Genetic, structural and functional profiling of the human antibody response to arenavirus infection

Arenaviruses are a family of zoonotic RNA viruses that can cause severe hemorrhagic fever disease in humans. There have been several instances of zoonotic crossover into humans over the past several decades, and emerging variants of known arenaviruses often display increased human-to-human transmissibility and broader geographic range. The World Health Organization and the United States Centers for Disease Control and Prevention have classified several human arenaviruses as high priority pathogens. Lassa virus (LASV), an Old World arenavirus which is endemic in regions of West Africa including Sierra Leone and is the causative agent of Lassa fever (LF), causes thousands of deaths annually. LASV is a global threat as well: the PREDICT consortium ranked LASV as the highest risk virus on their watchlist of potential pandemic pathogens. Broadly effective arenavirus vaccines and therapeutics are urgently needed; however, we must first gain a much deeper understanding of the molecular mechanisms that result in protective humoral immunity. This project focuses on leveraging innovative, high-throughput antibody discovery and characterization tools to define the genetic, functional and structural properties of anti-LASV antibodies with broad specificity across all human arenaviruses. We have assembled a collaborative, multidisciplinary group of investigators with a long history of productive collaboration in viral immunology and with complementary areas of expertise. The foreign component of this project is scientifically essential and narrowly focused. LASV transmission is endemic in Sierra Leone and as such Kenema Government Hospital (KGH) has enrolled a unique, well-characterized cohort of 134 Lassa fever survivors. An equivalent naturally infected cohort cannot be assembled domestically. We expect our work will generate thousands of novel arenavirusspecific antibodies, characterization of which will reveal conserved sites of viral vulnerability and uncover the precise molecular mechanisms of viral neutralization. These fundamental studies directly address critical gaps in our understanding of the interplay between humoral immunity and hemorrhagic fever-causing arenaviruses and will serve as a foundation for future translational studies. The work directly benefits the health of Americans. Travel-associated Lassa fever has occurred in the United States, and related arenaviruses circulate and cause disease domestically. Defining human immunity across natural LASV diversity, identifying broadly reactive antibodies, and mapping conserved neutralization epitopes across Old World and New World arenaviruses will strengthen U.S. preparedness for domestic, imported, and emerging threats. The results will provide candidate antibodies for prophylactic or therapeutic development and conserved antigenic targets for vaccine design, strengthening our ability to protect Americans.