Early 2022 breakthrough infection sera from India target the conserved cryptic class 5 epitope to counteract immune escape by SARS-CoV-2 variants

Worldwide implementation of coronavirus disease 2019 (COVID-19) vaccines and the parallel emergence of newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have shaped the humoral immune response in a population-specific manner. While characterizing this immune response is important for monitoring disease progression at the population level, it is also imperative for developing effective countermeasures in the form of novel vaccines and therapeutics. India has implemented the world's second largest COVID-19 vaccination drive and encountered a large number of post-vaccination "breakthrough" infections. From a cohort of patients with breakthrough infection, we identified individuals whose sera showed broadly neutralizing immunity against different SARS-CoV-2 variants. Interestingly, these sera primarily target a novel cryptic epitope, which was not identified in previous population-level studies conducted in Western countries. This rare cryptic epitope remains conserved across all SARS-CoV-2 variants, including recently emerged ones and for the SARS-like coronaviruses that may cause future outbreaks, thus representing a potential target for future vaccines.