Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice.

Authors:
Marcelo M Samsa
Marcelo M Samsa
FundaciĆ³n Instituto Leloir-CONICET
Lesley C Dupuy
Lesley C Dupuy
United States Army Medical Research Institute of Infectious Diseases
United States
Clayton W Beard
Clayton W Beard
University of North Carolina at Chapel Hill
United States
Connie S Schmaljohn
Connie S Schmaljohn
United States Army Medical Research Institute of Infectious Diseases
United States
Peter W Mason
Peter W Mason
University of Texas Medical Branch
United States
Andrew J Geall
Andrew J Geall
Novartis Vaccines and Diagnostics
United Kingdom
Jeffrey B Ulmer
Jeffrey B Ulmer
Novartis Vaccines
Germany

Mol Ther 2019 Apr 7;27(4):850-865. Epub 2019 Jan 7.

GSK, Rockville, MD 20850, USA. Electronic address:

Venezuelan equine encephalitis virus (VEEV) is a known biological defense threat. A live-attenuated investigational vaccine, TC-83, is available, but it has a high non-response rate and can also cause severe reactogenicity. We generated two novel VEE vaccine candidates using self-amplifying mRNA (SAM). LAV-CNE is a live-attenuated VEE SAM vaccine formulated with synthetic cationic nanoemulsion (CNE) and carrying the RNA genome of TC-83. IAV-CNE is an irreversibly-attenuated VEE SAM vaccine formulated with CNE, delivering a TC-83 genome lacking the capsid gene. LAV-CNE launches a TC-83 infection cycle in vaccinated subjects but eliminates the need for live-attenuated vaccine production and potentially reduces manufacturing time and complexity. IAV-CNE produces a single cycle of RNA amplification and antigen expression without generating infectious viruses in subjects, thereby creating a potentially safer alternative to live-attenuated vaccine. Here, we demonstrated that mice vaccinated with LAV-CNE elicited immune responses similar to those of TC-83, providing 100% protection against aerosol VEEV challenge. IAV-CNE was also immunogenic, resulting in significant protection against VEEV challenge. These studies demonstrate the proof of concept for using the SAM platform to streamline the development of effective attenuated vaccines against VEEV and closely related alphavirus pathogens such as western and eastern equine encephalitis and Chikungunya viruses.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S15250016193000
Publisher Site
http://dx.doi.org/10.1016/j.ymthe.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453513PMC
April 2019
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