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

James Brett Case, Shilpa Sanapala, Carly Dillen, Victoria Rhodes, Christian Zmasek, Taras M. Chicz, Charlotte E. Switzer, Suzanne M. Scheaffer, George Georgiev, Catherine Jacob-Dolan, Blake M. Hauser, Déborah Carolina Carvalho Dos Anjos, Lucas J. Adams, Nadia Soudani, Chieh Yu Liang, Baoling Ying, Ryan P. McNamara, Richard H. Scheuermann, Adrianus C.M. Boon, Daved H. FremontSean Whelan, Aaron G. Schmidt, Alessandro Sette, Alba Grifoni, Matthew B. Frieman, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2131-2147.e8
JournalCell Host and Microbe
Volume32
Issue number12
DOIs
StatePublished - Dec 11 2024

Keywords

  • antibody
  • cellular immunity
  • coronavirus
  • immunity
  • mucosal
  • phylogenetic
  • Sarbecovirus
  • T cell
  • vaccine
  • viral vector

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