mRNA-LNP vaccine-induced CD8+ T cells protect mice from lethal SARS-CoV-2 infection in the absence of specific antibodies

Brian Montoya; Carolina R Melo-Silva; Lingjuan Tang; Samita Kafle; Peter Lidskiy; Csaba Bajusz; Máté Vadovics; Hiromi Muramatsu; Edit Abraham; Zoltan Lipinszki; Debotri Chatterjee; Gabrielle Scher; Juliana Benitez; Molly M H Sung; Ying K Tam; Nicholas J Catanzaro; Alexandra Schäfer; Raul Andino; Ralph S Baric; David R Martinez; Norbert Pardi; Luis J Sigal

doi:10.1016/j.ymthe.2024.04.019

mRNA-LNP vaccine-induced CD8⁺ T cells protect mice from lethal SARS-CoV-2 infection in the absence of specific antibodies

Mol Ther. 2024 Apr 11:S1525-0016(24)00236-3. doi: 10.1016/j.ymthe.2024.04.019. Online ahead of print.

Authors

Brian Montoya¹, Carolina R Melo-Silva¹, Lingjuan Tang¹, Samita Kafle¹, Peter Lidskiy², Csaba Bajusz³, Máté Vadovics⁴, Hiromi Muramatsu⁴, Edit Abraham⁵, Zoltan Lipinszki⁵, Debotri Chatterjee⁶, Gabrielle Scher¹, Juliana Benitez¹, Molly M H Sung⁷, Ying K Tam⁷, Nicholas J Catanzaro⁸, Alexandra Schäfer⁸, Raul Andino², Ralph S Baric⁸, David R Martinez⁹, Norbert Pardi¹⁰, Luis J Sigal¹¹

Affiliations

¹ Department of Microbiology and Immunology, Bluemle Life Science Building, Thomas Jefferson University, Philadelphia, PA 19107, USA.
² Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; National Laboratory for Biotechnology, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary.
⁴ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ National Laboratory for Biotechnology, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary; MTA SZBK Lendület Laboratory of Cell Cycle Regulation, Synthetic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary.
⁶ Department of Neurosciences, Thomas Jefferson University Vickie and Jack Farber Institute for Neuroscience, Philadelphia, PA, USA.
⁷ Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada.
⁸ Department of Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Department of Immunobiology, Center for Infection and Immunity, Yale School of Medicine, New Haven, CT 06520, USA.
¹⁰ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: pnorbert@pennmedicine.upenn.edu.
¹¹ Department of Microbiology and Immunology, Bluemle Life Science Building, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: luis.sigal@jefferson.edu.

PMID: 38605519
DOI: 10.1016/j.ymthe.2024.04.019

Abstract

The role of CD8⁺ T cells in SARS-CoV-2 pathogenesis or mRNA-LNP vaccine-induced protection from lethal COVID-19 is unclear. Using mouse-adapted SARS-CoV-2 virus (MA30) in C57BL/6 mice, we show that CD8⁺ T cells are unnecessary for the intrinsic resistance of female or the susceptibility of male mice to lethal SARS-CoV-2 infection. Also, mice immunized with a di-proline prefusion-stabilized full-length SARS-CoV-2 Spike (S-2P) mRNA-LNP vaccine, which induces Spike-specific antibodies and CD8⁺ T cells specific for the Spike-derived VNFNFNGL peptide, are protected from SARS-CoV-2 infection-induced lethality and weight loss, while mice vaccinated with mRNA-LNPs encoding only VNFNFNGL are protected from lethality but not weight loss. CD8⁺ T cell depletion ablates protection in VNFNFNGL but not in S-2P mRNA-LNP-vaccinated mice. Therefore, mRNA-LNP vaccine-induced CD8⁺ T cells are dispensable when protective antibodies are present but essential for survival in their absence. Hence, vaccine-induced CD8⁺ T cells may be critical to protect against SARS-CoV-2 variants that mutate epitopes targeted by protective antibodies.

Keywords: CD8 T cells; SARS-CoV-2; antibodies; mRNA-LNP vaccines; mice.

Abstract

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