The overall aim of this Program Project is to develop and evaluate strategies for preventing congenital cytomegalovirus (CMV) infection and the central nervous system damage associated with it. Although congenital CMV infection is the leading infectious cause of brain damage and of sensorineural hearing loss in children, there is currently no means of preventing or treating congenital CMV infection. The Program is comprised for four scientific Projects and three Cores. The four projects will evaluate immunologic (vaccine), chemotherapeutic, and behavioral interventions that could provide the foundation for new approaches to prevention or treatment of congenital CMV infection. Project 1, "A Phase II/III Clinical Trial of Recombinant CMV gB Vaccine in Postpartum Women," will evaluate the safety, immunogenicity and efficacy of a subunit vaccine. Project 1 will also evaluate a strategy for testing the efficacy of CMV vaccines for prevention of maternal and congenital CMV infections that should facilitate the testing of future vaccines. The study vaccine is comprised of a recombinant CMV envelope glycoprotein B (the major target of neutralizing antibody) construct formulated with a novel oil in water adjuvant, MF59. Project 2, "Immunological Correlates of Vaccine- Induced Prevention of Congenital HCMV Infection," will examine in detail the immune response to vaccine and to acquired CMV infection in vaccine and placebo recipients. It will compare vaccine induced immunity to that induced by infection. Project 3, "Pathogenesis and Antiviral Therapy of Hearing Loss in Congenital CMV Infection," seeks to define pathogenic factors in the newborn or young infant, such as viral load, that are associated with adverse outcome. In addition the role of immunity (neutralizing antibody, CMV specific CD4 and CD8 precursor frequency) in controlling infection or leading to progressive hearing loss will be studied. Antiviral therapy in symptomatic infants will be evaluated for its effect on viral load or other pathogenic factors. The incidence of CMV infection is very high in teenagers as is the rate of congenital CMV infection in offspring of adolescent mothers. Project 4, "Understanding and preventing CMV Infection in Adolescents," will develop an approach for preventing acquired CMV infection in adolescents. Through studying factors related to acquisition of CMV in this population and examining viral strains from contacts to identify the source of infection, this Project will provide the knowledge from which an intervention strategy can be developed. Three Cores, Administrative, Laboratory and Data Management will provide scientific leadership, virology and immunology laboratory support and data management respectively to the scientific projects.