HCMV glycoprotein B, but not the pentameric complex, is a key target of antibody-mediated phagocytosis

Human cytomegalovirus (HCMV) is a leading infectious cause of birth defects globally with devastating fetal health outcomes, and there is currently no HCMV vaccine available. Glycoprotein B (gB) and the pentameric complex (PC) are immunodominant HCMV envelope proteins and candidates of interest in vaccine development due to their ability to elicit strong anti-HCMV neutralization responses. Recent evidence implicates non-neutralizing antibody functions in protection from vertical HCMV transmission, but the involvement of gB and PC in these responses remains incompletely understood. We evaluated immune responses against HCMV elicited by a gB protein subunit vaccine with and without PC in a preclinical rabbit study. Despite improved neutralization and inhibition of cell-associated viral spread, the inclusion of PC did not enhance antibody-mediated phagocytosis or FcγR activation against HCMV virions or infected cells compared to gB alone. We additionally found a reduction in phagocytosis function by an HCMV hyperimmune globulin when blocked against gB, but not PC, suggesting that gB is a target of phagocytosis-mediating antibodies while PC is not. Given that antibody-mediated phagocytosis but not neutralization has been associated with protection from vertical HCMV transmission, these findings support the continued assessment of gB, but not PC, as a vaccine antigen for the prevention of vertical transmission via non-neutralizing antibodies to reduce the congenital HCMV burden worldwide.