A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models.

RNA vaccines have demonstrated efficacy against SARS-CoV-2 in humans, and the technology is being leveraged for rapid emergency response. In this report, we assessed immunogenicity and, for the first time, toxicity, biodistribution, and protective efficacy in preclinical models of a two-dose self-amplifying messenger RNA (SAM) vaccine, encoding a prefusion-stabilized spike antigen of SARS-CoV-2 Wuhan-Hu-1 strain and delivered by lipid nanoparticles (LNPs). In mice, one immunization with the SAM vaccine elicited a robust spike-specific antibody response, which was further boosted by a second immunization, and effectively neutralized the matched SARS-CoV-2 Wuhan strain as well as B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta) variants. High frequencies of spike-specific germinal center B, Th0/Th1 CD4, and CD8 T cell responses were observed in mice. Local tolerance, potential systemic toxicity, and biodistribution of the vaccine were characterized in rats. In hamsters, the vaccine candidate was well-tolerated, markedly reduced viral load in the upper and lower airways, and protected animals against disease in a dose-dependent manner, with no evidence of disease enhancement following SARS-CoV-2 challenge. Therefore, the SARS-CoV-2 SAM (LNP) vaccine candidate has a favorable safety profile, elicits robust protective immune responses against multiple SARS-CoV-2 variants, and has been advanced to phase 1 clinical evaluation (NCT04758962).

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Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests G.M., C.P.M., J.W., T.C., G.L., K.F., L.Q., J.T.S., J.M., A.K., K.A., K-F.W., I.M., R.T., A.R., M.A.R., A-M.S., R.Jo., S.N., R.J., K.L., S.B., J.B.U., A.H.S., and D.Y. are current or former employees of the GSK group of companies and may own GSK shares and/or restricted GSK shares. G.M., J.W., L.Q., K.L., J.B.U., and D.Y. are inventors on a patent application claiming subject matter related to the SARS-CoV-2 SAM vaccine candidates described herein. P.Y.S. is a member of the Scientific Advisory Boards of AbImmune and is Founder of FlaviTech. X.X. and P.-Y.S. have filed a patent on the reverse genetic system of SARS-CoV-2. M.A.A., M.G., and C.S. received compensation from GSK to perform the rat toxicity and biodistribution assays. The other authors declare no other competing interests.