UNLABELLED: A major challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been assessing the intensity, dynamics, and determinants of the antibody responses after infection and/or vaccination. Therefore, we aimed to characterize the longitudinal dynamics of the antibody responses among naturally infected individuals and individuals who achieved hybrid immunity in a large Canadian cohort. We demonstrate that anti-Spike IgGs and neutralizing antibody dynamics vary greatly among individuals with COVID-19, in peak antibody levels, rate of waning, and longevity of the antibody response. Additionally, we found an association between robust antibody responses and individuals with severe COVID-19 clinical symptoms during the first-month post-symptom onset. For individuals who achieved hybrid immunity, a robust increase in anti-S1 IgGs and neutralizing antibodies followed the first vaccination dose
however, there was a minimal increase in the anti-S1 IgGs and neutralizing antibody titers after administration of the second dose of the vaccine. Furthermore, neutralizing antibodies elicited by the wild-type virus alone were largely ineffective against emerging variants of concern in our natural infection-only cohort, in contrast to a much broader and more robust neutralization profile observed in individuals who achieved hybrid immunity. Our findings emphasize the need for global SARS-CoV-2 vaccination efforts to further sustain protective immune responses required to minimize viral spread and disease severity in the population. As SARS-CoV-2 variants continue to emerge, understanding the interplay between previous infections, vaccine durability, and virus evolution will be critical for guiding ongoing vaccination strategies. IMPORTANCE: A major challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been assessing the intensity, dynamics, and determinants of the antibody response after infection and/or vaccination. Our paper addresses this in a large Canadian cohort with antibody responses that were generated by natural infection as well as vaccine in some persons studied.