Overview

West Nile virus (WNV) is an emerging infectious disease that made its first appearance in the United States in 1999. The microbe that causes the infection belongs to a group of disease-causing viruses known as flaviviruses that are usually spread by ticks or mosquitoes. Other well-known diseases caused by flaviviruses include yellow fever, Japanese encephalitis, dengue, and Saint Louis encephalitis.

People who contract WNV usually experience only mild symptoms—fever, headache, body aches, skin rash, and swollen lymph glands. If WNV enters the brain, however, it can cause life- threatening encephalitis (inflammation of the brain) or meningitis (inflammation of the lining of the brain and spinal cord). Most cases of disease occur in elderly people and those with impaired immune systems. Recent cases have shown that WNV can be transmitted through blood transfusions and organ transplants from WVN-infected donors. Health experts also believe it is possible for WVN to be transmitted from a mother to her unborn child and through breast milk.

The first step in the transmission cycle of WNV occurs when a mosquito bites an infected bird or other infected animal. Crows are commonly associated with the virus because they are highly susceptible to infection. Scientists have identified more than 138 bird species that can be infected, and more than 43 mosquito species that can transmit WNV. Although the virus primarily cycles between mosquitoes and birds, infected female mosquitoes also can transmit WNV through their bites to humans and other “incidental hosts?such as horses. With so many susceptible hosts to amplify the virus and so many types of mosquitoes to transmit it, WNV has spread rapidly across the United States.

WNV 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 was found in the Western Hemisphere for the first time in the New York City area. In early spring 2000, it appeared again in birds and mosquitoes and then spread to other parts of the eastern United States. By 2004, the virus had been found in birds and mosquitoes in every state except Alaska and Hawaii.

In 2005, WNV caused 2,949 cases of disease in the United States, including 116 deaths, according to the Centers for Disease Control and Prevention (CDC). Human cases have now been reported throughout the continental United States and in Canada and Mexico. The CDC Web site has the most recent numbers of reported human cases of WNV infection in the United States (www.cdc.gov/ncidod/dvbid/westnile/index.htm).

Although licensed WNV vaccines exist for horses, there are no specific vaccines or treatments for human WNV disease. Faced with a potentially deadly illness spreading quickly across the United States, scientists and public health officials have accelerated research on developing tools to prevent and treat WNV disease. The National Institute of Allergy and Infectious Diseases (NIAID) supports research on WNV disease through its comprehensive emerging infectious disease program, which supports research on bacterial, viral, and other types of disease-causing microbes.

BASIC RESEARCH

Complex interactions between the virus, birds and other animals, mosquitoes, and the environment have influenced the pattern of WNV emergence and distribution across the United States. Yet specific factors contributing to the emergence of WNV are poorly understood. Knowledge of these principles is essential in planning strategies to prevent, treat, and control this disease. The goal of NIAID basic research on WNV is to develop a knowledge base to enable the development of medical countermeasures against WNV.

NIAID supports basic research at universities and other institutions to better understand the infection in animals and humans, the virus itself, and the environmental factors that influence disease emergence. For example, researchers are

• Determining how the virus replicates and spreads throughout the body in order to develop vaccines and drugs to prevent and treat disease
• Determining which viral proteins contribute to the virus?ability to cause disease
• Investigating how the immune system responds in the most serious form of the disease, West Nile encephalitis
• Examining the ecology and year-to-year maintenance of mosquito-borne encephalitis viruses and how genetic variation affects spread and virulence of the virus
• Studying whether migrating bird populations carry the virus to points in Central and South America

The emergence of WNV in Central and South America, which harbor abundant mosquito populations, could set up conditions for a potentially severe epidemic.

Researchers also are working to better understand other insects and ticks that transmit other flaviviruses. Such an understanding will allow improved monitoring and surveillance, and enable development and preliminary testing of strategies to control carriers of the virus.

RESEARCH TO PREVENT WNV DISEASE

NIAID supports the development of several WNV vaccine approaches, including chimeric vaccines (which combine genes from more than one virus into a single vaccine), naked DNA vaccines, and vaccines containing cocktails of individual West Nile proteins.

In November 2003, Acambis, a biotechnology company with vaccine development laboratories in Cambridge, Massachusetts, started the first human clinical trial of a WNV vaccine. The Acambis vaccine is based on work performed under a fast-track project funded by NIAID in 2000. Scientists based the vaccine on one already licensed for preventing yellow fever, which is caused by another flavivirus.

Called a chimeric virus vaccine, the Acambis vaccine contains genes from two different viruses? yellow fever and West Nile. Researchers replaced some of the yellow fever virus genes with genes for a surface protein of WNV. They are also developing similar chimeric vaccines for dengue fever and for Japanese encephalitis. The Acambis West Nile vaccine performed well in hamsters, mice, monkeys, and horses, and has now entered human clinical trials.

