Development of Live-Attenuated Old World Arenavirus Vaccines Based on Temperature-Sensitive Viruses
Abstract
Topic Area: This proposal highly relates to the Topic Area “Vaccine Development for Infectious Disease.” More narrowly, it addresses the Area of Encouragement “Development and fielding of vaccines to prevent U.S. Service members from becoming ill from endemic disease exposure during operational deployments.” This proposal seeks to develop, for the first time, temperature-sensitive live-attenuated vaccines to combat infections caused by human pathogenic Old World arenaviruses (OWA). Arenaviruses comprise important human pathogens and some of them, chiefly the OWA Lassa virus (LASV) in West Africa, cause hemorrhagic fever (HF) disease and represent a serious public health concern within their endemic regions. Notably, increased traveling into and from endemic areas has led to the importation of Lassa fever (LF) cases into non-endemic metropolitan areas around the globe, including the U.S. Moreover, novel HF-causing OWA are likely to emerge, as illustrated by Lujo virus (LUJV) that caused an outbreak of viral HF in Southern Africa in 2008. Evidence also indicates that the prototype member in the family lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance. Besides the impact on public health, several arenaviruses, including LASV, pose a credible bioweapons threat and are classified as National Institute of Allergy and Infectious Diseases Category A Priority Pathogens. No Food and Drug Administration-licensed arenavirus vaccines are available, and current anti-arenavirus therapy is limited to the use of ribavirin, which is only partially effective and associated with side effects. The significance of HF-causing OWA in human health and biodefense readiness, together with the limited existing armamentarium to combat them, demonstrate the urgent need of developing effective countermeasures to combat HF-causing OWA infection in humans. In this application, we will test the novel hypothesis that a temperature sensitive (ts)-based strategy can be used to develop safe, stable, immunogenic, and protective live-attenuated vaccines (LAV) for the treatment of OWA HF disease in humans. Our studies will provide a comprehensive assessment of the feasibility of using, for the first time, a ts-based approach to develop LAV to combat OWA infections. Although a few ts mutants have been previously used to generate attenuated viruses for their implementation as LAV (e.g., influenza), this will be the first demonstration that this ts-based approach could be used to develop LAV for the treatment of OWA in humans. Importantly, our studies will also provide essential information on the biology of OWA and how mutations in their genome affect viral fitness at different temperatures. Moreover, results from this proposal will allow us to demonstrate that our ts-based approach also represents an excellent strategy to generate valid OWA surrogates that could be used safely in Biosafety Level 2 (BSL2) containment to facilitate the study of these important human pathogens without the use of restrictive BSL4 laboratories. These ts OWA will provide investigators with the capability to work with these viruses outside BSL4 containment to facilitate, for instance, the study of OWA-host cell interactions and to identify and characterize therapeutics for the treatment of these important human pathogens. Because of the safety concerns and costs associated with HF-causing OWA work under BSL4 facilities, we will use, as a proof of concept, the LCMV system. The prototype OWA LCMV provides us with a BSL2 agent to demonstrate that ts mutations can convert a virulent LCMV into a suitable attenuated viral form with features of LAV. To that end, we will combine the identification of mutations found in our ts r3LCMV individual clones with the power of reverse genetic approaches to generate unique rLCMV containing mutation(s) responsible of the ts phenotype (rLCMV/ts). The generated rLCMV/ts will be evaluated for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810071
Entities
People
- Luis Martinez-Sobrido
Organizations
- United States Army
- University of Rochester