EVALUATION OF THE ROLE OF ANTIBODIES IN MEDIATING ALPHA VIRUS VACCINE INTERFERENCE

Abstract

The phenomenon of alphavirus vaccine interference was evaluated by establishing a BALB/c mouse model. Interference was defined as a three-fold or more reduction in the neutralization antibody titers induced to an alphavirus immunogen in the presence of prior alphavirus immunity. Immunity to the formalin-inactivated Eastern equine encephalitis (EEE) vaccine significantly interfered with subsequent immunization with the liveattenuated Venezuelan equine encephalitis (VEE) TC-83 vaccine. Increasing the dose of TC-83 in EEE immune mice did not overcome vaccine interference. Passive transfer experiments indicated that antibodies, specifically a cross-reactive monoclonal antibody (MAb) K42 that recognizes a cryptic epitope, can mediate interference in this system. Formalin-inactivated vaccines (C-84, LEE and Western-equine encephalitis (WEE)) were not interfered with when administered as the secondary immunogen. While both the live and formalin-inactivated vaccines are accessible to the immune system extracellularly, only live vaccines express their epitopes on infected cells. Viral proteins expressed on infected cells may allow cross-reactive antibodies to mediate interference by binding to and causing lysis of infected cells. The observations with the new VEE vaccine candidate (V3526) were promising since prior alphavirus immunity only moderately decreased the secondary antibody neutralization responses. V3526 has a mutation at El:253 and a deletion of a cleavage site that results in the viral spikes containing PE2-E1 heterodimers instead of the E2-E1 heterodimer spikes on TC-83. These changes may have decreased the accessibility of the El cross-reactive epitope and reduced interference with the V3526 vaccine. The findings with the new vaccine candidate are encouraging for alphavirus vaccine development and demonstrates the vaccine's potential for veterinary and human immunizations.