ABSTRACT Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of birth defects and brain damage worldwide, leaving >5,000 infants with permanent disabilities each year in the U.S. alone, with a disproportionate proportion in minority populations. While a vaccine to prevent cCMV has been labeled “tier 1 priority” for over 20 years, we remain without a licensed vaccine product, in part due to limited understanding of the types of immune responses that are protective against placental CMV transmission. Primary infection during pregnancy is high risk for cCMV transmission, yet only approximately a third of mothers acutely-infected during pregnancy will transmit the virus to their infants, suggesting that the rapidity and magnitude of the maternal immune responses plays a role in protection against placental virus transmission. The overarching goal of this proposal is to define CMV-specific humoral and cellular immune responses associated with reduced risk of fetal transmission and model their impact on placental transmission. To address this goal, we have access to a unique cohort of 399 acutely CMV-infected transmitting and non-transmitting pregnant women enrolled in the NIH National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Unit (MFMU) CMV hyperimmunoglobulin trial (NCT01376778). This trial was a double-blind randomized trial that screened >100,000 pregnant women for acute CMV infection for enrollment to receive either CMV hyperimmunoglobulin (HIG) or placebo, yet was stopped for futility, creating a unique opportunity to define the acute cellular and humoral immune responses that are associated with transmission risk since HIG infusion after seroconversion did not change transmission risk. Our hypothesis is that the combination of early, functional CMV-specific IgG responses and CD4+ T cell and specialized innate immune cell responses to primary CMV infection during pregnancy will predict reduced risk of fetal transmission and disease. The combined strength of this uniquely large acutely CMV-infected pregnant cohort, our expertise in measuring CMV-specific humoral and cellular immune responses, and expertise in novel mathematical and placental organoid models will inform immune targets of CMV vaccine development that will be predicted to reduce the risk of cCMV transmission. Our Specific Aims include: 1) Define the CMV-specific IgG binding and functional responses associated with reduced transmission and disease following primary CMV infection in pregnancy; 2) Define the cellular immune responses elicited during primary CMV infection that associate with reduced transmission in pregnancy; 3) Develop an in silico model that can predict candidate CMV vaccine efficacy for prevention of placental transmission based on maternal immune correlates of cCMV transmission and the rate of viral spread in placental organoid models. Defining immune targets that will reduce fetal transmission and infant disease following primary maternal CMV infection will speed the design of effective vaccines to drastically decrease neurologic impairment and long-term disabilities in children worldwide.

PUBLIC NARRATIVE Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of birth defects in the US, causing long-term neurologic deficits, most commonly hearing loss, in up to 5,000 births each year in the US alone. This common infection, most dangerous to the fetus when acquired for the first time during pregnancy, is the cause of up to 25% of infant hearing loss. This project will use a unique cohort of 399 mothers acutely infected with CMV during pregnancy to define immune correlates associated with reduced fetal transmission and disease and define mechanistic impact of these responses in mathematical and placental organoid models.