The binding and neutralizing activity of SARS-CoV-2 antibodies are important correlates of protection of current COVID-19 vaccines. SARS-CoV-2 exposure status and COVID-19 vaccine types can influence these responses and the breadth of cross-reactivity to variants. In this longitudinal cohort study, we used SARS-CoV-2-specific multiplex Luminex antibody assays and live virus neutralization of ancestral (VIC01/2020), Delta and Omicron (BA1, BA2, and BA5) SARS-CoV-2 variants to compare antigen-specific binding, and neutralizing antibody (nAb) responses to primary vaccination (two doses) of adenovirus vectored (AdVV) or mRNA vaccines followed by a booster dose of mRNA vaccine in convalescent (= 51) and infection-naïve individuals (= 47). In a subset of individuals, we performed additional analysis of antibody responses following breakthrough infection. We found that titers of anti-SARS-CoV-2 nAb following primary vaccination (two doses) with AdVV vaccine were significantly lower than those following mRNA vaccine, irrespective of prior SARS-CoV-2 infection status. However, an mRNA vaccine booster dose resulted in equivalent binding and nAb titers to the ancestral virus in all individuals, irrespective of primary vaccine type. Notably, vaccinated infection-naïve, but not convalescent individuals required the third dose of vaccine (mRNA) to induce nAbs to Omicron subvariants BA1, BA2, and BA5 though titers against the variants were lower than those against the ancestral strain. Importantly, breakthrough infection with Omicron strains induced higher nAb titer rises against the ancestral strain than against Omicron variants consistent with imprinting of the immunologic response and recall of pre-existing immunity to the ancestral strain.IMPORTANCEStudies on binding and neutralizing antibody responses to COVID-19 vaccines and breakthrough infections were frequently confounded by unsuspected exposure to intercurrent natural infections with SARS-CoV-2 in the community particularly during year 1 and 2 of the pandemic. This study is extraordinary in that it was conducted in Australia, where SARS-CoV-2 circulation was largely contained by public health and social measures for the first 2 years of the pandemic. We followed well-defined study populations who received vaccines in a natural infection-free setting or a separate subgroup who had natural infection. Thus, the study provides unique insights in infection-naïve, vaccinated individuals and those with breakthrough infections with Omicron variants. In this setting, we had an opportunity to demonstrate evidence of antigenic imprinting, with neutralizing antibody responses to the ancestral vaccine antigen being higher than responses to the infecting Omicron variant. n n
