Vaccines and antibodies for arenaviruses

PROJECT SUMMARY - RP5 Arenaviruses, a family of viruses with pandemic potential, can cause hemorrhagic fever, meningitis, and other clinical syndromes. These viruses include highly pathogenic strains such as Lassa virus (LASV) and Junín virus (JUNV), as well as less pathogenic strains like lymphocytic choriomeningitis virus (LCMV). In this project, we aim to focus on two major areas, active immunity induced by experimental vaccines and passive immunity conferred by injection with human monoclonal antibodies. The later studies will include the study of extended half-life protective antibodies bearing Fc mutations that cause ≥90-day half-life profiles in humans and thus enable a vaccine-like prophylactic profile of a year or more. First, in studies in Aim 1, we will compare leading vaccine platform technologies and define immune correlates of protection for LCMV in nonhuman primate models of infection (macaques) as a virus prototype. Understanding the principles of immunity to this prototype virus will allow us then to pivot and use those mechanistic insights to design and test vaccines for other arenaviruses. This work will allow us to fully explore replicating attenuated LCMV vectors as a strategy for developing candidate arenavirus vaccines. We also will explore the hypothesis that both antibodies and T cell responses contribute to vaccine -induced protection against LCMV. Next, in studies in Aim 2, we will focus on deploying optimal vaccine strategies for other arenaviruses of pandemic concerns, LASV and JUNV. Lastly, in work in Aim 3, we will identify and characterize fully human neutralizing monoclonal antibodies and their epitope targets, with initial work in LCMV antibody discovery providing a platform for further work on other medically important arenaviruses. This project will be synergistic with other projects in the BP4 center focusing on picornavirus and hantavirus vaccines and with the BP4 human monoclonal antibody projects to develop candidate arenavirus, picornavirus, and hantavirus medical countermeasures.