Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination

Jordan J. Clark, Irene Hoxie, Daniel C. Adelsberg, Iden A. Sapse, Robert Andreata-Santos, Jeremy S. Yong, Fatima Amanat, Johnstone Tcheou, Ariel Raskin, Gagandeep Singh, Irene González-Domínguez, Julia E. Edgar, Stylianos Bournazos, Weina Sun, Juan Manuel Carreño, Viviana Simon, Ali H. Ellebedy, Goran Bajic, Florian Krammer

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Neutralizing antibodies correlate with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection against disease progression. Non-neutralizing antibodies cannot directly protect against infection but may recruit effector cells and thus contribute to the clearance of infected cells. Additionally, they often bind conserved epitopes across multiple variants. Here, we characterize 42 human monoclonal antibodies (mAbs) from coronavirus disease 2019 (COVID-19)-vaccinated individuals. Most of these antibodies exhibit no neutralizing activity in vitro, but several non-neutralizing antibodies provide protection against lethal challenge with SARS-CoV-2 in different animal models. A subset of those mAbs shows a clear dependence on Fc-mediated effector functions. We have determined the structures of three non-neutralizing antibodies, with two targeting the receptor-binding domain and one that binds the subdomain 1 region. Our data confirm the real-world observation in humans that non-neutralizing antibodies to SARS-CoV-2 can be protective.

Original languageEnglish
Article number114922
JournalCell Reports
Volume43
Issue number11
DOIs
StatePublished - Nov 26 2024

Keywords

  • ADCC
  • ADCP
  • CP: Immunology
  • effector functions
  • immunology
  • mAbs
  • non-neutralizing mAbs
  • spike

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