A trivalent mucosal vaccine encoding phylogenetically inferred ancestral RBD sequences confers pan-Sarbecovirus protection in mice

James Brett Case¹, Shilpa Sanapala¹, Carly Dillen², Victoria Rhodes², Christian Zmasek³, Taras M Chicz⁴, Charlotte E Switzer⁵, Suzanne M Scheaffer¹, George Georgiev⁶, Catherine Jacob-Dolan⁶, Blake M Hauser⁶, Déborah Carolina Carvalho Dos Anjos⁷, Lucas J Adams⁸, Nadia Soudani⁹, Chieh-Yu Liang⁹, Baoling Ying¹, Ryan P McNamara⁴, Richard H Scheuermann³, Adrianus C M Boon¹⁰, Daved H Fremont¹¹, Sean P J Whelan⁷, Aaron G Schmidt⁶, Alessandro Sette¹², Alba Grifoni¹³, Matthew B Frieman², Michael S Diamond¹⁴

Affiliations

¹ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
² Department of Microbiology and Immunology, Center for Pathogen Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³ Department of Informatics, J. Craig Venter Institute, La Jolla, CA 92037, USA.
⁴ Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA.
⁵ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston 02115, MA, USA; Department of Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁸ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁹ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁰ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹¹ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹² Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
¹⁴ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Vaccines and Immunity against Microbial Pathogens, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mdiamond@wustl.edu.

PMID: 39561781
PMCID: PMC11637904 (available on 2025-12-11)
DOI: 10.1016/j.chom.2024.10.016

A trivalent mucosal vaccine encoding phylogenetically inferred ancestral RBD sequences confers pan-Sarbecovirus protection in mice

James Brett Case et al. Cell Host Microbe. 2024.

. 2024 Dec 11;32(12):2131-2147.e8.

doi: 10.1016/j.chom.2024.10.016. Epub 2024 Nov 18.

Authors

Affiliations

¹ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
² Department of Microbiology and Immunology, Center for Pathogen Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³ Department of Informatics, J. Craig Venter Institute, La Jolla, CA 92037, USA.
⁴ Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA.
⁵ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston 02115, MA, USA; Department of Bioengineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁸ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁹ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁰ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹¹ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹² Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
¹⁴ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Vaccines and Immunity against Microbial Pathogens, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mdiamond@wustl.edu.

PMID: 39561781
PMCID: PMC11637904 (available on 2025-12-11)
DOI: 10.1016/j.chom.2024.10.016

Abstract

The continued emergence of SARS-CoV-2 variants and the threat of future Sarbecovirus zoonoses have spurred the design of vaccines that can induce broad immunity against multiple coronaviruses. Here, we use computational methods to infer ancestral phylogenetic reconstructions of receptor binding domain (RBD) sequences across multiple Sarbecovirus clades and incorporate them into a multivalent adenoviral-vectored vaccine. Mice immunized with this pan-Sarbecovirus vaccine are protected in the upper and lower respiratory tracts against infection by historical and contemporary SARS-CoV-2 variants, SARS-CoV, and pre-emergent SHC014 and Pangolin/GD coronavirus strains. Using genetic and immunological approaches, we demonstrate that vaccine-induced protection unexpectedly is conferred principally by CD4⁺ and CD8⁺ T cell-mediated anamnestic responses. Importantly, prior mRNA vaccination or SARS-CoV-2 respiratory infection does not alter the efficacy of the mucosally delivered pan-Sarbecovirus vaccine. These data highlight the promise of a phylogenetic approach for antigen and vaccine design against existing and pre-emergent Sarbecoviruses with pandemic potential.

Keywords: Sarbecovirus; T cell; antibody; cellular immunity; coronavirus; immunity; mucosal; phylogenetic; vaccine; viral vector.

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Conflict of interest statement

Declaration of interests M.S.D. is a consultant or advisor for Inbios, Vir Biotechnology, IntegerBio, Moderna, Merck, Akagera Medicines, and GlaxoSmithKline. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, Bavarian Nordic, and IntegerBio. M.B.F. and the Frieman laboratory have sponsored research agreements with Novavax, AstraZeneca, Eli Lilly, Regeneron, and Irazu Bio. A.S. is a consultant for Darwin Health, EmerVax, Gilead Sciences, Guggenheim Securities, RiverVest Venture Partners, and Arcturus. La Jolla Institute for Immunology has filed for patent protection for various aspects of T cell epitope and vaccine design work. A provisional patent for the vaccine sequences used in this paper has been filed, for which J.B.C., C.Z., R.H.S., M.B.F., and M.S.D. are co-inventors.

References

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A trivalent mucosal vaccine encoding phylogenetically inferred ancestral RBD sequences confers pan-Sarbecovirus protection in mice

Affiliations

A trivalent mucosal vaccine encoding phylogenetically inferred ancestral RBD sequences confers pan-Sarbecovirus protection in mice

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous