Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines
Alexandra C. Walls, Marcos C. Miranda, Alexandra Schäfer, Minh N. Pham, Allison J. Greaney, Prabhu S. Arunachalam, Mary-Jane Navarro, M. Alejandra Tortorici, Kenneth A. Rogers, Megan A. O’Connor, Lisa Shirreff, Douglas E. Ferrell, John E. Bowen, Natalie Brunette, Elizabeth Kepl, Samantha K. Zepeda, Tyler N. Starr, Ching‐Lin Hsieh, Brooke Fiala, Samuel Wrenn, Deleah Pettie, Claire Sydeman, Kaitlin R. Sprouse, Max Johnson, Alyssa Blackstone, Rashmi Ravichandran, Cassandra Ogohara, Lauren Carter, Sasha W. Tilles, Rino Rappuoli, Sarah R. Leist, David R. Martinez, Matthew Clark, Roland Tisch, Derek T. O’Hagan, Robbert van der Most, Wesley C. Van Voorhis, Davide Corti, Jason S. McLellan, Harry Kleanthous, Timothy P. Sheahan, Kelly D. Smith, Deborah H. Fuller, François Villinger, Jesse D. Bloom, Bali Pulendran, Ralph S. Baric, Neil P. King, David Veesler
Abstract
Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.