Defining neutralization and allostery by antibodies against COVID-19 variants

The changing landscape of mutations in the SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. A major factor that contributes to the functional activity of neutralizing antibodies are the intrinsic quaternary changes that occur as a result of antibody-Spike trimer interactions. In this study, we reveal the conformational dynamics and allosteric perturbations linked to binding of human monoclonal antibodies and the viral Spike protein. We identify epitope hotspots of known and novel antibodies, and associated changes in Spike dynamics that distinguish weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan-Hu-1, Delta, and Omicron variants of concern (VoCs) on differences in the antibody-induced conformational changes in Spike and illustrate how these render certain antibodies ineffective. Our comparative analyses of the antibody-footprints on Spike variants reveal how antibodies with similar binding affinities may induce destabilizing or stabilizing allosteric effects. These differences have important implications for neutralization efficacy and for developing new antibodies targeting emerging variants. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19, and provide a foundation for the design of effective antiviral strategies.