Long-term cross-variant Fc-mediated immune responses against SARS-CoV-2 induced by a heterologous adenoviral/inactivated virus prime-boost vaccination strategy.

Limited vaccine availability and logistical barriers during the COVID-19 pandemic have hindered homologous boosting in resource-limited regions. Therefore, heterologous prime-boost regimens have gained attention as versatile and practical alternatives. We evaluated the immunogenicity and longevity of four vaccine regimens in adults from Mozambique and Madagascar: single-dose Ad26.COV2.S (Ad26.S), homologous BBIBP-CorV (BBIBP), and two heterologous combinations (BBIBP-Ad26.S and Ad26.S-BBIBP, in prime-boost order). Using systems serology, we characterized Fc-mediated antibody responses against SARS-CoV-2 wild-type and Omicron BA.1. Among all regimens, Ad26.S-BBIBP elicited broad and sustained humoral immunity for up to 6 months, with enhanced IgG levels, Fcγ receptor binding, and Fc-mediated effector functions. These responses declined more slowly than with single-Ad26.S. Compared to the other regimens, antibody-dependent natural killer cell activation (ADNKA) emerged as a distinct characteristic of durable cross-variant immunity in Ad26.S-BBIBP recipients. These findings highlight that the Ad26.S-BBIBP regimen is immunologically advantageous, with Fc-mediated effector functions, particularly ADNKA, representing an important characteristic of its relatively durable and cross-strain protection even as neutralizing antibody titers decline.