Antigen presentation dynamics shape the antibody response to variants like SARS-CoV-2 Omicron after multiple vaccinations with the original strain

The Omicron variant of SARS-CoV-2 is not effectively neutralized by most antibodies elicited by two doses of mRNA vaccines, but a third dose increases anti-Omicron neutralizing antibodies. We reveal mechanisms un-derlying this observation by combining computational modeling with data from vaccinated humans. After the first dose, limited antigen availability in germinal centers (GCs) results in a response dominated by B cells that target immunodominant epitopes that are mutated in an Omicron-like variant. After the second dose, these memory cells expand and differentiate into plasma cells that secrete antibodies that are thus ineffective for such variants. However, these pre-existing antigen-specific antibodies transport antigen efficiently to second-ary GCs. They also partially mask immunodominant epitopes. Enhanced antigen availability and epitope mask-ing in secondary GCs together result in generation of memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.

Automated summary

The Omicron variant is resistant to neutralization by most antibodies produced from two doses of mRNA vaccines, but a third dose enhances the production of anti-Omicron neutralizing antibodies. Through computational modeling and data from vaccinated individuals, we have identified the mechanisms behind this observation. Limited antigen availability after the first dose leads to a dominant B cell response targeting immunodominant epitopes that are mutated in the Omicron-like variant. The second dose expands memory cells that produce ineffective antibodies for such variants, but also facilitates antigen transport and masking of antigenic sites, resulting in the generation of memory B cells targeting less mutated subdominant epitopes in Omicron. The third dose further expands these cells and boosts the production of neutralizing antibodies against the variant.