Background Heterologous vaccine regimens have been widely discussed as a way to mitigate intermittent supply shortages and to improve immunogenicity and safety of COVID-19 vaccines. We aimed to assess the reactogenicity and immunogenicity of heterologous immunisations with ChAdOx1 nCov-19 (AstraZeneca, Cambridge, UK) and BNT162b2 (Pfizer-BioNtech, Mainz, Germany) compared with homologous BNT162b2 and ChAdOx1 nCov-19 immunisation. Methods This is an interim analysis of a prospective observational cohort study enrolling health-care workers in Berlin (Germany) who received either homologous ChAdOx1 nCov-19 or heterologous ChAdOx1 nCov-19-BNT162b2 vaccination with a 10-12-week vaccine interval or homologous BNT162b2 vaccination with a 3-week vaccine interval. We assessed reactogenicity after the first and second vaccination by use of electronic questionnaires on days 1, 3, 5, and 7. Immunogenicity was measured by the presence of SARS-CoV-2-specific antibodies (full spike-IgG, S1-IgG, and RBD-IgG), by an RBD-ACE2 binding inhibition assay (surrogate SARS-CoV-2 virus neutralisation test), a pseudovirus neutralisation assay against two variants of concerns (alpha [B.1.1.7] and beta [B.1.351]), and anti-S1-IgG avidity. T-cell reactivity was measured by IFN-γ release assay.

Heterologous prime-boost vaccination is of increasing interest for COVID-19 vaccines. Evidence of rare thrombotic events associated with ChAdOx1-nCoV19 (Vaxzevria, ChAdOx) has lead several European countries to recommend a heterologous booster with mRNA vaccines for certain age groups (e.g. persons <60years in Germany), who have already received one dose of ChAdOx, although data on reactogenicity and safety of this vaccination regimen are still missing. Here we report reactogenicity data of homologous BNT162b2 (Comirnaty, BNT) or heterologous ChAdOx/BNT prime-boost immunisations in a prospective observational cohort study of 326 healthcare workers. Reactogenicity of heterologous ChAdOx/BNT booster vaccination was largely comparable to homologous BNT/BNT vaccination and overall well-tolerated. No major differences were observed in the frequency or severity of local reactions after either of the vaccinations. In contrast, notable differences between the regimens were observed for systemic reactions, which were most frequent after prime immunisation with ChAdOx (86%, 95CI: 79-91), and less frequent after homologous BNT/BNT (65%, 95CI: 56-72), or heterologous ChAdOx/BNT boosters (48%, 95CI: 36-59). This interim analysis supports the safety of currently recommended heterologous ChAdOx/BNT prime-boost immunisations with 12-week intervals.