Human antibodies against West Nile virus and related Orthoflaviviruses 9100

Abstract Description West Nile virus (WNV), a member of the Orthoflavivirus genus, can cause fatal encephalitis in humans. With no specific treatment available, WNV remains the leading cause of mosquito-borne disease in the continental United States, spreading globally. The antiviral antibody response is important for protection against WNV disease, while anti-interferon type I (IFN-I) autoantibodies have been linked to higher risk of WNV encephalitis. We show that the presence of anti-IFN-I autoantibodies does not impair the development of antiviral antibodies in individuals with WNV neuroinvasive disease. From selected convalescent individuals with high WNV serum neutralizing activity we isolated W010, a potent monoclonal antibody targeting the virus envelope domain III (EDIII). In a lethal mouse model, W010 provides significant protection even at low doses and when administered up to five days post-infection. Unlike previously reported antibodies, W010 is highly effective against both lineages of WNV that cause human disease. Other EDIII-specific antibodies that were discovered are broadly cross-reactive, also neutralizing other members of the Japanese encephalitis virus serocomplex in vitro (JEV, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus). Thus, human pan-neutralizing antibodies exist that simultaneously protect against viruses of the JEV-serocomplex. The structural basis of neutralization by the lead antibodies for clinical development is revealed. Funding Sources Swiss National Science Foundation (no. 310030L_196866), NIH U01 AI151698 Topic Categories Vaccines and Immunotherapy (VAC)