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

During the COVID-19 pandemic, the vast majority of epitope mapping studies have focused on sera from mRNA-vaccinated populations from high-income countries. In contrast, here we report an analysis of 164 serum samples isolated from breakthrough infection patients in India during early 2022 who received two doses of the ChAdOx viral vector vaccine. Sera were screened for neutralization breadth and potency against wildtype, Delta, and Omicron BA.1 viruses amongst which three were shortlisted for epitope mapping using charged scanning mutagenesis. These sera majorly targeted the recently identified class 5 cryptic epitope which is completely conserved across all SARS-CoV-2 variants and for different Sarbecoviruses. Consistent with these results, the sera show broad neutralizing activity against recent Omicron subvariants including XBB.1.5. Our study demonstrates that two vaccinations with the ChAdOx vaccine in a highly exposed population are sufficient to drive substantial neutralization breadth against emerging and future SARS-CoV-2 variants of concern.