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Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.

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.

SUBMITTER: Inoue T

PROVIDER: S-EPMC9750191 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.

Inoue Takeshi T Shinnakasu Ryo R Kawai Chie C Yamamoto Hiromi H Sakakibara Shuhei S Ono Chikako C Itoh Yumi Y Terooatea Tommy T Yamashita Kazuo K Okamoto Toru T Hashii Noritaka N Ishii-Watabe Akiko A Butler Noah S NS Matsuura Yoshiharu Y Matsumoto Hisatake H Otsuka Shinya S Hiraoka Kei K Teshima Takanori T Murakami Masaaki M Kurosaki Tomohiro T

The Journal of experimental medicine 20221213 2

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 ...[more]

PMID: 36512034

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Project description:Feedback inhibition of humoral immunity by antibodies was initially documented in guinea pigs by Theobald Smith in 1909, who showed that passive administration of excess anti-Diphtheria toxin inhibited immune responses1. Subsequent work documented that antibodies can enhance or inhibit immune responses depending on antibody isotype, affinity, the physical nature of the antigen, and engagement of immunoglobulin (Fc) and complement (C') receptors2,3. However, little is known about how pre-existing antibodies might influence the subsequent development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity IgG1 anti-SARS-CoV-2 receptor binding domain (RBD)-specific monoclonal antibodies, C144-LS and C135-LS, and subsequently two doses of a SARS-CoV-2 mRNA vaccine. The two antibodies target Class 2 and 3 epitopes that dominate the initial immune response to SARS-CoV-2 infection and mRNA vaccination4-8. Antibody responses to the vaccine in C144-LS and C135-LS recipients produced plasma antigen binding and neutralizing titers that were fractionally lower but not statistically different to controls. In contrast, memory B cells enumerated by flow cytometry after the second vaccine dose were present in higher numbers than in controls. However, the memory B cells that developed in antibody recipients differed from controls in that they were not enriched in VH3-53, VH1-46 and VH3-66 genes and predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations. These antibodies showed altered RBD target specificity consistent with epitope masking, and only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The results indicate that pre-existing high-affinity antibodies bias memory B cell selection and have a profound effect on the development of immunological memory in humans that may in part explain the shifting target profile of memory antibodies elicited by the 3rd mRNA vaccine dose.

Dataset Information

Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.

Publications

Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.

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