Chikungunya virus E2 B domain nanoparticle immunogen elicits homotypic neutralizing antibody in mice

Alphaviruses are enveloped, positive-sense single-stranded RNA viruses that cause severe human and animal illness. Arthritogenic alphaviruses, such as Chikungunya virus (CHIKV) and Mayaro virus (MAYV), are globally distributed, transmitted by mosquitoes, and can cause rheumatic disease characterized by fever, rash, myalgia, and peripheral polyarthralgia that can persist for years post-infection. These infections can also result in more severe clinical manifestations such as hemorrhage, encephalopathy, and mortality. Several potent monoclonal antibodies (mAbs) with broad neutralizing activity have been shown to bind to the E2 B domain (E2-B) of the alphavirus glycoprotein, suggesting that E2-B epitopes are a site of susceptibility for multiple arthritogenic alphaviruses. However, it is unknown whether E2-B alone can elicit a broadly neutralizing humoral response. Here, we generate and characterize nanoparticle-based immunogens containing CHIKV and MAYV E2-B. Immunization with the CHIKV E2-B nanoparticle elicited sera that were cross-reactive toward CHIKV and MAYV E2-B, but had only homotypic neutralizing activity (serum titer of 1:512) against CHIKV vaccine strain 181/25. Furthermore, immunization with MAYV E2-B nanoparticles elicited non-neutralizing antibody, but sera were cross-reactive for both CHIKV and MAYV E2-B. Our findings suggest that the immunodominant epitopes within CHIKV and MAYV E2-B are bound by cross-reactive, but not cross-neutralizing antibody. Therefore, development of broad E2-B based vaccines that induce broadly neutralizing antibody responses will require engineering to alter the immunodominant landscape.