ABSTRACT Human cytomegalovirus (HCMV) is the most common in utero infection, causing hearing loss and other neurodevelopmental defects in congenitally infected infants. Despite high prioritization and over 40 years of research in the field, a CMV vaccine has yet to be licensed for clinical use. We are just beginning to understand immune correlates of protection against HCMV, and Fc-mediated antibody effector functions, such as antibody dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), have recently been implicated in prevention of placental CMV transmission. CMV is adept at immune evasion, and targeting immune evasion mechanisms that interfere with key immune responses is a promising strategy for producing more effective vaccines, potentially through simple modification to vaccines already in development. HCMV expresses three viral Fcγ receptors (vFcγRs), glycoproteins capable of binding to the Fc portion of immunoglobulin G (IgG), that interfere with antiviral Fc-mediated effector responses. The purpose of this work is to define the humoral immune responses against vFcγRs, both during natural infection and following vaccination with vFcγR protein subunits, to determine if antibodies targeting these proteins can block their Fc-binding ability, thereby improving Fc-mediated effector responses. In Aim 1, we propose to define vFcγR-specific immune responses in chronically HCMV-infected individuals. We will then utilize a rabbit immunogenicity model to define the immunogenicity of vFcγR protein subunit vaccine antigens (gp34, gp68, gp95) in combination with common glycoprotein immunogens, glycoprotein B (gB) and/or the pentameric complex (PC), adjuvanted with squalene emulsion. The primary goal will be to identify the optimal combination of vFcγRs and glycoproteins that elicit the best ADCP and ADCC responses, in terms of both magnitude and breadth. In Aim 2, we will define vaccine-elicited gB-, PC-, and vFcγR-specific B and T cell responses. In Aim 3, we will test our primary hypothesis that co-immunization with glycoprotein(s) and vFcγRs will result in improved glycoprotein-specific Fc-mediated functional antibody responses. Given the importance of Fc mediated effector responses in prevention of congenital CMV, observed improvements in these responses upon co-immunization would suggest that such a vaccine would have greater efficacy in preventing congenital CMV given the demonstrated importance of those responses in preventing vertical CMV transmission. Additionally targeting vFcγRs through active vaccination may be a simple modification to current vaccine strategies to yield stronger responses that have a demonstrated impact on vertical CMV transmission.