Identifying maternal humoral immune responses associated with control of viremia after primary maternal CMV infection in a rhesus macaque model

Abstract

Congenital cytomegalovirus (cCMV) is the most common in utero infection and causes major neurodevelopmental deficits, but there remains no licensed vaccine to prevent cCMV. Little is known about maternal immune responses that can prevent placental CMV transmission, which could guide rational design of an effective vaccine. Using the rhesus macaque (RM) model of primary RM CMV (RhCMV) infection during pregnancy, we established that pre-existing RhCMV-neutralizing IgG protected against cCMV, even in the setting of CD4+ T cell depletion, where vertical transmission occurs consistently in RhCMV-seronegative RMs. However, the antibody (Ab) functions mediating this protection have not been fully defined. To identify humoral immune correlates of containment of viremia and protection against cCMV we used samples from previous studies in this model to measure Ab binding to whole RhCMV virus and key glycoproteins, neutralization, Ab dependent cellular phagocytosis (ADCP), and cytotoxicity (ADCC). Immunocompetent RMs developed both RhCMV-specific neutralizing and Fc-mediated effector functions (ADCP, ADCC) 2–4 weeks post infection. However, Ab responses were not statistically distinct between transmitters and non-transmitters during this period. Maternal viremia outperformed maternal Ab responses as a predictor of placental transmission. Therefore, we correlated each Ab response with maternal plasma viral load at day 21 post infection. Interestingly, IgG binding to gB and the pentamer, immunodominant viral glycoproteins involved in viral entry, displayed significant inverse relationships with maternal viremia (n=15, Spearman r=−0.71, p=0.003 for both), highlighting these as critical targets for vaccine design. Supported by grants from NIH (NIAID P01-AI129859, NCI T32-CA009111)