Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus.

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with the antigenicity of their spike (S) glycoproteins remain uncharacterized. Here, we show that the African Rhinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad angiotensin-converting enzyme 2 (ACE2) usage and that receptor-binding domain (RBD) mutations further expand receptor promiscuity and enable human ACE2 utilization. We determine a cryo-EM structure of the PRD-0038 RBD bound to Rhinolophus alcyone ACE2, explaining receptor tropism and highlighting differences with SARS-CoV-1 and SARS-CoV-2. Characterization of PRD-0038 S using cryo-EM and monoclonal antibody reactivity reveals its distinct antigenicity relative to SARS-CoV-2 and identifies PRD-0038 cross-neutralizing antibodies for pandemic preparedness. PRD-0038 S vaccination elicits greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses compared with SARS-CoV-2 S due to broader antigenic targeting, motivating the inclusion of clade 3 antigens in next-generation vaccines for enhanced resilience to viral evolution.
Competing Interests: Declaration of interests N.P.K. and D.V. are named as inventors on patents for coronavirus nanoparticle vaccines filed by the University of Washington. N.P.K. is a co-founder, shareholder, paid consultant, and chair of the scientific advisory board of Icosavax, Inc. and has received an unrelated sponsored research agreement from Pfizer. D.C. is an employee of Vir Biotechnology and may hold shares in Vir Biotechnology. T.N.S. consults for Apriori Bio on DMS. The lab of T.N.S. has received sponsored research agreements unrelated to the present work from Vir Biotechnology and Aerium Therapeutics, Inc. T.N.S. may receive a share of intellectual property revenue as inventor on a Fred Hutchinson Cancer Center-optioned patent related to stabilization of SARS-CoV-2 RBDs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)