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Immunogenicity and efficacy of          heterologous ChAdOx1–BNT162b2 vaccination

Immunogenicity and efficacy of          heterologous ChAdOx1–BNT162b2 vaccination

Heterologous prime–boost vaccinations have been reported to be more immunogenic than homologous ones in experimental settings11. This has also been proven for some human vaccines12,13. Moreover, studies using mice have demonstrated the strong immunogenicity of the ChAd–BNT combination14. Here we report that heterologous ChAd–BNT vaccination confers better protection against infection—which is associated with more switched mBCs and higher virus neutralizing antibody titres—irrespective of the variant analysed. This finding is of particular importance considering the global increase in the SARS-CoV-2 Delta variant15. Other studies reported better neutralizing potential of sera from ChAd–BNT vaccinated individuals compared with BNT–BNT vaccinated individuals, but these studies only used surrogate16,17 or pseudovirus18 neutralization assays. Moreover, the ability of such assays to predict neutralizing activity against authentic clinical virus isolates is still debated19.

Heterologous vaccination induced antibodies with a stronger neutralization potential than homologous vaccination, but the spike-specific IgG antibody titres were comparable. This result suggests that it is the quality of the antibodies that underlies the neutralization potential of the antibody response induced by heterologous vaccination. Assuming that the secondary antibody response is primarily derived from the mBC clones generated by primo-immunization, we can postulate that ChAd and BNT formulations elicit different mBC compartments. mBCs generated by the ChAd formulation could, for example, bear antigen receptors displaying a larger breadth of epitope recognition or a better fit for the SARS-CoV-2 spike protein. This could be linked to the different conformations of the spike protein, as that of the BNT vaccine bears a mutation stabilizing the protein in its pre-fusion conformation20. Our data showed that mBCs still exhibit features of activation 4 weeks after the booster dose in the heterologous regimen, which suggests that the post-boost process of mBC differentiation is more active in this schedule. This could result from a more efficient or long-lasting germinal centre reaction that facilitates an extended cycle of somatic hypermutations and possibly output of B cell clones with higher affinity antigen receptors. An enlarged pool of CD4+ T helper cells could contribute to an amplified or prolonged germinal centre reaction. In keeping with this notion, we report here a higher frequency of spike-specific CD4 T cells after priming with the ChAd vaccine, which has been observed in other studies6,7. Moreover, stronger T cell responses may contribute to better protection independently of B cell responses21.

Immunogenicity and efficacy of          heterologous ChAdOx1–BNT162b2 vaccination

The better neutralization potential of sera from ChAd–BNT vaccinated individuals could also be linked to their relatively lower level of S1-specific IgA levels. Indeed, plasma IgA monomers specific to SARS-CoV-2 proteins are twofold less potent than IgG equivalents22. Furthermore, IgA levels persist better than IgG after infection, which coincides with a reduction in the serum neutralizing potential23. Following a possible competition between serum IgA and IgG, the decrease in IgA levels in heterologous vaccination conditions may lead to better neutralization effects. This phenomenon has already been observed in the context of the RV144 vaccination trial against HIV-1, in which the level of envelope-specific IgA correlated with the risk of infection24. In this context, IgA was also found to inhibit antibody-dependent cell cytotoxicity by competing with IgG25.

Our data do not allow the discarding of the possibility that the later timing of administration of the booster dose contributed to the high efficacy of the heterologous regimen. Still, it is noteworthy that the size of the RBD+ mBC pool after the prime dose was comparable for both groups of vaccinees, despite the disparity in the analysis time point after the prime vaccination (4 versus 12 weeks). This observation indicates that the extended interval between prime and boost in the ChAd–BNT cohort has not been translated into a greater size of the RBD-specific mBC compartment. It has been recently demonstrated for both the ChAd vaccine26 and the BNT vaccine27 that long injection time intervals (12 weeks or more) provide higher binding and neutralizing antibody titres than shorter intervals (less than 6 weeks). For a comparable long vaccination interval (more than 9 weeks), the heterologous ChAd–BNT vaccination schedule induced better humoral immunity (titres and neutralization) than the homologous ChAd–ChAd combination28. To our knowledge, there is only one study in which ChAd–BNT and BNT–BNT vaccination schedules were compared with the same prime–boost interval (4 weeks)6. That study6 concluded that for short intervals, the humoral responses induced by both regimens were comparable. However, a longer interval (that is, 12 weeks) between prime and boost could be needed to allow the synergy between heterologous vaccines.

Together, we present a real-world observational study of HCWs showing that the heterologous ChAd–BNT vaccination regimen confers stronger protective immunity than the homologous BNT–BNT prime–boost schedule. As hidden confounding factors might be present in our study (for example, different levels of exposure to the virus), confirmatory studies and a longer follow-up of vaccinated participants are warranted. However, our data suggest that the heterologous combination could be particularly suitable for immunocompromised individuals.