Long-Term Analyses of SARS-CoV-2 Humoral and T Cell Responses and Breakthrough SARS-CoV-2 Infections after Two Doses of BNT162b2 Followed by mRNA-1273 and Bivalent Omicron-Adapted BNT162b2 Vaccines: A Prospective Study over 2 Years in Non-Immunocompromised Individuals

Long-term analyses of the immune response following SARS-CoV-2 mRNA vaccines are essential to determining its characteristics and providing the basis for vaccination strategies. We conducted a prospective study in a cohort of 268 healthy adults followed for >2 years after two doses of BNT162b2. Antibodies targeting the receptor-binding domain of the S1 subunit of the spike of SARS-CoV-2 (anti-RBD) were measured at eight time points; T cell response was analyzed using an interferon-gamma release assay. A total of 248 (93%) subjects received mRNA-1273 on month 9; 93 (35%) received the bivalent Omicron-adapted BNT162b2 vaccine between months 19 and 26. Breakthrough infections occurred in 215 (80%) participants, with frequencies unaffected by the additional vaccines. Anti-RBD declined over the initial 9 months, increased after mRNA-1273, and declined gradually thereafter. In 50 (17%) previously infected subjects, anti-RBD levels were significantly higher up to month 9 (p < 0.05) but subsequently declined below those of uninfected individuals. Anti-RBD titers protective against SARS-CoV-2 could not be defined. Most subjects developed a positive T cell response that remained after 26 months. Waning of protection against SARS-CoV-2 infection occurred over time, resulting in non-severe breakthrough infections in most participants. The evolution of anti-RBD suggests modulation of the immune response through immune imprinting.