The Role of Maternal Antibodies in Prevention of Congenital Cytomegalovirus Infection

Abstract

Cytomegalovirus (CMV) is the most common congenital infection and a problematic opportunistic pathogen for immunocompromised patient populations. Despite the immense global burden of CMV and many years of research, the licensed interventions for prevention of CMV disease, and congenital CMV in particular, are very limited. The goal of the work presented in this dissertation is to inform vaccine design for the prevention of congenital CMV by enhancing maternal humoral immunity. We initially investigated the humoral immune responses that associate with protection from vertical CMV transmission in a rhesus macaque model of congenital CMV, evaluating Fc mediated effector responses, which had not previously been measured in the context of rhesus CMV (RhCMV) infection. This study suggested that the humoral response develops too late following primary infection to play a significant role in prevention of vertical transmission but demonstrated a role for pre-existing, potently neutralizing antibodies in prevention of vertical CMV transmission. While this study did not find an association between Fc mediated antibody effector responses, clinical observational studies have implicated these antibody functions in protection from congenital CMV. Interestingly, human CMV (HCMV) is known to encode multiple proteins capable of binding to immunoglobulin G (IgG) antibodies, which have demonstrated the ability to interfere with host Fcγ receptor (FcγR) activation and effector function. We have identified homolog viral FcγRs (vFcγRs) in RhCMV, which allows us a unique opportunity to study these proteins in vivo for the first time by infecting RhCMV-seronegative rhesus macaques with RhCMV lacking all three identified vFcγRs and validating the role vFcγRs have demonstrated in vitro in immune evasion. Lastly, we evaluated a novel HCMV vaccine strategy in which we targeted this immune evasion mechanism through active vaccination against glycoprotein B (gB) alone or in combination with one of the vFcγRs. This proof-of-concept study demonstrated that immune responses against the vFcγRs, gp34 in particular, can improve host FcγR activation and effector function, with initial focus on FcRI (CD64). These results suggest that a simple addition of one or more vFcγRs to vaccines already in development may have a significant impact on the effectiveness of Fc mediated effector responses, which could in turn reduce the risk of vertical CMV transmission.