Spike Antibody Fc Drives Protection from SARS-CoV-2 Challenge in Macaques

A definitive correlate of protection (CoP) for SARS-CoV-2 has yet to be formally established. Previously, using data from a series of non-human primate vaccine challenge studies, we reported that neutralising antibodies (NAbs) are the strongest candidate for clinical protection against COVID-19 and that spike binding antibody is the strongest candidate CoP for viral burden post-challenge. In this study, we further characterised the protective binding antibody profile by analysing spike antibody-dependent complement deposition, FcgR binding, isotype and antibody glycosylation. Using the machine learning platform SIMON, we demonstrate that antibody-dependent complement deposition (ADCD) and FcgR binding are strong candidate co-correlates for each of the post-challenge outcomes; viral load and lung pathology. We found that spike antibody sialylation closely followed by FcgR2A, was the spike antibody feature with the strongest negative correlation with histopathology score. Spike antibody ADCD, FcgR binding, isotype and glycosylation significantly differed by immunisation regimen and sex, which demonstrates the heterogeneity of immune mechanisms induced by different immunisation platforms. We conclude that spike binding antibody, with the protective functional characteristics described herein, is a candidate CoP that captures both protection from severe clinical disease and protection against a high viral burden. These findings should be taken into consideration for future SARS-CoV-2 vaccine development.