Functional antibody signatures following therapeutic immunization in Simian and Human immunodeficiency virus infection.

Reducing the latent HIV-1 reservoir is essential to achieving a functional cure, and therapeutic vaccination is a promising strategy. While most approaches emphasize cytotoxic CD8⁺ T-cell responses, the role of antibodies-particularly Fc-mediated effector functions-remains incompletely defined. We evaluated the immunogenicity and functional antibody responses induced by Ad26- and MVA-based HIV-1 mosaic vaccines in SHIV-infected rhesus macaques and ART-suppressed people with HIV. In nonhuman primates, vaccination significantly increased Env-specific antibody titers, Fcγ receptor binding, and Fc-dependent functions, including cellular phagocytosis, complement deposition, and NK cell activation. Responses peaked following MVA boosting and, although they declined over time, remained elevated compared with unvaccinated controls. Humoral responses did not predict viral rebound during analytic treatment interruption but correlated inversely with post-ART viral setpoints, suggesting a role in viral control. In a parallel human study, therapeutic vaccination similarly elicited functional antibody responses, with the strongest effects observed following Ad26 mosaic vaccination combined with a gp140 protein boost, whereas Ad26 and MVA alone induced more modest responses. Ad26-based HIV vaccines, especially with protein boosting, elicit robust, multifunctional antibody responses; although human virologic outcomes remain untested, these findings support exploring Fc-mediated humoral immunity for viral control and cure strategies.