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

PROJECT SUMMARY
Arenaviruses are a family of zoonotic RNA viruses that are capable of causing severe hemorrhagic fever disease
in humans. 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. Arenaviruses
have repeatedly crossed over into humans over the past several decades, and emerging variants of known
arenaviruses often display increased human-to-human transmissibility and broader geographic range. For these
reasons, the CDC and WHO have classified several human arenaviruses as high priority pathogens and the
PREDICT consortium ranked LASV as the highest risk virus on their watchlist of potential pandemic pathogens.
Vaccines and therapeutics against arenaviruses are urgently needed, however, we must first gain a much deeper
understanding of the molecular mechanisms that result in protective humoral immunity. Although the discovery
of effective clinical countermeasures is the ultimate goal, this collaborative 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 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. Additionally, we have access to a singular cohort
of LF survivors at Kenema Government Hospital, which is located in Sierra Leone and is at the heart of the LF
zone. We expect our work will result in the discovery of thousands of novel anti-LASV 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.

Grant Number: 5R01AI171438-04
NIH Institute/Center: NIH
Principal Investigator: Bryan Briney