Serological fingerprints link antiviral activity of therapeutic antibodies to affinity and concentration

Abstract

The Omicron variant of SARS-CoV-2, first detected in November 2021, is rapidly becoming the dominant lineage worldwide. We assessed the affinities of two monoclonal antibodies (mAbs), casirivimab and imdevimab, to wild type, Delta and Omicron spike; to provide context, we compared the properties of these therapeutic mAbs to the affinities and concentrations of wild-type RBD specific antibodies in 74 convalescent sera. The affinities of both mAbs to wild type and Delta RBDs were in the same range as the polyclonal responses of the convalescents. Antibodies in a pooled, convalescent plasma from early 2020 retained nanomolar affinities to wild type, Delta and Omicron RBDs; however, the concentration of Omicron-specific antibodies decreased considerably. By contrast, the affinity of casirivimab to Omicron RBD decreased by factors >1000 and 600 compared with wild type and Delta RBDs, respectively. Imdevimab did not bind to Omicron at ≤10 μM. These results corroborate the finding that casirivimab and imdevimab do not prevent infection of cells by the Omicron variant.

Both COVID-19 infection and vaccination induce high-affinity cross-clade responses to SARS-CoV-2 variants

“…We have recently described a powerful microfluidics-based technology that enables the affinity determination of complex antibody mixtures in solution in plasma samples (Schneider et al ., 2022). Our finding that affinity of therapeutic monoclonal antibodies are markedly decreased against the SARS-CoV-2 omicron RBD variant (Fiedler et al ., 2022) prompted us to investigate the anti-omicron affinity of serum responses in patients who had suffered from pre-omicron COVID-19, or were vaccinated with pre-omicron vaccines.…”

“…Our finding that affinity of therapeutic monoclonal antibodies are markedly decreased against the SARS-CoV-2 omicron RBD variant (Fiedler et al, 2022) prompted us to investigate the anti-omicron affinity of serum responses in patients who had suffered from pre-omicron COVID-19, or were vaccinated with pre-omicron vaccines.…”

“…The high-affinity responses to the omicron spike protein contrast starkly with those of current therapeutic monoclonal antibodies (Fiedler et al ., 2022) whose neutralization of omicron was poor or absent (Dejnirattisai et al ., 2021; Planas et al ., 2021; VanBlargan et al ., 2022). The K A of plasma antibodies against SARS-CoV-2 RBD variants were in a similar range of 16.9-684.9 μM -1 for WT, 13.5-471.7 μM -1 for delta, and 3.6-943.4μM -1 for omicron.…”

“…We have recently employed Microfluidic Antibody Affinity Profiling (MAAP) to simultaneously determine the affinity and concentration of antibodies against WT RBD in convalescent sera (Schneider et al ., 2022), to study the antibody-based inhibition of RBD-ACE2 interactions (Fiedler et al ., 2021) and to understand memory re-activation and cross-reactivity (Denninger et al ., 2021). We have also characterized the affinity of multiple therapeutic antibodies (cilgavimab, tixagevimab, casirivimab, and imdevimab) to the omicron RBD variant (Fiedler et al ., 2022). While most of these antibodies exhibited a striking loss of affinity, a pooled plasma standard of anti-SARS-CoV-2 immunoglobulins (Mattiuzzo et al ., 2020) retained substantial cross-reactivity to the omicron spike RBD with only moderately decreased antibody concentration and affinity against the omicron variant (Fiedler et al ., 2022).…”

“…We have also characterized the affinity of multiple therapeutic antibodies (cilgavimab, tixagevimab, casirivimab, and imdevimab) to the omicron RBD variant (Fiedler et al ., 2022). While most of these antibodies exhibited a striking loss of affinity, a pooled plasma standard of anti-SARS-CoV-2 immunoglobulins (Mattiuzzo et al ., 2020) retained substantial cross-reactivity to the omicron spike RBD with only moderately decreased antibody concentration and affinity against the omicron variant (Fiedler et al ., 2022).…”