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 Spickler; Xuping 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

doi:10.1016/j.ymthe.2022.01.001

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

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 language	English (US)
Pages (from-to)	1897-1912
Number of pages	16
Journal	Molecular Therapy
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.ymthe.2022.01.001
State	Published - 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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Maruggi, G., Mallett, C. P., Westerbeck, J. W., Chen, T., Lofano, G., Friedrich, K., Qu, L., Sun, J. T., McAuliffe, J., Kanitkar, A., Arrildt, K. T., Wang, K. F., McBee, I., McCoy, D., Terry, R., Rowles, A., Abrahim, M. A., Ringenberg, M. A., Gains, M. J., ... Yu, D. (2022). A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models. Molecular Therapy, 30(5), 1897-1912. https://doi.org/10.1016/j.ymthe.2022.01.001

Maruggi, G, Mallett, CP, Westerbeck, JW, Chen, T, Lofano, G, Friedrich, K, Qu, L, Sun, JT, McAuliffe, J, Kanitkar, A, Arrildt, KT, Wang, KF, McBee, I, McCoy, D, Terry, R, Rowles, A, Abrahim, MA, Ringenberg, MA, Gains, MJ, Spickler, C, Xie, X, Zou, J, Shi, P-Y, Dutt, T, Henao-Tamayo, M, Ragan, I, Bowen, RA, Johnson, R, Nuti, S, Luisi, K, Ulmer, JB, Steff, AM, Jalah, R, Bertholet, S, Stokes, AH & Yu, D 2022, 'A self-amplifying mRNA SARS-CoV-2 vaccine candidate induces safe and robust protective immunity in preclinical models', Molecular Therapy, vol. 30, no. 5, pp. 1897-1912. https://doi.org/10.1016/j.ymthe.2022.01.001

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

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).",

keywords = "SARS-CoV-2 vaccine, biodistribution, efficacy, immunogenicity, self-amplifying mRNA, spike antigen, toxicity",

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

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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

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).

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

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Keywords

ASJC Scopus subject areas

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