected female mosquitoes can transmit West Nile virus to incidental hosts, including humans, when taking a blood meal. Crows are commonly associated with the virus because they are highly susceptible to infection, but scientists have identified at least 75 other infected bird species.
West Nile virus was first isolated in Uganda in 1937. Today it is most commonly found in Africa, West Asia, Europe, and the Middle East. In 1999, it emerged in the Western Hemisphere for the first time in the New York City area. Although health officials hoped the virus would not survive the first winter, in early spring 2000 it re-emerged in birds and mosquitoes and spread to other parts of the eastern United States.
Between 1999 and 2001, West Nile virus caused 18 deaths and sickened 131 other people. By the
summer of 2002, the virus had spread west and south. As of August 23, state health departments had
reported 371 cases of West Nile virus in people, resulting in 16 deaths so far in 2002 (see
www.cdc.gov/od/oc/media/wncount.htm for the CDC's page about the current number of reported
human cases of West Nile virus infections in the United States). Researchers continue to monitor and
test birds and mosquitoes throughout the United States for evidence of the virus (see
www.nationalatlas.gov/virusmap.html for the latest information).
There are no drugs to treat the virus and no vaccines available to prevent infection. Because West Nile virus is now established in the United States, scientists and health experts at the National Institute of Allergy and Infectious Diseases (NIAID), along with public health officials, have enhanced research. This effort is part of NIAID's comprehensive emerging infectious disease program, which supports research on bacterial, viral, and other types of disease-causing microbes.
Research is underway to develop a vaccine, antiviral medicines, and new diagnostic assays for West Nile virus. Additionally, basic research is providing new clues about the virus itself, the disease in humans and animals, and how the virus is maintained in the environment. This knowledge is essential in developing strategies to prevent, treat, and eventually control this disease.
In brief, these areas of research include:
Basic research on the virus itself, on the disease in humans, and on its maintenance in nature
NIAID supports basic research to better understand the host, pathogen, and environmental factors that influence disease emergence. For example, basic research is helping scientists determine which flavivirus proteins contribute to the virus' ability to cause disease. Researchers also investigate how protective immune responses are elicited within the central nervous system during acute flavivirus encephalitis.
Factors influencing the pattern of emergence and distribution of West Nile include those associated with the virus itself, the agent's hosts and vectors, and the environment in which agent and host interact. The specific factors contributing to emergence of West Nile, however, are poorly understood. Nonetheless, knowledge of these principles is essential in planning strategies to prevent, treat, and control this disease. The overall objective of this basic research is to develop the knowledge and public health tools needed for the United States to combat West Nile virus.
NIAID also supports researchers investigating how West Nile virus disseminates throughout the environment. An International Centers for Infectious Disease Research (ICIDR) program is supporting research in Mexico to study whether migrating bird populations carry the virus from its presumed point of entrance into the Western Hemisphere (New York City) to points in Central and South America. The emergence of West Nile virus in these new areas, which harbor abundant mosquito populations, could set up conditions for a potentially severe epidemic. Wild birds and chickens in the Yucatan Peninsula are being examined for evidence of exposure to West Nile virus.
Researchers are also examining the ecology and persistence of mosquito-borne encephalitis viruses and the effect of genetic variation on the virus' spread and virulence. They are examining how birds might be year-round reservoirs for the viruses that cause encephalomyelitis and St. Louis encephalitis. They are also comparing the genetics of St. Louis encephalitis viruses from throughout California and different parts of the United States to determine the rate at which the virus is changing, and whether birds carry it between discrete geographic areas.
NIAID also supports research to better understand the insects and ticks that transmit flaviviruses. Such an understanding will allow improved monitoring and surveillance, and enable the development and preliminary testing of strategies to control carriers of the virus.
Lastly, NIAID-supported basic research is important for maintaining the national and international scientific expertise required to respond to future health threats.
Research to prevent and control spread of the disease
For several years, NIAID has supported research to develop a vaccine against West Nile. In 1999, NIAID funded a fast-track project to develop a candidate West Nile virus vaccine with Acambis. Since then, scientists have developed a prototype vaccine that has shown promise in animal tests. The vaccine is constructed using vaccine licensed for preventing yellow fever (caused by another flavivirus) as the backbone.
For the West Nile vaccine, researchers substituted the surface protein of West Nile virus for the deleted yellow fever virus protein. This method of creating chimeric flavivirus vaccines is also being applied to developing a vaccine for dengue and Japanese encephalitis virus. The Acambis vaccine has undergone preclinical evaluations in in hamsters, mice, monkeys, and horses with encouraging results. The company is moving forward with Phase I trials. Vaccine is now being produced and an investigational new drug (IND) application will be filed with the Food and Drug Administration. Trials are anticipated to begin in early 2003.
Other NIAID scientists, working on the National Institutes of Health (NIH) campus, also have developed a West Nile vaccine candidate which they have tested in monkeys with promising results. That vaccine uses an experimental dengue virus vaccine as a backbone. A DNA vaccine is also being explored through NIAID support.
Last year, NIAID researchers developed a hamster model of West Nile virus, which closely mimics human disease. This animal model has proved useful in evaluating strategies for preventing the complications associated with this emerging infectious disease. Using this animal model, researchers were able to determine that prior infection with other related viruses provides complete or partial immunity to West Nile virus.
Research to treat the disease
Drugs may be effective against West Nile virus because the infection is typically not chronic and antiviral drugs have been identified to be effective in vitro against other flaviviruses. The National Institutes of Health has funded investigators to establish a system to screen chemical compounds for possible antiviral activity against West Nile virus. Any promising antiviral drug candidates will be tested in the hamster model. This resource allows scientists to evaluate a drug's safety and efficacy before moving on to possible human trials. Other research projects are investigating emerging diseases and developing candidate drugs to fight West Nile virus. More than 300 drugs have been screened, and twelve have shown promise for additional testing in animals. Immunotherapeutics (treatments that modify the body's immune response) are also being explored.
Research to improve rapid diagnosis
Research is also underway to allow for more rapid detection of West Nile in samples from humans, other animals, or vectoring mosquitoes. This research occurs mainly at small biotechnology companies attempting to develop new, commercially available diagnostic assays.
NIAID maintains the World Reference Center for Arboviruses at the University of Texas Medical Branch at Galveston, The Center has reference anti-West Nile virus sera and seed lots of various strains of the virus. This international program involves characterizing viruses transmitted to people and domestic animals by mosquitoes and other arthropods, and researching the epidemiology of arboviruses of the United States and overseas. During the last 3 years, these reagents were provided on request to investigators in the United States and Canada.
NIAID expects to increase its portfolio of research on West Nile. New NIAID programs, such as the U.S. Based Collaborations in Emerging Viral and Prion Diseases and Partnerships for Development of Novel Therapeutic and Vector-Control Strategies, are also encouraging research on West Nile virus. Awards for these programs are expected in the early fall of 2002. In addition, many of the programs that have been recently developed and expanded for biodefense are available for other emerging infectious diseases, including West Nile.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.