Background: Comparative analyses of SARS-CoV-2-specific immune responses elicited by diverse prime -boost regimens are required to establish efficient regimens for the control of COVID-19. Method: In this prospective observational cohort study, spike-specific immunoglobulin G (IgG) and neu-tralizing antibodies (nAbs) alongside spike-specific T-cell responses in age-matched groups of homolo-gous BNT162b2/BNT162b2 or AZD1222/AZD1222 vaccination, heterologous AZD1222/BNT162b2 vaccination, and prior wild-type SARS-CoV-2 infection/vaccination were evaluated. Results: Peak immune responses were achieved after the second vaccine dose in the naive vaccinated groups and after the first dose in the prior infection/vaccination group. Peak titers of anti-spike IgG and nAb were significantly higher in the AZD1222/BNT162b2 vaccination and prior infection/vaccination groups than in the BNT162b2/BNT162b2 or AZD1222/AZD1222 groups. However, the frequency of interferon-c-producing CD4' T cells was highest in the BNT162b2/BNT162b2 vaccination group. Similar results were observed in the analysis of polyfunctional T cells. When nAb and CD4' T-cell responses against the Delta variant were analyzed, the prior infection/vaccination group exhibited higher responses than the groups of other homologous or heterologous vaccination regimens. Conclusion: nAbs are efficiently elicited by heterologous AZD1222/BNT162b2 vaccination, as well as prior infection/vaccination, whereas spike-specific CD4' T-cell responses are efficiently elicited by homologous BNT162b2 vaccination. Variant-recognizing immunity is more efficiently generated by prior infection/-vaccination than the other homologous or heterologous vaccination regimens. (c) 2023 Elsevier Ltd. All rights reserved.