Within a year after the emergence of SARS-CoV-2, several vaccines had been developed, clinically evaluated, proven to be efficacious in preventing symptomatic disease, and licensed for global use. The remaining questions about the vaccines concern the duration of protection offered by vaccination and its efficacy against variants of concern. Therefore, we set out to analyze the humoral and cellular immune responses 6 months into homologous and heterologous prime-boost vaccinations. We recruited 190 health care workers and measured their anti-spike IgG levels, their neutralizing capacities against the Wuhan-Hu-1 strain and the Delta variant using a surrogate viral neutralization test, and their IFNγ-responses towards SARS-CoV-2-derived spike peptides. We here show that IFNγ secretion in response to peptide stimulation was significantly enhanced in all three vaccination groups and comparable in magnitude. In contrast, the heterologous prime-boost regimen using AZD1222 and BNT162b2 yielded the highest anti-spike IgG levels, which were 3–4.5 times more than the levels resulting from homologous AZD1222 and BNT162b2 vaccination, respectively. Likewise, the neutralizing capacity against both the wild type as well as the Delta receptor binding domains was significantly higher following the heterologous prime-boost regimen. In conclusion, our results suggest that mixing different SARS-CoV-2 vaccines might lead to more efficacious and longer-lasting humoral protection against breakthrough infections.

More than a year after the first vaccines against the novel SARS-CoV-2 were approved, many questions still remain about the long-term protection conferred by each vaccine. How long the effect lasts, how effective it is against variants of concern and whether further vaccinations will confer additional benefits remain part of current and future research. For this purpose, we examined 182 health care employees—some of them with previous SARS-CoV-2 infection—12 months after different primary immunizations. To assess antibody responses, we performed an electrochemiluminescence assay (ECLIA) to determine anti-spike IgGs, followed by a surrogate virus neutralization assay against Wuhan-Hu-1 and B.1.1.529/BA.1 (Omicron). T cell response against wild-type and the Omicron variants of concern were assessed via interferon-gamma ELISpot assays and T-cell surface and intracellular cytokine staining. In summary, our results show that after the third vaccination with an mRNA vaccine, differences in antibody quantity and functionality observed after different primary immunizations were equalized. As for the T cell response, we were able to demonstrate a memory function for CD4+ and CD8+ T cells alike. Importantly, both T and antibody responses against wild-type and omicron differed significantly; however, antibody and T cell responses did not correlate with each other and, thus, may contribute differentially to immunity.