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

Evolving respiratory viruses such as influenza and COVID-19 cause seasonal respiratory illness and death. 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. Thus, infection can narrow the cross-reactivity of the memory B cell repertoire.