The Protective and Pathologic Features of the LASV Immune Response (LASV Legacy)

Modified Project Summary/Abstract Section Lassa virus (LASV) is a persistent global public health threat that infects 2.7M and kills more than 5,000 individuals each year, principally in Nigeria, Liberia, and Sierra Leone. Annual outbreaks of Lassa fever (LF) contribute to more infections and deaths than all outbreaks of filoviruses, including Ebola virus, combined and is the most common cause of imported viral hemorrhagic fever to non-endemic countries. The permanence of LASV in the rodent reservoir in West Africa, coupled an expansion of their range and numbers have led to a steady increase in LF in this region. Despite the burden of LASV infection in West Africa there remain substantial gaps in our understanding of fundamental aspects of this emerging infection including host humoral and cellular immune responses to LASV, their potential protective and pathologic roles in LASV-related disease, and longterm complications of LF. The overarching objective of the proposed studies is to rigorously characterize the longitudinal humoral and cellular response to LASV across the spectrum of illness severity, identify the longerterm consequences of both LASV infection and LF, and evaluate the role of sustained immune activation as a pathogenic mechanism underlying LF and LASV infection sequelae. Specifically: Aim I: Characterize and compare the humoral and cellular immune responses following subclinical LASV infection and LF. AIM 2: Describe the prevalence, characteristics, and natural history of long-term clinical complications of LASV infection and LF and explore their association with host, viral and immune response factors. The findings of these investigations will have direct and practical value for the design of trials of LASV vaccine candidates and potentially identify strategies to prevent and treat longer-term sequelae of LASV infection. We will conduct this work in the context of close and strong working relationships with healthcare and community leaders in a hyperendemic region for Lassa fever and well-developed infrastructure for clinical research that we have established in Liberia where we have recruited, enrolled, and longitudinally followed and sampled more than 5000 participants including 79 patients with acute LF, 68 with subclinical LASV infection and 61 survivors of severe LF as well as hundreds of uninfected seronegative controls. The proposed work will provide a muchneeded longitudinal characterization of the humoral and cellular immune responses, evaluation of the long-term complications of subclinical LASV infection/severe LF and investigation of sustained immune activation as a mechanism underlying the long-term complications of surviving subclinical LASV infection/severe LF. With yearly outbreaks, this study will ensure that the world is better prepared through an improved understanding of the durability of the humoral and cellular immune responses to infection and of the clinical complications of LASV infection across the spectrum of disease severity.