RT Journal Article SR Electronic T1 Antigen presentation dynamics shape the response to emergent variants like SARS-CoV-2 Omicron strain after multiple vaccinations with wild type strain JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.08.24.505127 DO 10.1101/2022.08.24.505127 A1 Leerang Yang A1 Matthew Van Beek A1 Zijun Wang A1 Frauke Muecksch A1 Marie Canis A1 Theodora Hatziioannou A1 Paul D. Bieniasz A1 Michel C. Nussenzweig A1 Arup K. Chakraborty YR 2022 UL http://biorxiv.org/content/early/2022/08/25/2022.08.24.505127.abstract AB The Omicron variant of SARS-CoV-2 evades neutralization by most serum antibodies elicited by two doses of mRNA vaccines, but a third dose of the same vaccine increases anti-Omicron neutralizing antibodies. By combining computational modeling with data from vaccinated humans we reveal mechanisms underlying this observation. After the first dose, limited antigen availability in germinal centers results in a response dominated by B cells with high germline affinities for immunodominant epitopes that are significantly mutated in an Omicron-like variant. After the second dose, expansion of these memory cells and differentiation into plasma cells shape antibody responses that are thus ineffective for such variants. However, in secondary germinal centers, pre-existing higher affinity antibodies mediate enhanced antigen presentation and they can also partially mask dominant epitopes. These effects generate 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.Competing Interest StatementThe authors have no competing interests. For completeness, it is noted that AKC is a consultant (titled Academic Partner) for Flagship Pioneering and also serves on the Strategic Oversight Board of its affiliated company, Apriori Bio, and is a consultant and SAB member of another affiliated company, FL72. MCN is on the SAB of Celldex, Walking Fish, and Frontier Bio.