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Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

ABSTRACT: Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited T_H1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with T_H2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

SUBMITTER: Kalnin KV

PROVIDER: S-EPMC8055913 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Kalnin Kirill V KV Plitnik Timothy T Kishko Michael M Zhang Jinrong J Zhang Donghui D Beauvais Adrien A Anosova Natalie G NG Tibbitts Tim T DiNapoli Josh J Ulinski Gregory G Piepenhagen Peter P Cummings Sheila M SM Bangari Dinesh S DS Ryan Susan S Huang Po-Wei D PD Huleatt James J Vincent Deanne D Fries Katherine K Karve Shrirang S Goldman Rebecca R Gopani Hardip H Dias Anusha A Tran Khang K Zacharia Minnie M Gu Xiaobo X Boeglin Lianne L Abysalh Jonathan J Vargas Jorel J Beaulieu Angela A Shah Monic M Jeannotte Travis T Gillis Kimberly K Chivukula Sudha S Swearingen Ron R Landolfi Victoria V Fu Tong-Ming TM DeRosa Frank F Casimiro Danilo D

NPJ vaccines 20210419 1

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycop ...[more]

PMID: 33875658

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Project description:BackgroundTo investigate a vaccine technology with potential to protect against coronavirus disease 2019 (COVID-19) and reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a single vaccine dose, we developed a SARS-CoV-2 candidate vaccine using the live vesicular stomatitis virus (VSV) chimeric virus approach previously used to develop a licensed Ebola virus vaccine.MethodsWe generated a replication-competent chimeric VSV-SARS-CoV-2 vaccine candidate by replacing the VSV glycoprotein (G) gene with coding sequence for the SARS-CoV-2 Spike glycoprotein (S). Immunogenicity of the lead vaccine candidate (VSV∆G-SARS-CoV-2) was evaluated in cotton rats and golden Syrian hamsters, and protection from SARS-CoV-2 infection also was assessed in hamsters.FindingsVSV∆G-SARS-CoV-2 delivered with a single intramuscular (IM) injection was immunogenic in cotton rats and hamsters and protected hamsters from weight loss following SARS-CoV-2 challenge. When mucosal vaccination was evaluated, cotton rats did not respond to the vaccine, whereas mucosal administration of VSV∆G-SARS-CoV-2 was found to be more immunogenic than IM injection in hamsters and induced immunity that significantly reduced SARS-CoV-2 challenge virus loads in both lung and nasal tissues.InterpretationVSV∆G-SARS-CoV-2 delivered by IM injection or mucosal administration was immunogenic in golden Syrian hamsters, and both vaccination methods effectively protected the lung from SARS-CoV-2 infection. Hamsters vaccinated by mucosal application of VSV∆G-SARS-CoV-2 also developed immunity that controlled SARS-CoV-2 replication in nasal tissue.FundingThe study was funded by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and The International AIDS Vaccine Initiative, Inc. (IAVI), New York, USA. Parts of this research was supported by the Biomedical Advanced Research and Development Authority (BARDA) and the Defense Threat Reduction Agency (DTRA) of the US Department of Defense.

Dataset Information

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Publications

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

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