Abstract: Congenital cytomegalovirus (CMV) transmission is the leading infectious cause of brain damage and hearing loss, affecting 1-2% of all live births (40,000 infants) in the U.S. annually. Up to 25% of infants who acquire CMV in utero following primary maternal infection develop long term virus- associated sequelae, including hearing loss, ocular defects, seizures, and cognitive deficits. Because of the public health impact and economic benefits of preventing congenital CMV transmission, development of a maternal CMV vaccine has been listed as a top priority by the Institute of Medicine. However, a limited understanding of how natural CMV immunity protects against symptomatic congenital CMV transmission and the lack of a relevant animal model, have hindered vaccine design. Therefore, there is an urgent need for multipronged, innovative investigations of immune responses that are protective against in utero CMV transmission in both human cohorts and relevant animal models. Elucidation of the maternal immune responses critical for protection against congenital CMV disease is vital to the design of immunologic interventions that will prevent CMV-associated brain damage and hearing loss. Primary infection of CMV-seronegative rhesus monkeys with rhesus CMV (rhCMV) has been used to investigate CMV pathogenesis. Further, fetal rhCMV inoculation leads to virus-associated neurologic sequelae similar to that of human congenital CMV infection. Therefore, I propose primary systemic infection of rhCMV-seronegative, pregnant rhesus monkeys as a model of congenital CMV transmission which can be used to dissect the roles of adaptive immune responses in containment of intrauterine CMV replication. Further, I propose detailed assessment of maternal cellular and humoral immune responses in mothers whose infants do and do not develop neurologic sequeale following primary maternal CMV infection, defining immune targets of a maternal CMV vaccine. I am uniquely well-suited to lead this multifacited approach towards the rational design of a maternal CMV vaccine, given my rigorous training in immunology and pediatric infectious diseases, clinical and research specialty in transmission of neonatal viral pathogens, and proven track record for designing and implementing nonhuman primate and human cohort studies. Taken together, these bold investigations of maternal immune protection against symptomatic congenital CMV infection in both a relevant nonhuman primate model and a large cohort of women screened for primary CMV transmission will speed the development of an effective maternal CMV vaccine, an intervention that will greatly reduce the prevalence of childhood neurologic deficits and hearing loss in our population.

Public Health Relevance

Congenital CMV infection is the leading infectious cause of neurologic deficits and hearing loss in children, complicating 40,000 births in the U.S. annually. The protection of the developing fetus from CMV infection will require protective maternal CMV-specific immune responses similar to that provided by natural immunity following CMV infection. Elucidation of the maternal immune correlates of protection against congenital CMV transmission and disease is vital to the design of effective maternal vaccine strategies in preventing CMV-associated brain damage and hearing loss.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
4DP2HD075699-02
Application #
8844114
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Reddy, Uma M
Project Start
2012-06-30
Project End
2018-06-30
Budget Start
2017-07-13
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Itell, Hannah L; Nelson, Cody S; Martinez, David R et al. (2017) Maternal immune correlates of protection against placental transmission of cytomegalovirus. Placenta 60 Suppl 1:S73-S79
Lantos, Paul M; Hoffman, Kate; Permar, Sallie R et al. (2017) Neighborhood Disadvantage is Associated with High Cytomegalovirus Seroprevalence in Pregnancy. J Racial Ethn Health Disparities :
Fan, Qihua; Nelson, Cody S; Bialas, Kristy M et al. (2017) Plasmablast Response to Primary Rhesus Cytomegalovirus (CMV) Infection in a Monkey Model of Congenital CMV Transmission. Clin Vaccine Immunol 24:
Nelson, Cody S; Cruz, Diana Vera; Tran, Dollnovan et al. (2017) Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys. JCI Insight 2:
Itell, Hannah L; Kaur, Amitinder; Deere, Jesse D et al. (2017) Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections. Curr Opin Virol 25:126-133
Bialas, Kristy M; Permar, Sallie R (2016) The March towards a Vaccine for Congenital CMV: Rationale and Models. PLoS Pathog 12:e1005355
Dudley, Dawn M; Aliota, Matthew T; Mohr, Emma L et al. (2016) A rhesus macaque model of Asian-lineage Zika virus infection. Nat Commun 7:12204
Bialas, Kristy M; Westreich, Daniel; Cisneros de la Rosa, Eduardo et al. (2016) Maternal Antibody Responses and Nonprimary Congenital Cytomegalovirus Infection of HIV-1-Exposed Infants. J Infect Dis 214:1916-1923
Bialas, Kristy M; Tanaka, Takayuki; Tran, Dollnovan et al. (2015) Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission. Proc Natl Acad Sci U S A 112:13645-50
Wright, Clyde J; Permar, Sallie R (2015) Preventing postnatal cytomegalovirus infection in the preterm infant: should it be done, can it be done, and at what cost? J Pediatr 166:795-8

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