Development of Live-Attenuated Old World Arenavirus Vaccines Based on Temperature-Sensitive Viruses
Abstract
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 Old World Arenavirus (OWA) disease in humans. 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. 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 BSL2 containment to facilitate the study of these important human pathogens without the use of restrictive BSL4 laboratories. Because of the safety concerns and costs associated with hemorrhagic fever (HF)-causing OWA work under BSL4 facilities, we will use, as a proof of concept, the prototype OWA lymphocytic choriomeningitis virus (LCMV).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 their potential as safe, stable, immunogenic and effective LAV, using the extensively validated and well characterized animal model of LCMV infection and associated disease. Our long-term goal is to implement the same ts-based approach to develop LAV to combat disease caused by HF-causing OWA (e.g. LASV), currently outside the scope of this proof-of-concept exploratory proposal.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2021
- Accession Number
- AD1145293
Entities
People
- David J Topham
Organizations
- University of Rochester