Project 2. Expansion of clinical research capacity at Kenema Government Hospital Lassa virus (LASV), a member of the family Arenaviridae, is the etiologic agent of Lassa fever (LF), a severe and often fatal hemorrhagic illness. It has been reported throughout West Africa from Guinea in the west to Nigeria in the east. Humans contract LASV primarily via direct or indirect contact with body fluids of rodents of the genus Mastomys, the natural reservoir. Nosocomial transmission can lead to large hospital outbreaks. The possibility of aerosol transmission and the lack of a vaccine have led to its classification as a BSL-4 and Category A Select Agent. Previous studies performed in the 1980's estimated up to 300,000 human LASV infections per year with 5,000 deaths per year. However, the natural history and mortality rate of disease remain poorly defined. Since these landmark studies were performed, significant advances have been made in LF clinical diagnostics as well as the laboratory capacity in endemic areas. Using newly developed Ag, IgG and IgM recombinant ELISAs (rELISA) and improved capacity at the site, we are now able to accurately study viremia and the immune response. This proposal will test the hypothesis: Development of IgM, but not a cellular inflammatory response, and decline in viremia during the early stages of symptomatic LF disease decreases mortality.
Aim 1 is too identify clinical and virological determinants of Lassa fever outcome in a cohort of symptomatic Lassa fever patients presenting to Kenema Government Hospital. Previous studies have identified several clinical features and clinical laboratory parameters that predict a poor prognosis. However, no study has determined if degree of viremia correlates with clinical features or laboratory test abnormalities. We will test the hypothesis: Prolonged viremia correlates with disease progression and increased mortality. We will identify clinical and laboratory diagnostic and prognostic risk factors for LF and correlate them with viremia and risk of mortality.
This aim will establish the natural history of LF disease and determine if the time course can be divided into distinct stages as previously suggested.
Aim 2 is to identify biomarkers of infection and mortality. Recent development of rLASV IgM and IgG ELISAs as well as increased capacity at the KGH Lassa Fever Laboratory provide a unique opportunity to identify specific immune correlates with disease severity and risk of mortality. We will test the hypothesis: Delayed development of the humoral and an increased TH1 inflammatory immune response correlates with increased mortality. We will correlate specific humoral and cytokine profiles with disease progression and outcome. These studies are critical for the design of future interventional trials and the development of therapies for LF and other viral hemorrhagic fevers.
Aim 3 will initiate Clinical trial capacity training. Over the past decade, a significant amount has been learned about the pathogenesis of LF and the human immune response. Trials are now needed to test existing and novel therapies for this disease. The objective of this aim is to build on previously funded capacity at the site and train critical team members in the essential elements needed to conduct clinical trials. This training is critical if the KGH site is to continue to contribute to our knowledge of and management strategies for VHFs.

Public Health Relevance

The objective of this proposal is to define the immune response to Lassa fever in symptomatic, hospitalized patients and to improve the clinical research capacity of this unique site. The long-term goal of this project is to further develop the highly productive partnership between Tulane University and the Sierra Leone Lassa Fever Project. This work is vital to the future design and implementation of definitive diagnostic and therapeutic trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI115589-05
Application #
9637235
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Tulane University
Department
Type
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Siddle, Katherine J; Eromon, Philomena; Barnes, Kayla G et al. (2018) Genomic Analysis of Lassa Virus during an Increase in Cases in Nigeria in 2018. N Engl J Med 379:1745-1753
Rudd, Kristina E; Seymour, Christopher W; Aluisio, Adam R et al. (2018) Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries. JAMA 319:2202-2211
Boisen, Matthew L; Hartnett, Jessica N; Shaffer, Jeffrey G et al. (2018) Field validation of recombinant antigen immunoassays for diagnosis of Lassa fever. Sci Rep 8:5939
Safronetz, David; Sogoba, Nafomon; Diawara, Sory Ibrahim et al. (2017) Annual Incidence of Lassa Virus Infection in Southern Mali. Am J Trop Med Hyg 96:944-946
He, Jing; Melnik, Lilia I; Komin, Alexander et al. (2017) Ebola Virus Delta Peptide is a Viroporin. J Virol :
Grubaugh, Nathan D; Ladner, Jason T; Kraemer, Moritz U G et al. (2017) Genomic epidemiology reveals multiple introductions of Zika virus into the United States. Nature 546:401-405
Goba, Augustine; Khan, S Humarr; Fonnie, Mbalu et al. (2016) An Outbreak of Ebola Virus Disease in the Lassa Fever Zone. J Infect Dis 214:S110-S121
Yozwiak, Nathan L; Happi, Christian T; Grant, Donald S et al. (2016) Roots, Not Parachutes: Research Collaborations Combat Outbreaks. Cell 166:5-8
Schieffelin, John; Moses, Lina M; Shaffer, Jeffrey et al. (2016) Clinical validation trial of a diagnostic for Ebola Zaire antigen detection: Design rationale and challenges to implementation. Clin Trials 13:66-72
Boisen, Matthew L; Schieffelin, John S; Goba, Augustine et al. (2015) Multiple circulating infections can mimic the early stages of viral hemorrhagic fevers and possible human exposure to filoviruses in Sierra Leone prior to the 2014 outbreak. Viral Immunol 28:19-31

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