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Publications

Journal Article Preprint Epublish

PubMed: 40463102 DOI: 10.1101/2025.05.11.652904

Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines.

bioRxiv

Authors: Amin Addetia, Alexandra Schäfer, Kaitlin Sprouse, Adian Valdez, Ashley Taylor, Mary-Jane Navarro, Jack T Brown, Elizabeth M Leaf, Marcos C Miranda, Alexandra C Walls, Jimin Lee, Nicholas J Catanzaro, Catherine Treichel, Isabelle Willoughby, John Powers, David R Martinez, Blue Vesari, Rashmi Ravichandran, Albert J Seo, Cameron Stewart, Benjamin Merz, Emily Beirne, Samantha Zepeda, Anthony Cook, Laurent Pessaint, Ankur Sharma, Darin Edwards, Kunse Lee, Kelly Smith, Tyler Starr, Ralph Baric, Neil P King, David Veesler

Affiliations

  • Department of Biochemistry, University of Washington, Seattle, Washington, USA.
  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  • Department of Immunobiology, Yale School of Medicine, New Haven, CT, 06511.
  • Department of Laboratory Medicine and Pathology, Seattle, WA 98195, USA.
  • BIOQUAL, Inc. Rockville, MD 20852, USA.
  • Moderna Inc. Cambridge, MA 02139, USA.
  • Department of R&D, SK Bioscience, Seongnam, Republic of Korea.
  • Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Abstract

Vaccines against emerging SARS-CoV-2 variants and sarbecoviruses with pandemic potential must elicit a robust humoral immune response in a population imprinted with the SARS-CoV-2 spike (S) protein. Here, we designed protein nanoparticle (NP) vaccines co-displaying the SARS-CoV-2 BA.5, SARS-CoV-1, and BtKY72 receptor-binding domains (RBDs) with or without the Wuhan-Hu-1 (Wu) RBD. We show that these vaccines elicit cross-reactive and broadly neutralizing plasma antibody responses against SARS-CoV-2 variants and sarbecoviruses in naive and pre-immune animals. Immunization with multivalent RBD-NPs overcomes immune imprinting and elicits neutralizing antibodies and memory B cells specific for the BA.5, SARS-CoV-1, and BtKY72 RBDs in mRNA-1273-vaccinated non-human primates. Multivalent RBD-NPs outperform a monovalent Wu RBD-NP vaccine by providing superior protection in mice and non-human primates challenged with the vaccine-mismatched SARS-CoV-2 XBB.1.5 or the pre-emergent RsSHC014. These data support the use of multivalent RBD-NP vaccines for SARS-CoV-2 variants and sarbecoviruses in naive and pre-immune populations.

MeSH

Vaccines, Nanoparticles, Phylogeny, Nanovaccines