SARS-CoV-2 Fusion Peptide-Directed Antibodies Are Elicited by Natural Infection and Can Mediate Broad Sarbecovirus Neutralization

SUMMARY Studies have demonstrated that repeated mRNA vaccination enhances the breadth of neutralization against diverse SARS-CoV-2 variants. However, the development of antibodies capable of neutralizing across the Coronavirinae subfamily is poorly understood. In this study, we analyze serum samples to determine their neutralization breadth and potency and identify their antigenic targets. Using a cohort of older individuals and healthcare workers, we track correlates of broad neutralizing responses, including fusion peptide (FP) antibody elicitation. We find that although broadly neutralizing responses are often a result of RBD-specific antibodies, a rare subset of donors produce FP-specific broadly neutralizing responses. Interestingly, FP-specific antibodies are not observed in COVID-naive individuals irrespective of vaccination regimen, but rather, they occur following natural infection or vaccine breakthrough. This study highlights which epitope targets underpin broadly neutralizing antibody responses to coronaviruses and suggests that existing vaccines are insufficient to promote the elicitation of FP-directed broadly neutralizing coronavirus antibodies. Competing Interest Statement A.B.B. is a founder of Cure Systems LLC. S. G. and D. H. C. are recipients of investigator-initiated grants to their universities from Pfizer to study pneumococcal vaccines, Sanofi Pasteur and Seqirus to study influenza vaccines, Moderna to study respiratory infection, and GSK to study herpes zoster. S. G. is the recipient of an investigator-initiated grant to the university from Genentech on influenza antivirals; reports consulting for GSK, Janssen/Johnson&Johnson, Merck, Novavax, Moderna, Seqirus, Sanofi, and Vaxart; he has received honoraria for speaking for AstraZeneca, Pfizer, Seqirus, Sanofi; reports personal fees from Pfizer; and reports data and safety monitoring board fees from Longevoron and SciClone. Funding Statement A.B.B. was supported by NIAID R01s AI174875, AI174276, AI129709-03S1 the NIDA Avenir New Innovator Award DP2DA040254, the NIDA Avant-Garde Award 1DP1DA060607, a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant, CDC subcontract 200-2016-91773-T.O.2 and a grant from Coalition for Epidemic Preparedness Innovations (CEPI). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Use of human samples was approved by Partners Institutional Review Board (protocol 2020P002274). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes This version of the manuscript has been revised to respond to reviews. Data Availability All data produced in the present study are available upon reasonable request to the authors