Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials

BACKGROUND: The COVID-19 Prevention Network (CoVPN) co-conducted six COVID-19 phase 3 vaccine efficacy (VE) trials that featured harmonized immunogenicity analyses using validated antibody assays. These trials enabled a uniquely comprehensive characterization of immunogenicity produced by different vaccine platforms and regimens in individuals with and without prior SARS-CoV-2 acquisition. METHODS: Comparisons of serum binding antibody concentration and serum neutralization antibody ID50 titers were performed across three strata: vaccine immunity (vaccination in SARS-CoV-2-naïve individuals), natural immunity (placebo with prior SARS-CoV-2 acquisition), and hybrid immunity (vaccination after prior SARS-CoV-2 acquisition). We compared immunogenicity across immunity strata for each trial and each dose, adjusting for age, sex assigned at birth, and body mass index. Antibody levels were also examined in relation to VE. RESULTS: Antibody levels in response to a single vaccine dose varied across trials and generally increased most substantially after a second dose in naïve participants. Fold rise in antibody levels after a single dose were more pronounced in participants with hybrid immunity: a single dose of any of the tested vaccine yielded responses comparable to or exceeding the post-dose-two (peak) response of any two-dose vaccine in naïve participants. Population-level antibody levels demonstrated high concordance with VE across trials and immunity strata. CONCLUSIONS: In SARS-CoV-2-naïve individuals, a two-dose vaccine regimen is needed to provide antibody levels correlated with protection against disease caused by the cognate virus strain. In contrast, in individuals with prior SARS-CoV-2 acquisition, a single dose of any of the tested vaccines/platforms (mRNA/protein/vector) provides comparably high antibody levels.