TY - JOUR
T1 - A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models
AU - Maruggi, Giulietta
AU - Mallett, Corey P.
AU - Westerbeck, Jason W.
AU - Chen, Tiffany
AU - Lofano, Giuseppe
AU - Friedrich, Kristian
AU - Qu, Lin
AU - Sun, Jennifer Tong
AU - McAuliffe, Josie
AU - Kanitkar, Amey
AU - Arrildt, Kathryn T.
AU - Wang, Kai Fen
AU - McBee, Ian
AU - McCoy, Deborah
AU - Terry, Rebecca
AU - Rowles, Alison
AU - Abrahim, Maia Araujo
AU - Ringenberg, Michael A.
AU - Gains, Malcolm J.
AU - Spickler, Catherine
AU - Xie, Xuping
AU - Zou, Jing
AU - Shi, Pei Yong
AU - Dutt, Taru
AU - Henao-Tamayo, Marcela
AU - Ragan, Izabela
AU - Bowen, Richard A.
AU - Johnson, Russell
AU - Nuti, Sandra
AU - Luisi, Kate
AU - Ulmer, Jeffrey B.
AU - Steff, Ann Muriel
AU - Jalah, Rashmi
AU - Bertholet, Sylvie
AU - Stokes, Alan H.
AU - Yu, Dong
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/5/4
Y1 - 2022/5/4
N2 - 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).
AB - 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).
KW - SARS-CoV-2 vaccine
KW - biodistribution
KW - efficacy
KW - immunogenicity
KW - self-amplifying mRNA
KW - spike antigen
KW - toxicity
UR - https://www.scopus.com/pages/publications/85123072871
UR - https://www.scopus.com/pages/publications/85123072871#tab=citedBy
U2 - 10.1016/j.ymthe.2022.01.001
DO - 10.1016/j.ymthe.2022.01.001
M3 - Article
C2 - 34990810
AN - SCOPUS:85123072871
SN - 1525-0016
VL - 30
SP - 1897
EP - 1912
JO - Molecular Therapy
JF - Molecular Therapy
IS - 5
ER -