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 - Funding Information:
We thank Shanshan Xu for in vitro testing of the LNP-formulated SAM vaccines; Jason Laliberte, Marco Biancucci, Sai Tian, Karen Matsuoka, and Ying Huang for cloning, expression, and purification of the recombinant SARS-CoV-2 spike protein used in the Luminex-based IgG binding antibody assay; Enrico Malito and Matthew J. Bottomley for antigen design advice; Leonard Azzarano for supporting the mouse studies; Ellen Gugel, Stephanie Fresnay, Maureen Stefaniak, and Glomil Corbin for supporting the mouse immunoassays; Jungeun Park for flow cytometry support; Bart Corsaro for human sample management; Madison Wallace for operational support; Erik Stemmy and Chelsea Lane from NIAID for coordinating the hamster study at Colorado State University through the National Institute of Allergy and Infectious Diseases (NIAID) preclinical study network. This work was funded by GlaxoSmithKline Biologicals SA. The Shi laboratory has received funding support in sponsored research agreements from GSK, Pfizer, Gilead, IGM Biosciences, and Atea Pharmaceuticals. The hamster study was funded by the National Institute of Allergy and Infectious Diseases preclinical study network. G.M. J.B.U. A.M.S. and D.Y. conceived and conceptualized the work and strategy. G.M. K.L. and J.W. designed constructs and planned in vitro studies; J.W. designed primers, performed oligo synthesis, and cloned constructs. J.M. performed RNA synthesis and analysis; J.W. and L.Q. performed and analyzed in vitro studies. I.M. and R.Jo. managed the formulation of RNA. C.P.M, G.L. and G.M. designed mouse immunogenicity studies and analyzed and interpreted data. D.M. performed the mouse studies. G.L. and K.A. supported the mouse studies. K.F. and C.P.M. designed, performed, and analyzed the spike-binding IgG assays in mice and rat sera. J.Z. and X.X. performed the VNTs experiment. J.Z. X.X. and P.Y.S. interpreted the VNTs results. T.C. G.L. J.T.S. A.K. S.N. R.J. and S.B. planned, performed, and analyzed T and B cell responses in mice. A.H.S. designed rat toxicity and biodistribution studies, oversaw the studies, and analyzed and interpreted data. M.A.A. and C.S. performed and analyzed the rat toxicity and biodistribution studies and their readouts. M.J.G. and M.A.R. read and interpreted histopathology slides and data for the rat study. A.H.S. A.M.S. G.M. R.A.B. R.T. and C.P.M. designed the hamster study; A.H.S. R.A.B. and C.P.M. oversaw the hamster study, analyzed and interpreted data. T.D. I.R. M.H-T. and R.A.B. performed the hamster study, immunology and virology readouts, and analyzed the data. R.T. and A.R. read and interpreted histopathology slides and data from the hamster study. K-F.W. performed statistical analysis of readouts from the mice and hamster studies. G.M. and C.P.M. contributed to synthesis and integrated interpretation of obtained data. G.M. and C.P.M. wrote the manuscript. All authors supported the review of the manuscript. 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.
Funding Information:
This work was funded by GlaxoSmithKline Biologicals SA . The Shi laboratory has received funding support in sponsored research agreements from GSK , Pfizer , Gilead , IGM Biosciences , and Atea Pharmaceuticals . The hamster study was funded by the National Institute of Allergy and Infectious Diseases preclinical study network.
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 - http://www.scopus.com/inward/record.url?scp=85123072871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123072871&partnerID=8YFLogxK
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 -