The three vaccines ChAdOx1 nCoV-19, BNT152b2, and mRNA-1273 were developed and authorized to be administered as a homologous prime/boost regimen. Our study now provides the first head-to-head immunogenicity and reactogenicity data comparing all three authorized homologous COVID-19 vaccine regimens with heterologous combinations of ChAdOx-priming followed by either BNT- or mRNA-1273-boosting. We show that all regimens are immunogenic, but show considerable differences in the extent of vaccine-induced antibody and T-cell responses. The most striking finding was that immunogenicity of the mRNA-1273 containing regimens was more pronounced than the respective BNT vaccine combinations, which held true for both the homologous and the heterologous regimens. Correspondingly, homologous or heterologous boosting with mRNA-1273 was less well tolerated as compared to the other regimens.
We and others have recently shown that heterologous prime/boost regimens led to a strong induction of antibodies and T cells, although this was so far largely characterized in individuals primed with ChAdOx followed by boosting with the BNT mRNA. We now show that heterologous boosting with mRNA-1273 led to similar antibody and T-cell response patterns with a particular strong induction of CD8 T cells. When comparing the two mRNA vaccines, immunogenicity was generally more pronounced after boosting with mRNA-1273 in both the heterologous and homologous vaccine group. This may be related to a higher dosage of the mRNA (100µg vs. 30µg) and/or different formulations of lipid nanoparticles11, 12. Our data confirm that a secondary vaccination with the vector is less potent in boosting antibodies and T cells as compared to all mRNA-containing regimens3–7. As this may be related to preformed or induced neutralizing immunity towards the vector backbone14, the boosting effect is superior using either heterologous combinations or homologous regimens with mRNA vaccines that use lipid nanoparticle vaccine carriers. Interestingly, despite poor immunogenicity after homologous ChAdOx-boosting, all three ChAdOx-primed regimens led to the highest percentage of multifunctional T cells upon secondary boosting, which may result from the potent ability of the ChAdOx vector for T-cell priming15. In general, spike-specific CD8 T cells known to mediate protection from severe COVID-1916 were most strongly induced after heterologous boosting. The fact that CD8 T cells did not correlate with antibody levels emphasizes that analysis of antibodies alone may be insufficient to evaluate protection from severe disease. We have previously shown that a pronounced induction of antigen-specific T-cell levels after infection with SARS-CoV-217, with varicella zoster virus18, or after influenza-vaccination19 is paralleled by an upregulation of CTLA-4 on specific T cells which may serve to counteract excessive T-cell proliferation and/or T-cell mediated immunopathology. Interestingly, we now show that the strongest expression of CTLA-4 on spike-specific CD4 and CD8 T cells was found in the four vaccine groups with the most pronounced induction of CD4 and CD8 T cells after vaccination, whereas CTLA-4 expression in individuals after homologous ChAdOx vaccination was significantly lower, which supports a less potent boost of T-cell immunity. On the B-cell side, a stronger immunogenicity of the heterologous as compared to the homologous BNT regimen was recently found to be associated with a higher percentage of spike-specific activated memory B cells20. While this finding may result from a more pronounced T-cell help, this may also explain the higher avidity4 and the higher neutralizing capacity20 of antibodies observed after heterologous boosting.
The three homologous regimens have shown remarkable but variable efficacy and effectiveness regarding protection from infection. The differences in immunogenicity between the homologous regimens largely correspond with similar differences in efficacy in the range of 70.4% for ChAdOx10, 95% for BNT212, and 94.1% for mRNA-127311. Similar differences among the three homologous vaccine regimens were also reported for effectiveness in nation-wide observational studies21–26, whereas real world effectiveness data for heterologous regimens had been limited. In this regard, a recent nationwide cohort study in ChAdOx-primed individuals from Sweden found an effectiveness of 50% after homologous boosting, 67% after BNT-boosting and the highest effectiveness of 79% after boost with mRNA-127327. This indicates that our observation of a higher immunogenicity of the ChAdOx/mRNA-1273 regimen may also translate into a higher effectiveness. In addition, in line with an equivalent or superior immunogenicity of heterologous mRNA-boosting, a study from France provided evidence for a higher effectiveness of the ChAdOx/BNT regimen as compared to homologous BNT vaccination20. Finally, the ChAdOx/BNT regimen in a Danish nationwide study reached a remarkable effectiveness of 88%, although no control groups with other regimens were analyzed in parallel28.
The strength of our study is the large head-to-head analysis of immunogenicity and reactogenicity of all recommended two-dose homologous and heterologous vaccine combinations, including a large group of individuals vaccinated with the ChAdOx/mRNA-1273 regimen in a real world setting. Our study is limited by convenience sampling in a non-randomized study design, where study participants were enrolled according to national recommendations. Although this led to some differences in age within the five groups, between-group differences of immunological parameters among age-matched subgroups remained largely the same. Within a given regimen, an effect of age was only observed for IgG levels within the homologous mRNA groups. Therefore, at least in our cohort of individuals mainly including health care workers, age is unlikely to have a strong confounding impact on our results. Based on national recommendations, the interval between the first and the second vaccination was longer for the ChAdOx-primed groups (9-12 weeks) as compared to the homologous mRNA-vaccine groups (3-6 weeks). Although this may influence immunogenicity in general, this did not account for the striking differences in immune responses among the three ChAdOx-primed groups, which had the same time interval between priming and boosting. Moreover, we observed notable differences in immunogenicity within the two homologous and the two heterologous regimens containing mRNA vaccines, although the respective intervals between priming and boosting was similar. A further limitation is the fact that we do not have any information on neutralizing activity towards variants of concern. However, the observational study from France showed that the heterologous ChAdOx/BNT regimen had superior activity towards the Delta variant as compared to homologous BNT vaccination20. Finally, information on the stability of antibody and T-cell levels over time are not available yet; together with data on effectiveness, collection of these data in follow-up studies is important to guide the potential need and timing for booster vaccinations.
Knowledge on the differences in immunogenicity and reactogenicity of homologous and heterologous vaccine combinations is of increasing importance for clinical practice. First, mixing different vaccine principles in heterologous vaccination regimens is already implemented for regular COVID-19 vaccination procedures in many countries due to the frequent occurrence of rare, but serious adverse events after ChAdOx-priming29, 30. Moreover, vaccine shortage in many countries may necessitate the use of heterologous combinations to ensure broad vaccine coverage. Finally, serial use of heterologous combinations of different vaccines is of increasing importance to optimize immunogenicity of single dose or poorly immunogenic homologous regimens. As illustrated by the favorable immunogenicity of heterologous regimens in solid organ transplant recipients15, this is of particular relevance for immunocompromised patients who exhibit a severely impaired immunogenicity after regular homologous vaccination; as reactogenicity is less of a concern in immunocompromised patients15, mix-and-match regimens may offer the most favorable risk-benefit ratio for this population. Finally, as with other widely used vaccines, deviation from homologous series may become common practice for booster vaccinations after waning of vaccine-induced protection.