Spike antibody Fc is associated with protection from SARS-CoV-2 challenge in macaques

A definitive correlate of protection (CoP) for SARS-CoV-2 has yet to be formally established. We previously reported that neutralising antibodies (NAbs) are the strongest candidate CoP for clinical protection against COVID-19 and that spike binding antibody is the strongest candidate CoP for viral burden post-challenge in our non-human primate vaccine candidate challenge study. In this study, we further characterised the protective binding antibody profile by analysing spike antibody-dependent complement deposition (ADCD), FcγR binding, isotype and antibody sialylation. Using the machine learning platform SIMON, we demonstrated that ADCD and FcγR binding are strong candidate co-correlates of clinical protection, as their addition to the model improved its performance. We found that FcγR2A binding, closely followed by spike antibody sialylation, was the spike antibody feature with the strongest negative correlation with histopathology score. Sialylation also negatively correlated with lung viral load six-to-eight days post-challenge. Spike antibody ADCD, FcγR binding, isotype and sialylation 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 Fc 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.