Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

Alexandra C Walls; Marcos C Miranda; Alexandra Schäfer; Minh N Pham; Allison Greaney; Prabhu S Arunachalam; Mary-Jane Navarro; M Alejandra Tortorici; Kenneth Rogers; Megan A O'Connor; Lisa Shirreff; Douglas E Ferrell; John Bowen; Natalie Brunette; Elizabeth Kepl; Samantha K Zepeda; Tyler 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; Francois Villinger; Jesse Bloom; Bali Pulendran; Ralph S Baric; Neil P King; David Veesler

doi:10.1016/j.cell.2021.09.015

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines

Cell. 2021 Oct 14;184(21):5432-5447.e16. doi: 10.1016/j.cell.2021.09.015. Epub 2021 Sep 15.

Authors

Alexandra C Walls¹, Marcos C Miranda², Alexandra Schäfer³, Minh N Pham², Allison Greaney⁴, Prabhu S Arunachalam⁵, Mary-Jane Navarro¹, M Alejandra Tortorici⁶, Kenneth Rogers⁷, Megan A O'Connor⁸, Lisa Shirreff⁷, Douglas E Ferrell⁷, John Bowen¹, Natalie Brunette², Elizabeth Kepl², Samantha K Zepeda¹, Tyler Starr⁹, Ching-Lin Hsieh¹⁰, Brooke Fiala², Samuel Wrenn², Deleah Pettie², Claire Sydeman², Kaitlin R Sprouse¹, Max Johnson², Alyssa Blackstone², Rashmi Ravichandran², Cassandra Ogohara², Lauren Carter², Sasha W Tilles¹¹, Rino Rappuoli¹², Sarah R Leist³, David R Martinez³, Matthew Clark¹³, Roland Tisch¹⁴, Derek T O'Hagan¹⁵, Robbert Van Der Most¹⁶, Wesley C Van Voorhis¹¹, Davide Corti¹⁷, Jason S McLellan¹⁰, Harry Kleanthous¹⁸, Timothy P Sheahan³, Kelly D Smith¹⁹, Deborah H Fuller⁸, Francois Villinger⁷, Jesse Bloom⁴, Bali Pulendran⁵, Ralph S Baric³, Neil P King²⁰, David Veesler²¹

Affiliations

¹ Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
² Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁴ Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
⁵ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁶ Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institut Pasteur and CNRS UMR 3569, Unité de Virologie Structurale, Paris, France.
⁷ New Iberia Research Center and Department of Biology, University of Louisiana at Lafayette, New Iberia, LA 70560, USA.
⁸ Washington National Primate Research Center, Seattle, WA 98121, USA; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
⁹ Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
¹⁰ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
¹¹ Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
¹² GSK, Siena, Italy.
¹³ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁵ GSK, Rockville, MD, USA.
¹⁶ GSK, Rixensart, Belgium.
¹⁷ Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
¹⁸ Bill & Melinda Gates Foundation, Seattle, WA 98109, USA.
¹⁹ UW Medicine Department of Laboratory Medicine and Pathology, Seattle, WA 98195, USA.
²⁰ Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
²¹ Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].

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.

Keywords: COVID-19; SARS-CoV-2; mosaic nanoparticle; receptor-binding domain; sarbecovirus; self-assembling nanoparticle; spike glycoprotein; vaccine design.

Abstract

Grants and funding