Immunization with Heterologous Flaviviruses
Prior immunization of hamsters with three heterologous flaviviruses (Japanese encephalitis virus [JEV] SA14-2-8 vaccine, wild-type St. Louis encephalitis virus [SLEV], and Yellow fever virus [YFV] 17D vaccine) reduces the severity of subsequent West Nile virus (WNV) infection. Groups of adult hamsters were immunized with each of the heterologous flaviviruses; approximately 30 days later, the animals were injected intraperitoneally with a virulent New York strain of WNV. Subsequent levels of viremia, antibody response, and deaths were compared with those in nonimmune (control) hamsters. Immunity to JEV and SLEV was protective against clinical encephalitis and death after challenge with WNV. The antibody response in the sequentially infected hamsters also illustrates the difficulty in making a serologic diagnosis of WNV infection in animals (or humans) with preexisting Flavivirus immunity.

West Nile virus (WNV) was detected for the first time in North America in summer of 1999, during an outbreak involving humans, equines, and birds in the New York City metropolitan area. Persistence of the virus and its spread to other states on the eastern seaboard during 2000 and 2001 suggest that WNV is now endemic in the United States and that its geographic range probably will continue to expand until it extends over much of the continent. Although many WNV infections in humans are asymptomatic or unrecognized, some patients have an acute dengue-like illness, and a small percentage have encephalitis or meningoencephalitis. The latter complication is most common among the elderly, with recent reported case-fatality rates from 4% to 11%. No specific treatment is available for WNV encephalitis, and no licensed vaccine is available for its prevention.

WNV is a positive-stranded RNA virus; based on its antigenic and genetic characteristics, it is included in the Japanese encephalitis virus (JEV) serocomplex of the genus Flavivirus, family Flaviviridae. The JEV serocomplex includes four antigenically related viruses that are important causes of encephalitis in humans: JEV, WNV, St. Louis encephalitis virus (SLEV), and Murray Valley encephalitis virus (MVEV). In addition to their antigenic and genetic relatedness, these four viruses have many epidemiologic similarities.

Because of the close antigenic relationships among many viruses in this genus, Flavivirus infections are difficult to differentiate by most serologic techniques, especially in persons or animals having a second or sequential Flavivirus infection. Considerable attention has been focused on the immune response in primary and secondary Flavivirus infection and the role of immunopathogenesis in the etiology of severe Flavivirus disease. In the case of dengue, enhancement of virus replication by heterologous flavivirus antibodies and T-cell activation are thought to occur in some patients during a second or sequential dengue infection, resulting in hemorrhagic fever or shock. In contrast, animal data indicate that prior infection with a heterologous Flavivirus reduces the severity of subsequent challenge with WNV. Results of experimental studies with rodents, monkeys, and pigs suggest that heterologous Flavivirus antibodies protect against or modify subsequent infection with WNV. This phenomenon could be important in vaccine development against WNV infection and in determining the ultimate geographic distribution and public health importance of WNV if it is introduced into areas of Central and South America where other flaviviruses, such as Dengue virus (DENV), Yellow fever virus (YFV), SLEV, and Ilhéus virus (ILHV), are endemic.

To determine more precisely the degree of cross-protection among members of the JEV serocomplex and the possibility that this phenomenon could be used to protect against severe WNV infection, a series of experiments was carried out with three heterologous flaviruses and a recently described model of WNV encephalitis. We report the results of these studies, which indicate that prior immunization of hamsters with a JEV vaccine strain and a wild-type SLEV--and to a lesser extent the 17-D YFV vaccine--modify subsequent WNV infection and protect the animals from fatal encephalitis.