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Antibody feedback regulates immune memory after SARS-CoV-2 mRNA vaccination

Author

Listed:
  • Dennis Schaefer-Babajew

    (The Rockefeller University)

  • Zijun Wang

    (The Rockefeller University)

  • Frauke Muecksch

    (The Rockefeller University)

  • Alice Cho

    (The Rockefeller University)

  • Maximilian Loewe

    (The Rockefeller University)

  • Melissa Cipolla

    (The Rockefeller University)

  • Raphael Raspe

    (The Rockefeller University)

  • Brianna Johnson

    (The Rockefeller University)

  • Marie Canis

    (The Rockefeller University)

  • Justin DaSilva

    (The Rockefeller University)

  • Victor Ramos

    (The Rockefeller University)

  • Martina Turroja

    (The Rockefeller University)

  • Katrina G. Millard

    (The Rockefeller University)

  • Fabian Schmidt

    (The Rockefeller University)

  • Leander Witte

    (The Rockefeller University)

  • Juan Dizon

    (The Rockefeller University)

  • Irina Shimeliovich

    (The Rockefeller University)

  • Kai-Hui Yao

    (The Rockefeller University)

  • Thiago Y. Oliveira

    (The Rockefeller University)

  • Anna Gazumyan

    (The Rockefeller University
    Howard Hughes Medical Institute)

  • Christian Gaebler

    (The Rockefeller University)

  • Paul D. Bieniasz

    (The Rockefeller University
    Howard Hughes Medical Institute)

  • Theodora Hatziioannou

    (The Rockefeller University)

  • Marina Caskey

    (The Rockefeller University)

  • Michel C. Nussenzweig

    (The Rockefeller University
    Howard Hughes Medical Institute)

Abstract

Feedback inhibition of humoral immunity by antibodies was first documented in 19091. Subsequent studies showed that, depending on the context, antibodies can enhance or inhibit immune responses2,3. However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies and subsequently two doses of an mRNA vaccine4–8. We found that the recipients of the monoclonal antibodies produced antigen-binding and neutralizing titres that were only fractionally lower compared than in control individuals. However, the memory B cells of the individuals who received the monoclonal antibodies differed from those of control individuals in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered receptor binding domain (RBD) target specificity, consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centres formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias germinal centre and memory B cell selection through two distinct mechanisms: (1) by lowering the activation threshold for B cells, thereby permitting abundant lower-affinity clones to participate in the immune response; and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations9.

Suggested Citation

  • Dennis Schaefer-Babajew & Zijun Wang & Frauke Muecksch & Alice Cho & Maximilian Loewe & Melissa Cipolla & Raphael Raspe & Brianna Johnson & Marie Canis & Justin DaSilva & Victor Ramos & Martina Turroj, 2023. "Antibody feedback regulates immune memory after SARS-CoV-2 mRNA vaccination," Nature, Nature, vol. 613(7945), pages 735-742, January.
  • Handle: RePEc:nat:nature:v:613:y:2023:i:7945:d:10.1038_s41586-022-05609-w
    DOI: 10.1038/s41586-022-05609-w
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    Cited by:

    1. Antonio Santos-Peral & Fabian Luppa & Sebastian Goresch & Elena Nikolova & Magdalena Zaucha & Lisa Lehmann & Frank Dahlstroem & Hadi Karimzadeh & Julia Thorn-Seshold & Elena Winheim & Ev-Marie Schuste, 2024. "Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Tomohiro Takano & Takashi Sato & Ryutaro Kotaki & Saya Moriyama & Shuetsu Fukushi & Masahiro Shinoda & Kiyomi Kabasawa & Nagashige Shimada & Mio Kousaka & Yu Adachi & Taishi Onodera & Kazutaka Terahar, 2023. "Heterologous SARS-CoV-2 spike protein booster elicits durable and broad antibody responses against the receptor-binding domain," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Marta Ferreira-Gomes & Yidan Chen & Pawel Durek & Hector Rincon-Arevalo & Frederik Heinrich & Laura Bauer & Franziska Szelinski & Gabriela Maria Guerra & Ana-Luisa Stefanski & Antonia Niedobitek & Ann, 2024. "Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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