Repeated vaccination of inactivated SARS-CoV-2 vaccine dampens neutralizing antibodies against Omicron variants in breakthrough infection

Dear Editor,

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, the virus has continued to evolve resulting in new waves of infection and immune escape in the vaccinated population.¹ The Omicron strains belong to newly prevailing variants of concern (VOCs). They acquired as many as 30 mutations in the spike (S) gene and half of which occur at the receptor-binding domain (RBD) of the S protein. Moreover, the Omicron variants can evade neutralization activity by most of the identified anti-SARS-CoV-2 antibodies.^2,3 Several reports have suggested that three-dose vaccination mounted better neutralizing activity against Omicron than two-dose vaccination.⁴ However, it is not clear how breakthrough infection would affect the immune responses of those who had three-dose compared to two-dose vaccination. Here, we compared neutralizing antibody (nAb) levels according to a vesicular stomatitis virus (VSV) pseudovirus-based neutralization assay in people who experienced breakthrough infection after receiving either two or three doses of inactivated SARS-CoV-2 vaccine during the Omicron BA.2 wave in Shanghai between March and June 2022. Strikingly, we found that although nAb titers against SARS-CoV-2 were comparable between the 2-dose and the 3-dose groups of patients with BA.2 breakthrough infection, nAb titers against the Omicron BA.2, BA.4 and BA.5 variants were significantly lower in the 3-dose group. Our data suggest that repeated vaccination with inactivated virus vaccine back-boosts previous memory and dampens the immune response to a new antigenically related but distinct viral strain. Such vaccination-induced immune imprint could reflect the “original antigenic sin” doctrine described in the influenza field, whereby individuals infected with a new circulating viral strain developed a strong immune response to a priorly exposed strain.⁵ Thus, careful considerations in this aspect should be taken when designing future vaccination and booster strategies.

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