NIAID intramural scientists pioneered the concept of creating chimeric vaccines for flaviviruses in 1992. These scientists, led by Dr. Brian Murphy, have now developed a chimeric West Nile vaccine and tested it in monkeys with promising results. This experimental vaccine, which uses an attenuated dengue virus as a backbone to carry WNV protective antigens, is in an ongoing Phase I human trial (see the NIAID press release for more details [www.niaid.nih.gov/newsroom/releases/wnv]).

Led by Dr. Gary Nabel, researchers at the NIAID Vaccine Research Center (VRC) have also developed an investigational vaccine for preventing WNV infection in collaboration with the San Diego based biotechnology company, Vical, Inc. The vaccine is based on an existing codon-modified gene-based DNA plasmid vaccine platform designed to express WNV proteins. In April 2005, following pre-clinical safety studies and viral challenge studies, VRC initiated a Phase I clinical trial to evaluate safety, tolerability, and immune responses of this recombinant DNA vaccine in human volunteers. Also in collaboration with Vical, Inc., VRC is currently developing a second generation DNA vaccine using an improved expression vector expressing the same WNV proteins. A Phase I clinical trial is planned for Spring 2006.

In 2002, NIAID-supported researchers developed a hamster model of WNV infection that closely mimics the human disease. This animal model has proved useful in evaluating ways to prevent serious complications associated with this emerging infectious disease. Using the hamster model, researchers were able to determine that prior infection with other related viruses may provide complete or partial immunity to WNV.

RESEARCH ON WNV TREATMENTS

No specific therapies for WNV infection currently exist; supportive care is generally the only treatment for those infected. NIAID supports research to develop and test antiviral drugs, antibody products, and other therapies to prevent or treat severe complications of WNV infection that may develop, such as encephalitis and meningitis.

NIAID currently funds a nationwide clinical trial to test whether antibodies from people who have recovered from WNV infection can be used to treat those with severe West Nile neurologic disease. Investigators are comparing this treatment to placebo treatments to assess safety and to determine whether these antibodies help overcome the severe disease symptoms. More information on this clinical trial is available on the NIAID Collaborative Antiviral Study Group Web site at www.casg.uab.edu.

Because some drugs are effective against related viruses in laboratory tests, scientists are optimistic that they will be able to develop drugs to treat WNV disease. Over the past several years, NIAID has expanded its in vitro and in vivo antiviral screening program to screen chemical compounds for possible effectiveness against WNV (www.niaid.nih.gov/dmid/viral). Promising antiviral drugs identified in vitro are subsequently tested in hamster or mouse models of the disease. These animal models allow scientists to evaluate a drug’s safety and efficacy before possible human trials. Since October 2003, more than 2,500 drugs have been screened in vitro, and about 1 to 2 percent have shown promise for additional testing in animals. NIAID also funds investigators in industry and academia for research and development of candidate antiviral drugs and other therapies.

NIAID clinicians are studying how WNV disease progresses in people who have or are at risk of developing its most serious complications. This research study, conducted through the Collaborative Antiviral Study Group and at the National Institutes of Health Clinical Center, measures the neurologic function of people hospitalized with WNV and will continue to monitor them as they recover. Data collected in this study will give doctors a better understanding of West Nile encephalitis and will assist in designing better treatments for this form of WNV disease.

RESEARCH TO IMPROVE THE DIAGNOSIS OF WNV

NIAID also sponsors research to develop methods that will more quickly and accurately detect WNV in humans, animals, and mosquitoes. NIAID has awarded Small Business Innovation Research grants to small biotechnology companies to support development of new diagnostic tests for WNV. At least one such test under development shows promise for more accurate diagnosis of WNV in people and animals. NIAID also funds academic investigators to develop tests to detect WNV and WNV antibodies in people, animals, mosquitoes, and in blood or organ donations.

RESEARCH RESOURCES

NIAID funds the World Reference Center for Emerging Viruses and Arboviruses at the University of Texas Medical Branch at Galveston. This international program characterizes numerous viruses spread by mosquitoes, ticks, and other insects and animals to people and domestic animals. It also investigates the epidemiology of the diseases these viruses cause. The center stores various strains of the WNV as well as samples of sera containing WNV antibodies. Qualified researchers in the United States and other countries may request samples for use in experiments.

Sets of overlapping peptides for 11 WNV proteins were made available in winter 2005 through the NIAID Biodefense and Emerging Infections Research Resources Program (www.beiresources.org). The peptides will be useful for vaccine research as well as immunologic research to assess the body’s response following exposure to WNV. NIAID has expanded its funding of WNV research in academic and private sector laboratories. This includes establishing two Emerging Viral Diseases Research Centers in New York and Texas with collaborating laboratories in Colorado, Massachusetts, and several other states. These centers focus on West Nile and other emerging viruses.

MORE INFORMATION

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.

The National Institutes of Health (NIH)-The Nation's Medical Research Agency- includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

U.S. Department of Health and Human Services