B cell immunity to the Lassa virus glycoprotein is a correlate of vaccination-induced viral load control

Lassa fever, a viral hemorrhagic fever caused by the arenavirus Lassa virus (LASV), affects thousands of individuals annually, highlighting the need for a vaccine. Yet, immunological correlates of viral load control remain poorly defined. Studying vaccination-induced immunity in a surrogate LASV challenge model we found that LASV-cross-reactive B cell immunity induced by the glycoprotein of distantly related arenaviruses, such as lymphocytic choriomeningitis virus (LCMV), provided significant viral load control in mice. Counter to common concepts, suppression of viremia was observed in the absence of CD8 T cells or neutralizing antibodies but correlated with non-neutralizing glycoprotein-specific antibody responses. Adoptive cell transfer experiments with monoclonal LCMV-specific B cells demonstrated that these cells suppressed viral loads when previously activated by a heterologous cross-reactive glycoprotein and diversified by somatic hypermutation. These findings establish vaccination-induced B cell immunity to the LASV glycoprotein as a correlate of viral load control, independently of virus-neutralizing antibody titers at the time of challenge. Overall design: The immunizing GPC determines the extent of HkiL cell hypermutation and clonal diversification. At week -1, TgL mice were depleted of CD8 T cells. At wk0 they were given 104 HkiL cells and were immunized with either rLCMV/LASVLIIA, rLCMVA or rLCMVA/LASVLIVC. At wk5 HkiL cell progeny in spleen were analyzed.