Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines
Year: 2025
Type: preprint
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.
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
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4410380753