Why can 3rd mRNA vaccination induce Omicron-neutralizing antibodies? -Contribution of antibody feedback to memory B cell selection-

Since the outbreak of COVID-19 in late 2019, several SARS-CoV-2 variants of concern have continuously emerged in the past years. Among them, the Omicron BA.1 variant, harboring ~15 mutations in the spike receptor-binding domain (RBD), showed a profound effect on evading the neutralizing antibody responses in those received 2-dose of mRNA vaccination (Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273). However, in contrast to a second dose vaccination, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential antibody response, we examined spike receptor-binding domain (RBD)-specific memory B cells in vaccinated individuals. The frequency of Omicron-reactive memory B cells increased ~9 months after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.