The SARS-CoV-2 Delta variant induces an antibody response largely focused on class 1 and 2 antibody epitopes

Abstract

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD’s class 1 and class 2 epitopes, including sites 417, 478, and 484–486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history. SARS-CoV-2 has been circulating among humans for over two years, and immune selection has become a major driver of its evolution. In addition to partially evading the immune response elicited by vaccination or infection with earlier variants, SARS-CoV-2 “variants of concern” can also elicit distinct antibody responses. Here, we use the high-throughput techniques of deep mutational scanning and yeast display to characterize the antibody response elicited by primary or vaccine-breakthrough infections with the Delta variant. We compare these responses to those elicited by mRNA vaccination, infection with early 2020 viruses, or infection the Beta variant. We find that the early 2020 and Delta-elicited antibody responses often target similar regions of the spike receptor-binding domain, with some subtle but notable differences. The antibody response to Delta and early 2020 strains are more similar to each other than to the Beta variant. As SARS-CoV-2 continues to evolve, individuals’ increasingly diverse exposure histories to vaccines and variants will influence their susceptibilities to future viral mutations.