Priming conditions shape breadth of neutralizing antibody responses to sarbecoviruses

Abstract

Vaccines that are broadly cross-protective against current and future SARS-CoV-2 variants of concern (VOC) or across the sarbecoviruses subgenus remain a priority for public health. Virus neutralization is the best available correlate of protection. We used sera from cohorts of individuals vaccinated with two or three doses of RNA (BNT162b2) or inactivated SARS-CoV-2 (Coronavac or Sinopharm) vaccines with or without a history of previous SARS-CoV-2 or SARS-CoV-1 (in 2003) infection, to define the magnitude and breath of cross-neutralization in a multiplex surrogate neutralization assay based on virus spike receptor binding domain of multiple SARS-CoV-2 variants of concern (VOC), SARS-CoV-2 related bat and pangolin viruses, SARS-CoV-1 and related bat sarbecoviruses. SARS-CoV-2 or SARS-CoV-1 infection followed by BNT162b2 vaccine, Omicron BA.2 breakthrough infection following BNT162b2 vaccine or a third dose of BNT162b2 following two doses of BNT162b2 or CoronaVac elicited the highest and broadest neutralization across VOCs. Considering breadth and magnitude of neutralization across all sarbecoviruses, those infected with SARS-CoV-1 immunized with BNT162b2 outperformed all other combinations of infection and/or vaccination. These data may inform vaccine design strategies for generating broadly neutralizing antibodies to SARS-CoV-2 variants or across the sarbecovirus subgenus.