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

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. ### Competing Interest Statement J.D.B. consults for Moderna and Flagship Labs 77 on topics related to viral evolution, and has the potential to receive a share of IP revenue as an inventor on a Fred Hutch optioned technology/patent (application WO2020006494) related to deep mutational scanning of viral proteins. A.J.G, T.N.S., and J.D.B have the potential to receive a share of IP revenue as an inventor on a Fred Hutch-optioned technology related to deep mutational scanning of the receptor-binding domain of SARS-CoV-2 Spike protein. H.Y.C. is a consultant for Merck, Pfizer, Ellume, and the Bill and Melinda Gates Foundation and has received support from Cepheid and Sanofi-Pasteur. The other authors declare no competing interests.