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Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination. 2024
Jordan Clark, and
Irene Hoxie, and
Daniel C Adelsberg, and
Iden A Sapse, and
Robert Andreata-Santos, and
Jeremy S Yong, and
Fatima Amanat, and
Johnstone Tcheou, and
Ariel Raskin, and
Gagandeep Singh, and
Irene González-Domínguez, and
Julia E Edgar, and
Stylianos Bournazos, and
Weina Sun, and
Juan Manuel Carreño, and
Viviana Simon, and
Ali H Ellebedy, and
Goran Bajic, and
Florian Krammer
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Neutralizing antibodies correlate with protection against SARS-CoV-2. Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection from disease progression. Non-neutralizing antibodies cannot directly protect from infection but may recruit effector cells thus contribute to the clearance of infected cells. Also, they often bind conserved epitopes across multiple variants. We characterized 42 human mAbs from COVID-19 vaccinated individuals. Most of these antibodies exhibited no neutralizing activity in vitro but several non-neutralizing antibodies protected against lethal challenge with SARS-CoV-2 in different animal models. A subset of those mAbs showed a clear dependence on Fc-mediated effector functions. We determined the structures of three non-neutralizing antibodies with two targeting the RBD, and one that targeting the SD1 region. Our data confirms the real-world observation in humans that non-neutralizing antibodies to SARS-CoV-2 can be protective.
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