DESCRIPTION (provided by applicant): Lassa fever is an acute and often-fatal hemorrhagic disease caused by Lassa virus (LASV), an arenavirus. Lassa fever is a zoonotic infection, transmitted to humans by Mastomys natalensis (the multimammate "rat"). The highest incidence of Lassa fever in the world is in the Eastern Province of Sierra Leone. Signs and symptoms of LF, which occur 1-3 weeks after virus exposure, are highly variable, and can include fever, facial swelling, conjunctival injection, and vomiting. Frank bleeding occurs in less than a third of cases, but confers a poor prognosis. Signs and symptoms in LF patients who survive begin to subside 2-3 weeks after onset, but full recovery can require many months or longer. Kenema Government Hospital (KGH) was an important site for Lassa fever clinical and laboratory research throughout the 1970s and 1980s. The violent civil conflict in Sierra Leone from 1991 to 2002, sometimes referred to as the Blood Diamonds War, forced suspension of Lassa fever research at KGH in 1993. Following cessation of hostilities, our consortium of Lassa fever researchers and other partners began rebuilding the scientific infrastructure at KGH, with a major focus of the development of improved laboratory diagnosis for Lassa fever. There is no vaccine for LF and the efficacy of the antiviral drug ribavirin in treating LF remains a matter of controversy. There is an urgent need to develop epidemiological and clinical measures to combat the public health challenges posed by Lassa fever in Sierra Leone and across West Africa. Promising next-generation Lassa fever diagnostic immunoassays, including rapid tests, require further development as epidemiological and clinical management tools. The overall hypothesis of the Lassa ICIDR is that further development of research capacity, with emphasis on training Sierra Leonean staff, will permit the KGH Lassa fever research program to emerge as an exceptional resource for human clinical trials of NIAID's promising portfolio of Lassa fever diagnostics, therapeutics, immunotherapeutics and vaccines. The Overall Specific Aims (listed in priority order) are: Aim 1. Further enhance and utilize the symmetrical and highly productive partnership developed over the last decade between Tulane University and the Lassa fever program at KGH; Aim 2. Promote the development of laboratory and clinical research capacity at KGH, with a particular emphasis on training Sierra Leonean staff; and Aim 3. Encourage future collaborative relationships with other research groups leading to improvements in detection, prevention, amelioration, and treatment of Lassa fever in the subregion. Research question(s) to be addressed in the Lassa ICIDR Projects include for Project 1: Can second generation Lassa fever recombinant immunoassays be used effectively as point-of-care diagnostics and surveillance tools for Lassa fever, and for Project 2: What are the clinical and virological determinants of Lassa Fever outcome and is it possible to identify biomarkers of LASV infection and Lassa Fever outcome. Through the proposed research we will acquire new information regarding the natural history of Lassa fever and the demographic distribution of people exposed to LASV using second generation Lassa fever recombinant immunoassays. We will also elucidate risk factors for acquiring serious or fatal LASV infection. This new informatio will guide evidence-based investments for public health programming and policy. We will also define biomarkers of Lassa fever pathobiology through the course of illness. Identification of these factors could lead to evidence-based approaches to reduce mortality from Lassa fever. We also propose to take a major step forward to confront the challenges of Lassa fever, namely developing the capacity to perform human clinical trials.

PUBLIC HEALTH RELEVANCE: Through the proposed research we will acquire new information regarding the natural history of Lassa fever and the demographic distribution of people exposed to LASV using second generation Lassa fever recombinant immunoassays. We will also elucidate risk factors for acquiring serious or fatal LASV infection. This new informatio will guide evidence-based investments for public health programming and policy. We will also define biomarkers of Lassa fever pathobiology through the course of illness. Identification of these factors could lead to evidence-based approaches to reduce mortality from Lassa fever. We also propose to take a major step forward to confront the challenges of Lassa fever, namely developing the capacity to perform human clinical trials.