SARS-Cov-2 antigen exposure history shapes post-infection antibody epitope and immune pressure distribution

The COVID-19 pandemic has led to a complex immunological landscape shaped by various vaccination regimens and SARS-CoV-2 variant infections. The effect of diverse exposure history on antibody response and virus evolution is a critical, unsolved issue. 

Using high-throughput single-cell V(D)J sequencing, high-throughput deep mutational scanning, and neutralization assays, we characterized epitope distributions and immune pressure of more than 6000 Receptor Binding Domain (RBD)-antibodies from various SARS-CoV-2 exposure histories, including ancestral strain vaccinated or unvaccinated individuals with single or dual infections with different variants.

We found that single variant breakthrough infections post-vaccination induce a high proportion of non-neutralizing antibodies due to immune imprinting. In contrast, dual breakthrough infections exhibit fewer non-neutralizing antibodies, akin to those in unvaccinated individuals. Furthermore, the initial infection variant influences the antibody repertoire to second infections, indicating that variant infections also induce immune imprinting. Antibody profiles shaped by diverse exposure histories exert distinct pressures on RBD, promoting the virus to evolve at convergent immune pressure sites. This is evidenced by frequent RBD mutations at positions 420, 455, 456, and 475 across different variants.

These findings highlight the potential of diversifying the antibody pressure across populations to reduce the pace of viral evolution.