question: BackgroundHomologous and heterologous SARS-CoV-2-vaccinations yield different spike protein-directed humoral and cellular immune responses. However, their interdependencies remain elusive. MethodsCOV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received homologous vaccination with Astra (ChAdOx1-S; AstraZeneca) or BNT (BNT162b2; Biontech/Pfizer) or heterologous vaccination with Astra/BNT. We assessed the humoral (anti-spike-RBD-IgG, neutralizing antibodies, antibody avidity) and cellular (spike-induced T cell interferon-{gamma} release) immune response in blood samples up to 2 weeks before (T1) and 2 to 12 weeks following secondary immunization (T2). FindingsInitial vaccination with Astra resulted in lower anti-spike-RBD-IgG responses compared to BNT (70{+/-}114 vs. 226{+/-}279 BAU/ml, p<0.01) at T1, whereas T cell activation did not differ significantly. Booster vaccination with BNT proved superior to Astra at T2 (anti-spike-RBD-IgG: Astra/BNT 2387{+/-}1627 and BNT/BNT 3202{+/-}2184 vs. Astra/Astra 413{+/-}461 BAU/ml, both p<0.001; spike-induced T cell interferon-{gamma} release: Astra/BNT 5069{+/-}6733 and BNT/BNT 4880{+/-}7570 vs. Astra/Astra 1152{+/-}2243 mIU/ml, both p<0.001). No significant differences were detected between BNT-boostered groups at T2. For Astra, we observed no booster effect on T cell activation. We found associations between anti-spike-RBD-IgG levels (Astra/BNT and BNT/BNT) and T cell responses (Astra/Astra and Astra/BNT) from T1 to T2. There were also links between levels of anti-spike-RBD-IgG and T cell at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. InterpretationInterdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T cell activation is unlikely to compensate for poor humoral responses. FundingDeutsche Forschungsgemeinschaft (DFG), ER723/3-1 Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Pubmed for papers published between 01/01/2019 and 14/05/2021 with the search terms "covid-19" combined with "vaccination" and "heterologous", excluding "BCG". Of the 41 papers found, none addressed the combination of ChAdOx1-S by AstraZeneca (Astra) and BNT162b2 by Biontech/Pfizer (BNT). After our study was initiated, the CombiVacS trial reported a significant booster effect when BNT was given after initial vaccination with Astra.1 The investigators of the CoCo trial subsequently published data on heterologous immunization in comparison to homologous Astra in a small population (n=87), with the heterologous immunization scheme showing a superior humoral and cellular immune response.2 Further studies investigated heterologous vaccinations with Astra and BNT as well as homologous Astra and BNT regimes and also found superior humoral and cellular immune responses in the heterologous regimes compared to homologous Astra, and comparable or slightly superior immune responses when compared to homologous BNT vaccination.3-6 The body of research covering the effects of heterologous immunization regimes has recently been aggregated in a systematic review.7 Added value of this studyTo our knowledge, this is the first study that evaluates the interdependencies of cellular and humoral immune responses following heterologous vaccination with Astra/BNT in a large group of individuals. Our data show strong correlations between humoral and cellular immune responses with the prime-boost combination Astra/BNT. The findings suggest that individuals with a robust initial response developed strong humoral and cellular immune responses after booster immunization. Implications of all the available evidenceOur study and the available data suggest that due to its superior capacity to elicit a humoral and cellular immune response, mRNA-based vaccines such as BNT should be chosen for booster vaccination rather than Astra. This seems to be particularly important in individuals whose immune response was poor after initial vaccination with Astra. We demonstrate here an association between humoral and cellular immune responses following vaccination. Our findings suggest that distinct differences between common COVID-19 vaccination regimes should be taken into account in population-based vaccine programs. The present data indicate that a poor humoral immune response is unlikely to be mitigated by a strong cellular immune response.