A SARS-CoV-2 variant elicits an antibody response with a shifted immunodominance hierarchy

Author summarySARS-CoV-2 has circulated among humans for approximately two years, and mutations in emerging variants can erode immunity elicited by prior infection or vaccination. Our understanding of the antibody response elicited by these new variants is still limited. For other viruses, such as influenza, antigenically drifted variants can elicit antibodies that target different sites. Here, we find that this principle also applies to SARS-CoV-2. While the "class 2" RBD antibody epitope is immunodominant for sera from donors infected with SARS-CoV-2 in early 2020, antibodies elicited by infection with the B.1.351 (Beta) variant are more focused on the "class 3 epitope." Notably, the class 3 epitope is conserved between the early 2020 and B.1.351 viruses, but is mutated in the Delta variant, which rose to high frequency globally in mid-2021. As SARS-CoV-2 continues to circulate among humans, individuals' prior infection and vaccination histories may partially determine their susceptibilities to viral mutants in new variants. Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.