SARS-CoV-2 spike sequence-based distance as a marker of binding antibody response to COVID-19 vaccines

COVID-19 vaccines based on ancestral SARS-CoV-2 have proven highly effective at reducing the risk of illness, especially severe disease. Both binding and neutralizing antibodies have been demonstrated to be strong predictors of the level of vaccine efficacy (VE). Both VE and vaccine-induced antibody responses have been shown to be lower against emergent SARS-CoV-2 viruses; therefore, predicting COVID-19 VE against emergent viruses is critical for decision-making regarding the composition of new vaccines. The data needed to enable such prediction are unclear. We report on 728 individuals without prior SARS-CoV-2 infection who received primary vaccination with ancestral-virus-based mRNA and vector-based COVID-19 vaccines and who were boosted in a homologous or heterologous fashion with mRNA, vector, or protein-based COVID-19 vaccines including a bivalent B.1.351 mRNA vaccine. Post-prime and post-boost binding antibody responses were used to evaluate the extent and drivers of variability in these responses to 22 SARS-CoV-2 Spike antigens from viruses that emerged between 2020 and 2021. We evaluated how well proteomic distance between the vaccine and assay Spike antigen predicted the vaccine-induced antibody response. Following primary vaccination, antibody responses varied across Spike antigens and were, on average, 36 % lower per 10-amino acid (AA) difference between the vaccine and assay Spike antigen (95 % CI: 30 % to 43 %). The geometric mean antibody response to a given antigen was nearly perfectly predicted by the sequence-based distance of the antigen to the vaccine. Post-boost responses were less variable across antigens and weakly associated with Spike distance (17 % lower per 10-AA difference; 95 % CI: 14 % to 20 %). The high variability in binding antibodies across individuals was only partially explained by participant characteristics. Given that populations now have experienced multiple rounds of prior vaccination and infection, measurement of vaccine-induced antibody responses from representative populations will likely be needed to predict the efficacy of COVID-19 vaccines against future strains.