SARS-CoV-2 Variant Boosters and Breakthrough Infections Drive Functional Differences in the Memory B Cell Repertoire

Updated vaccines with virus variants are made to increase efficacy, but pre-existing immunity affects the response. To understand if variant boosters modify the memory B cell (MBC) repertoire, we analyzed the human MBC response in the COVAIL vaccine trial where individuals previously vaccinated with COVID-19 prototype spike immunogens were boosted with prototype spike, variant spikes, or both.

We analyzed the cross-reactivity, phenotype and functionality of the MBC response and determined that variant vaccine boosters led to greater recall of cross-reactive MBCs compared to a prototype but limited de novo variant-specific MBC responses. Some study participants also experienced breakthrough infections with SARS-CoV-2 Omicron variants after the vaccine boost that primarily expanded cross-reactive MBCs. These MBCs potently neutralized closely related Omicron virus strains, but displayed less breadth toward more distant Omicron subvariants than MBCs from uninfected individuals.