Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees
Takeshi Inoue, Ryo Shinnakasu, Kawai Chie, Hiromi Yamamoto, Shuhei Sakakibara, Chikako Ono, Yumi Itoh, Tommy Terooatea, Kazuo Yamashita, Toru Okamoto, Noritaka Hashii, Akiko Ishii‐Watabe, Noah S. Butler, Yoshiharu Matsuura, Hisatake Matsumoto, Shinya Otsuka, Kei Hiraoka, Takanori Teshima, Masaaki Murakami, Tomohiro Kurosaki
Abstract
In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, 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. Frequency of Omicron-reactive memory B cells increased ∼9 mo 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.