Efficacy of an Unmodified Bivalent MRNA Vaccine Against SARS-CoV-2 Variants in Female Small Animal Models

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Feb 13

PMID 36781853

Authors

Bjorn Corleis

Donata Hoffmann

Susanne Rauch

Charlie Fricke

Nicole Roth

Janina Gergen

Kristina Kovacikova

Kore Schlottau

Nico Joel Halwe

Lorenz Ulrich

Jacob Schon

Kerstin Wernike

Marek Widera

Sandra Ciesek

Stefan O Mueller

Thomas C Mettenleiter

Domenico Maione

Benjamin Petsch

Martin Beer

Anca Dorhoi

Affiliations

Soon will be listed here.

Abstract

Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve control of the COVID-19 pandemic. We compare monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein in a transgenic mouse and a Wistar rat model. The blended low-dose bivalent mRNA vaccine contains half the mRNA of each respective monovalent vaccine, but induces comparable neutralizing antibody titres, enrichment of lung-resident memory CD8 T cells, antigen-specific CD4 and CD8 responses, and protects transgenic female mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduces viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized female Wistar rats also contain neutralizing antibodies against the B.1.1.529 (Omicron BA.1 and BA.5) variants. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins are feasible approaches for extending the coverage of vaccines for emerging and co-circulating SARS-CoV-2 variants.

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References

de Alwis R, Gan E, Chen S, Leong Y, Tan H, Zhang S . A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice. Mol Ther. 2021; 29(6):1970-1983. PMC: 8019652. DOI: 10.1016/j.ymthe.2021.04.001. View

Liu J, Yu J, McMahan K, Jacob-Dolan C, He X, Giffin V . CD8 T cells contribute to vaccine protection against SARS-CoV-2 in macaques. Sci Immunol. 2022; 7(77):eabq7647. PMC: 9407944. DOI: 10.1126/sciimmunol.abq7647. View

Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J . Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020; 26(6):842-844. DOI: 10.1038/s41591-020-0901-9. View

Dejnirattisai W, Huo J, Zhou D, Zahradnik J, Supasa P, Liu C . SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses. Cell. 2022; 185(3):467-484.e15. PMC: 8723827. DOI: 10.1016/j.cell.2021.12.046. View

Scheaffer S, Lee D, Whitener B, Ying B, Wu K, Liang C . Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice. Nat Med. 2022; 29(1):247-257. PMC: 11752949. DOI: 10.1038/s41591-022-02092-8. View

Li C, Lee A, Grigoryan L, Arunachalam P, Scott M, Trisal M . Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine. Nat Immunol. 2022; 23(4):543-555. PMC: 8989677. DOI: 10.1038/s41590-022-01163-9. View

McCallum M, Czudnochowski N, Rosen L, Zepeda S, Bowen J, Walls A . Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement. Science. 2022; 375(6583):864-868. PMC: 9427005. DOI: 10.1126/science.abn8652. View

Hajnik R, Plante J, Liang Y, Alameh M, Tang J, Bonam S . Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models. Sci Transl Med. 2022; 14(662):eabq1945. PMC: 9926941. DOI: 10.1126/scitranslmed.abq1945. View

Gebre M, Rauch S, Roth N, Yu J, Chandrashekar A, Mercado N . Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine. Nature. 2021; 601(7893):410-414. PMC: 8770133. DOI: 10.1038/s41586-021-04231-6. View

10.

John S, Yuzhakov O, Woods A, Deterling J, Hassett K, Shaw C . Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine. 2018; 36(12):1689-1699. DOI: 10.1016/j.vaccine.2018.01.029. View

11.

Scialo F, Daniele A, Amato F, Pastore L, Matera M, Cazzola M . ACE2: The Major Cell Entry Receptor for SARS-CoV-2. Lung. 2020; 198(6):867-877. PMC: 7653219. DOI: 10.1007/s00408-020-00408-4. View

12.

Gruell H, Vanshylla K, Tober-Lau P, Hillus D, Schommers P, Lehmann C . mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant. Nat Med. 2022; 28(3):477-480. PMC: 8767537. DOI: 10.1038/s41591-021-01676-0. View

13.

Roth N, Schon J, Hoffmann D, Thran M, Thess A, Mueller S . Optimised Non-Coding Regions of mRNA SARS-CoV-2 Vaccine CV2CoV Improves Homologous and Heterologous Neutralising Antibody Responses. Vaccines (Basel). 2022; 10(8). PMC: 9414064. DOI: 10.3390/vaccines10081251. View

14.

Kent S, Khoury D, Reynaldi A, Juno J, Wheatley A, Stadler E . Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?. Nat Rev Immunol. 2022; 22(6):387-397. PMC: 9047577. DOI: 10.1038/s41577-022-00716-1. View

15.

Tegally H, Wilkinson E, Giovanetti M, Iranzadeh A, Fonseca V, Giandhari J . Detection of a SARS-CoV-2 variant of concern in South Africa. Nature. 2021; 592(7854):438-443. DOI: 10.1038/s41586-021-03402-9. View

16.

Planas D, Saunders N, Maes P, Guivel-Benhassine F, Planchais C, Buchrieser J . Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022; 602(7898):671-675. DOI: 10.1038/s41586-021-04389-z. View

17.

Wilhelm A, Widera M, Grikscheit K, Toptan T, Schenk B, Pallas C . Limited neutralisation of the SARS-CoV-2 Omicron subvariants BA.1 and BA.2 by convalescent and vaccine serum and monoclonal antibodies. EBioMedicine. 2022; 82:104158. PMC: 9271884. DOI: 10.1016/j.ebiom.2022.104158. View

18.

Cromer D, Reynaldi A, Steain M, Triccas J, Davenport M, Khoury D . Relating In Vitro Neutralization Level and Protection in the CVnCoV (CUREVAC) Trial. Clin Infect Dis. 2022; 75(1):e878-e879. PMC: 9383389. DOI: 10.1093/cid/ciac075. View

19.

Turner J, OHalloran J, Kalaidina E, Kim W, Schmitz A, Zhou J . SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Nature. 2021; 596(7870):109-113. PMC: 8935394. DOI: 10.1038/s41586-021-03738-2. View

20.

Chivukula S, Plitnik T, Tibbitts T, Karve S, Dias A, Zhang D . Development of multivalent mRNA vaccine candidates for seasonal or pandemic influenza. NPJ Vaccines. 2021; 6(1):153. PMC: 8677760. DOI: 10.1038/s41541-021-00420-6. View