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

Giulietta Maruggi, Corey P. Mallett, Jason W. Westerbeck, Tiffany Chen, Giuseppe Lofano, Kristian Friedrich, Lin Qu, Jennifer Tong Sun, Josie McAuliffe, Amey Kanitkar, Kathryn T. Arrildt, Kai Fen Wang, Ian McBee, Deborah McCoy, Rebecca Terry, Alison Rowles, Maia Araujo Abrahim, Michael A. Ringenberg, Malcolm J. Gains, Catherine SpicklerXuping Xie, Jing Zou, Pei Yong Shi, Taru Dutt, Marcela Henao-Tamayo, Izabela Ragan, Richard A. Bowen, Russell Johnson, Sandra Nuti, Kate Luisi, Jeffrey B. Ulmer, Ann Muriel Steff, Rashmi Jalah, Sylvie Bertholet, Alan H. Stokes, Dong Yu

Research output: Contribution to journalArticlepeer-review

Abstract

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).

Original languageEnglish (US)
Pages (from-to)1897-1912
Number of pages16
JournalMolecular Therapy
Volume30
Issue number5
DOIs
StatePublished - May 4 2022

Keywords

  • SARS-CoV-2 vaccine
  • biodistribution
  • efficacy
  • immunogenicity
  • self-amplifying mRNA
  • spike antigen
  • toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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