June 2003 NIAID Research on West Nile VirusOverviewWest 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). Recent cases have indicated that West Nile virus can be transmitted by transfusion or transplantation. In addition, it appears that West Nile virus can also be transmitted from mother to child before birth and through breast milk. 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 humans and other incidental “hosts” when they bite and take a blood meal. Crows are commonly associated with the virus because they are highly susceptible to infection. Scientists have identified at least 75 other infected bird species as well. 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 quickly spread west and south. For 2002, state health departments reported 4,156 cases of West Nile virus in people, resulting in 284 deaths. (See www.cdc.gov/od/oc/media/wncount.htm for the Centers for Disease Control and Prevention [CDC] Web 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. NIAID ResearchResearch is underway to develop a vaccine, antiviral medicines, and new diagnostic tests 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 to develop strategies to prevent, treat, and eventually control this disease. These areas of research include the following. Basic research on the virus, on the disease in humans, and on its maintenance in nature NIAID supports basic research to better understand factors associated with the animal or human hosts, the microbe, and the environment that influence disease emergence. For example, basic research is helping scientists determine which flavivirus proteins contribute to the virus' ability to cause disease. Researchers are investigating 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 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.
Researchers are examining wild birds and chickens in the Yucatan Peninsula for
evidence of exposure to West Nile virus. 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 developing and preliminary testing 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, a biotechnology company with vaccine development laboratories in Boston. Since then, scientists have developed a prototype vaccine that has shown promise in animal tests. Scientists construct the vaccine by 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. They are also applying this method of creating so-called chimeric flavivirus vaccines to make vaccines for dengue and for Japanese encephalitis virus. The Acambis vaccine has undergone preclinical evaluations in hamsters, mice, monkeys, and horses with encouraging results. The company is moving forward toward Phase I human trialsand is expected to soon file an investigational new drug (IND) application with the U.S. Food and Drug Administration. Trials are anticipated to begin in 2003. NIAID intramural scientists, who pioneered the concept of creating chimeric flavivirus vaccines in 1992, also have developed a West Nile vaccine candidate which they have tested in monkeys with promising results. This experimental vaccine, using a dengue virus as a backbone to carry West Nile virus genes, will be tested in Phase I human trials beginning in late 2003. The NIAID Vaccine Research Center (VRC) has started to develop a candidate vaccine for West Nile virus. The VRC's proposed candidates are DNA constructs that express West Nile virus proteins. Vectors have been constructed using West Nile virus genes modified to increase protein expression. Preclinical studies are now underway. Further preclinical evaluation and viral challenge studies will be performed in the near future. The VRC plans to produce clinical grade plasmid DNA for future Phase I trials in hopes of identifying a protective vaccine against the virus. Last year, NIAID-supported 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 the laboratory against other flaviviruses. NIH 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 550 drugs have been screened, and about 3 percent have shown promise for additional testing in animals. Immunotherapeutics (treatments that supply protective antibodies donated from other patients that have recovered from West Nile) 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 mosquitoes. This research occurs mainly at small biotechnology companies attempting to develop new, commercially available diagnostic tests. Research ResourcesNIAID 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 has recently expanded its West Nile and related viruses research portfolio. This includes establishing two Emerging Viral Diseases Research Centers in New York and Texas, with collaborating laboratories in Colorado, Massachusetts, and elsewhere. These centers include a focus on West Nile and related viruses. NIAID has also funded a project entitled “Development of Novel Antiviral Agents Against West Nile Virus” under the Partnerships for Development of Novel Therapeutic and Vector-Control Strategies. 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.
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