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.

, DMS antibody-esca pe mapping *One participant was excluded from analysis due to not receiving a second vaccination dose but their demographic information is unknown.
. CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 29 . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022  Plasma or serum binding to D614G RBD after mock or depletion of D614G RBD-binding antibodies. Note that the D614G RBD is identical to the Wuhan-Hu-1 RBD.
. CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 yeast expressing Delta RBD mutants (measured via a C-terminal MYC tag, green star) were incubated with polyclonal antibodies from plasmas or sera and fluorescence-activated cell sorting (FACS) was used to enrich for cells expressing RBD with reduced antibody binding, as detected using an IgA+IgG+IgM secondary antibody. Deep sequencing was used to quantify the frequency of each mutation in the pre-selection and antibody-escape cell populations. The escape fraction represents the fraction of cells expressing RBD with that mutation that fell in the antibody escape FACS bin. Experimental and computational filters were used to remove RBD mutants that were misfolded or unable to bind the ACE2 receptor. . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022  . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 (29)) or 2x BNT162b2 against the Delta mutant libraries. Key epitopes . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022 are shaded. (D) The average site-total antibody escape mapped to the surface of the Wuhan-Hu-1 RBD (PDB 6M0J, (64)), with red indicating the site with the strongest antibody escape, and white indicating no escape. Key sites are labeled, with labels colored according to antibody epitope. The vaccine sera in B-D are from individuals who were not exposed to the Delta spike via infection or vaccination. The L452R mutation in the Delta RBD can disrupt antibody binding to both the class 2 and class 3 antibody epitopes (24,42), and thus the 2x BNT162b2 (x Delta mutant libraries) plasmas are mostly escaped by mutations in the class 4 epitope (including sites 365, 383, 384) or a non-canonical class 3 epitope that includes site 357.
The antibody-escape maps against the Delta RBD mutant libraries are newly generated in this study, whereas the 2x mRNA-1273 antibody-escape maps against the Wuhan-Hu-1 RBD mutant libraries were first reported in (29) and are reanalyzed here.
. CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 14, 2022. ;https://doi.org/10.1101https://doi.org/10. /2022