Immunologic and virologic determinants of congenital Cytomegalovirus transmission and disease in rhesus monkeys

Sponsored By: NIH: 1P01-AI129859

The overarching goal of our Program is to advance congenital CMV vaccine research by defining the key immune responses and viral-host interactions that dictate primary fetal CMV transmission and disease in a highly relevant animal model.

Our Program is uniquely positioned to address this problem: Our team members have made breakthroughs in animal models of cCMV in the discovery that placental CMV transmission could be modeled in nonhuman primates (NHP). This work has opened new avenues for CMV vaccine discovery in a robust in vivo system that is highly translational for vaccine development. Dr. Barry and colleagues first established that direct fetal inoculation with rhesus CMV (RhCMV) resulted in fetal disease that highly resembled that of congenital HCMV in human infants, including intracranial calcifications, microcephaly, and CNS virus replication.  Building on this foundation of pathogenesis and increasing the relevancy of the NHP model of cCMV, Drs. Permar and Kaur made the pivotal discovery that RhCMV was capable of crossing the placenta following primary infection of a pregnant rhesus monkey and infecting the fetus, which then resulted in fetal loss, asymptomatic, or symptomatic cCMV disease. This NHP model of cCMV disease is the closest to that of human fetal infection and opened new opportunities for cutting-edge research into prevention of placental cCMV transmission and fetal disease following primary maternal infection.

We have brought together a uniquely qualified, collaborative team of investigators with internationally-recognized expertise in the following areas: nonhuman primate models of CMV persistence and pathogenesis, sequence analysis of HCMV diversity, construction and analyses of novel RhCMV variants, RhCMV-specific immunology, and the clinical care of congenitally HCMV-infected infants.

Given our team’s unique strengths and capabilities, our goal is to use this recently developed, highly relevant NHP model of cCMV in addition to robust viral sequencing and cloning tools to define the antiviral immune responses and viral characteristics that impact primary cCMV transmission and the outcome of fetal infection.  We will address the hypothesis that both maternal humoral and cellular immunity contribute to protection against placental HCMV transmission observed in CMV-immune animals and that immune responses to primary infection exert immune pressures that select for placentally-transmitted and fetal HCMV variants.  Together, we will identify the immune responses that CMV vaccines should elicit to prevent cCMV infection and address major gaps that currently impede CMV vaccine design, notably an incomplete understanding of protective maternal immune responses and virologic targets that are required for an effective vaccine against cCMV

Humoral immune correlates of protection against congenital CMV and HSV transmission in HIV-infected women

Sponsored by NIH: 1R21-AI147992

Currently, the primary causes for increased risk of perinatal herpes virus infections in HIV-exposed, uninfected (HEU) infants remain unexplored. We hypothesize that HIV-infected mothers have impaired HSV/CMV-specific IgG responses, including protective antiviral functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and virus neutralization and in the context of HIV, these maternal antibodies are variably transplacentally transferred to the infant, leaving HEU infants at higher risk for severe perinatal infections.

This study aims to define the placental transmission rate of and characteristics of CMV and HSV-specific IgG in HIV-infected pregnant women and their infants. Furthermore, this study will define the humoral immune correlates of protection against congenital CMV transmission. The investigation of maternal antibodies will include the identification of Fc region characteristics associated with efficient placental IgG transfer and assessment of the role of antiviral antibody functions in perinatal virus transmission, including neutralization, ADCC, and ADCP. This work will establish the immunologic basis for increased risk for CMV and HSV infections in HEU infants, and importantly, will provide insight into rational vaccine design to ultimately reduce the risk and severity of congenital CMV and neonatal HSV infections for all children.