Th2-Oriented Immune Serum After SARS-CoV-2 Vaccination Does Not Enhance Infection In Vitro.

The relatively lower protection rate of the alum-adjuvanted inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines reminds us of the antibody-dependent enhancement (ADE) phenomenon observed in preclinical studies during the development of vaccines for Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1). In this study, using the S1 segment of the SARS-CoV-2 spike protein or inactivated whole SARS-CoV-2 virus as an antigen and aluminum as an adjuvant, the risk of ADE of infection with T helper 2 (Th2)-oriented immune serum from mice (N=6) and humans (N=5) was examined in immune cell lines, which show different expression patterns of Fc receptors. Neither the immune serum from alum-adjuvanted S1 subunit vaccines nor inactivated SARS-CoV-2 vaccination enhanced SARS-CoV-2 S pseudotyped virus infection in any of the tested cell lines in vitro. Because both of these Th2-oriented immune sera could block SARS-CoV-2 infection without ADE of infection, we speculate that the lower protection rate of the inactivated SARS-CoV-2 vaccine may be attributed to the lower neutralizing antibody titers induced or the pulmonary eosinophilic immunopathology accompanied by eosinophilic infiltration in the lungs upon virus exposure. Adjustment of the immunization schedule to elevate the neutralizing antibody levels and skew adjuvants toward Th1-oriented responses may be considered to increase the efficacies of both inactivated and spike protein-based subunit SARS-CoV-2 vaccines.

An Established Th2-Oriented Response to an Alum-Adjuvanted SARS-CoV-2 Subunit Vaccine Is Not Reversible by Sequential Immunization with Nucleic Acid-Adjuvanted Th1-Oriented Subunit Vaccines.

A recently reported parallel preclinical study between a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine and an inactivated SARS-CoV-2 vaccine adjuvanted with alum showed pulmonary immunopathology typical of eosinophil accumulation in a mouse pneumonia model for the latter, which implied a potential role of cellular immunity in the difference in the protection rate between these two forms of vaccines. For those who have been vaccinated with alum-adjuvanted subunit or inactivated SARS-CoV-2 vaccines, whether the Th2 responses that have been established and the absence of induced cellular immunity could be changed is an open question. Using two heterologous boosts with Th1-oriented CpG ODN-adjuvanted S1-based SARS-CoV-2 subunit vaccines for mice that were primed with two doses of Th2-oriented alum-adjuvanted S1-based SARS-CoV-2 subunit vaccines, we demonstrated that established Th2 orientation could not be reversed to Th1 orientation and that no cellular immunity was induced, which should have been induced if the boosting vaccines were used as the prime vaccines. These results remind us that if widely administered alum-adjuvanted SARS-CoV-2 vaccines cannot overcome the challenge of coronavirus disease 2019 (COVID-19) and that if cellular immunity is important for the efficacy of SARS-CoV-2 vaccines in the future, the choice of more powerful heterologous boosting vaccine forms that can induce cellular immunity should be considered very carefully before application.