What can neutralizing antibodies tell us about the quality of immunity in COVID-19 convalescents and vaccinees?

Abstract In the COVID-19 pandemic, we have witnessed an impressive speed in the development of effective vaccines approved for human use, based on clinical studies comparing their efficacy to placebo. A head-to-head comparison of the neutralizing antibody (NAb) responses elicited by four vaccines used in Europe during 2021 (BNT162b2, mRNA-1273, ChAdOx nCoV-19, Ad26.COV2.S) and their comparison to NAb responses in convalescents showed that while the amount was comparable, NAbs induced by natural infection were of superior quality. The highly scattered immune responses elicited by the four vaccines were equalled by booster mRNA vaccination, reaching the highest, plateau level of NAb at the population level. Equally high NAbs were induced in convalescents after a single injection of either vaccine. The use of wild-type virus as a challenge in the NAb determination revealed that NAbs produced by disease were better activators of the complement system than NAbs induced by vaccination. The contribution of spike protein-specific IgGs to the SARS-CoV-2 neutralization was lower in convalescents compared to vaccinees, indicating that those who recovered from COVID-19 were armed with antibodies of additional specificities and/or classes that contributed to virus neutralization. Such findings point to the need to re-examine the correctness of certain epidemiological measures applied in the current epidemic. We also highlight the importance of a standardized approach in assessing humoral immunity by the usage of the most comprehensive assays as early as possible in future epidemics.