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.