Booster dose of BNT162b2 after two doses of CoronaVac improves neutralization of SARS-CoV-2 Omicron variant

In the process of developing vaccines, to achieve an effectiveness level that is acceptable for the regulatory agencies, it is expected that the new vaccine is able to stimulate the immune response in both cellular and serological levels. Thus, the detection and quantification of neutralizing antibodies is one of the fundamental steps during this procedure. In a pandemic situation, some unusual measures are necessary, such as the combination of different vaccines, with different immunological mechanisms, to improve protection, and in these cases the immune response follow-up is crucial. In this scenario, our data showed that BNT162b2 mRNA vaccine booster dose, after a full vaccination protocol with CoronaVac inactivated virus vaccine, is able to increase the antibody neutralization capacity against SARS-CoV-2 Omicron variant.

The neutralizing improvement here described could be explained by the fact that beta-coronaviruses, including SARS-CoV-2 variants, share a conserved site into Spike protein. Since BNT162b2 vaccine uses Spike mRNA from the original Wuhan SARS-CoV-2 isolate, this conserved region could allow the recognition of Omicron variant by the induced antibodies, independently on the number of accumulated mutations¹¹. Furthermore, our findings are in agreement with recent studies that also evaluated antibody neutralization pattern in similar vaccination protocols. The work of Khong et al. showed that, among different vaccine combinations, the use of BNT162b2 after CoronaVac presented higher immunogenicity against SARS-CoV-2, including the Omicron variant¹², and this is reinforced by our data, where we tested a higher number of samples. Likewise, the study conducted by Cheng et al. highlighted that the combination of BNT162b2 booster dose and CoronaVac two doses scheme achieved 80% of seroconversion (24 of 30 individuals)¹³close to the 76.6% observed in our assays (23 of 30).

It is worth to notice that our data corroborate with some findings recently published by GeurtsvanKessel et al. analyzing the BNT162b2 booster dose effect in other vaccination schemes, both in the serological and cellular immune response¹⁴. In the study, the authors evaluated four different immunization schemes, two using adenovirus-vector technologies and two using the mRNA platform (including BNT162b2 original scheme). They observed that neutralizing antibodies against Omicron variant were significantly lower or absent, depending on the used vaccine, when compared to VOCs like Beta and Delta. However, just as shown by our data, the booster dose with BNT162b2 restored neutralization titers against Omicron for all the tested schemes. It is interesting to highlight that the cellular response against Omicron, mediated by T-cells, was maintained in all the tested vaccination protocols, showing that the highest impact of this variant in the immune response is mainly in the antibody neutralization ability¹⁴.

From the clinical point of view, a recent article showed, in a Brazilian cohort, that administration of BNT162b2 after CoronaVac increased protection against infection when comparing to CoronaVac original protocol. The CoronaVac two doses scheme presented effectiveness of 34.7% against new infections when compared to unvaccinated individuals, and this protection showed to decrease over time. However, the administration of BNT162b2 booster was responsible to increased protection against infection to 82.6%. The same pattern was observed for COVID-19 disease progression, showing that the booster dose reduces the chances of severe outcomes, especially in risk groups¹⁵. Another study, also from the clinical area, but analyzing this booster after the BNT162b2 original vaccination scheme, showed a reduction of 90% in the mortality rate¹⁶. Once our results describe the protection improvement caused by BNT162b2 booster from the perspective of the serological response, all of these studies complement our observations, showing the impact of this immunization approach on distinct branches of the immune system.

As limitations of our study, the neutralization analyzes were performed randomly, with different individuals for each time point. Despite bringing heterogeneity to the study and representing a more realistic picture of the real life situation, without selection bias, performing these analyzes using samples from the same patients over the time-points, as a follow-up, could bring some different insights about serological response durability. Also, it is well known that serological response is not the only immunological aspect that is stimulated by the vaccination, and that cellular immunity, in association with clinical data, is required to successfully determine the effectiveness of a vaccine. Nevertheless, the data here presented are reinforced by the study of GeurtsvanKessel et al.¹⁴emphasizing the need for constant monitoring of neutralizing antibody capacity, especially given the possibility of novel variants emerging in the future.

Thus, our data show that, against Omicron variant, neutralization titers induced by primary vaccination with CoronaVac decreased with time and was 43.1 times lower when compared to the use of a booster dose with BNT162b2. Therefore, this neutralization enhancement after booster dose could reflect, clinically, in higher protection and lower risk of disease progression.