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

被引：67

作者：

Maruggi, Giulietta ^{[1
]}

Mallett, Corey P. ^{[1
]}

Westerbeck, Jason W. ^{[1
]}

Chen, Tiffany ^{[1
]}

Lofano, Giuseppe ^{[1
]}

Friedrich, Kristian ^{[1
]}

Qu, Lin ^{[1
,8
]}

Sun, Jennifer Tong ^{[1
]}

McAuliffe, Josie ^{[1
]}

Kanitkar, Amey ^{[1
]}

Arrildt, Kathryn T. ^{[1
,9
]}

Wang, Kai-Fen ^{[1
]}

McBee, Ian ^{[1
,10
]}

McCoy, Deborah ^{[3
]}

Terry, Rebecca ^{[2
]}

Rowles, Alison ^{[2
]}

Abrahim, Maia Araujo ^{[4
]}

Ringenberg, Michael A. ^{[3
]}

Gains, Malcolm J. ^{[4
]}

Spickler, Catherine ^{[4
]}

Xie, Xuping ^{[7
]}

Zou, Jing ^{[7
]}

Shi, Pei-Yong ^{[7
]}

Dutt, Taru ^{[5
]}

Henao-Tamayo, Marcela ^{[5
]}

Ragan, Izabela ^{[6
]}

Bowen, Richard A. ^{[6
]}

Johnson, Russell ^{[1
,11
]}

Nuti, Sandra ^{[1
]}

Luisi, Kate ^{[1
]}

Ulmer, Jeffrey B. ^{[1
]}

Steff, Ann-Muriel ^{[1
]}

Jalah, Rashmi ^{[1
]}

Bertholet, Sylvie ^{[1
]}

Stokes, Alan H. ^{[3
]}

Yu, Dong ^{[1
,12
]}

机构：

[1] GSK, Rockville, MD 20850 USA

[2] GSK, Ware SG12 ODP, Herts, England

[3] GSK, Upper Providence, PA 19426 USA

[4] Charles River Labs, Laval, PQ H7V 4B3, Canada

[5] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80521 USA

[6] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80521 USA

[7] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

[8] Venatorx Pharmaceut Inc, Malvern, PA USA

[9] Lawrence Livermore Natl Lab, Livermore, CA 94550 USA

[10] Novavax, Gaithersburg, MD 20878 USA

[11] RVAC Med, Medford, MA 02155 USA

[12] Dynavax Technol, Emeryville, CA 94608 USA

来源：

MOLECULAR THERAPY | 2022年 / 30卷 / 05期

关键词：

SEX-DIFFERENCES; SINGLE; DELIVERY; MEMORY;

D O I：

10.1016/j.ymthe.2022.01.001

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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 SARSCoV-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).

引用

页码：1897 / 1912

页数：16

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