Summary
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.
Competing Interest Statement
The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines influenza virus vaccines and influenza virus therapeutics which list Florian Krammer as co-inventor. Dr. Simon is also listed on the SARS-CoV-2 serological assays patent. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines. Florian Krammer is co-founder and scientific advisory board member of Castlevax. Florian Krammer has consulted for Merck, Curevac, Seqirus and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. The Ellebedy laboratory has received funding under sponsored research agreements from Moderna, Emergent BioSolutions, and AbbVie. A.H.E. has received consulting and speaking fees from InBios International, Inc, Fimbrion Therapeutics, RGAX, Mubadala Investment Company, AstraZeneca, Moderna, Pfizer, GSK, Danaher, Third Rock Ventures, Goldman Sachs, and Morgan Stanley; is the founder of ImmuneBio Consulting and a recipient of royalties from licensing agreements with Abbvie and Leyden Laboratories B.V.
Footnotes
An author was added who was accidentally omitted in version 1 (but who was named in the version 1 pdf of course).
Data availability
The atomic models and corresponding maps are available online under the following accession codes. For the PVI.V5-4 complex, the atomic model is available in the Protein Data Bank (PDB) under accession code 8VIA. The cryo-EM maps and the raw micrographs are available in the Electron Microscopy Data Bank (EMDB) and in the Electron Microscopy Public Image Archive (EMPIAR) under accession codes EMD-43255 and EMPIAR-11847, respectively. Additionally, cryo-EM maps for the PVI.V3-21 and PVI.V6-12 complexes have been deposited to EMDB under accession codes EMD-43306 and EMD-43314, respectively. All other data underlying figures in this paper can be found in ImmPort under identifier xxx.