The fundamental objective of this Vaccine Immunology Basic Research Center is to address the deficiencies in knowledge about the developing immune system. This proposal on 'Antiviral Immune Mechanisms in Early Childhood' will enhance knowledge about the developmental biology of the host response in infants and young children, emphasizing adaptive virus-specific immunity mediated by CD4 and CD8 T cells, and the postnatal ontogeny children, emphasizing adaptive virus-specific immunity mediated by CD4 and CD8 T cells, and the postnatal ontogeny of antigen-presenting cell function. Whereas most viral pathogens are encountered during the first few years of life, and most viral vaccines must be given during this interval in order to provide maximum benefit, very little is known about the acquisition of memory T cell immunity in the young child. Human cytomegalovirus (HCMV) is a 'model' since it is common in early childhood, HCMV is readily detected in urine, and immunologic control of infection can be defined in relation to cessation of virus shedding. Three Research Projects will use innovative flow- cytometry based methods to analyze antiviral immune mechanisms in young children, including Project 1: Postnatal ontogeny of HCMV- specific CD4 T cell immunity, Project: The evolution of CD8 T cell responses to HCMV in infants, and Project 3: Antigen presentation: ontogeny and modulation by HCMV. Conceptually, these three projects taken as a whole, will define the contributions and interactions between the three components of the adaptive immune response, including CD4 T cells, CD8 T cells and antigen-presenting cells (APC), necessary to achieve effective antiviral immunity. The common focus is of identifying differences between the functional capacities of CD4 T cells, CD8 T cells and APCs in young children compared to adults, that may account for the prolonged interval required for the immature host to control HCMV replication. The goal is to reveal patterns of impaired or delayed immunity in early childhood. The Program Project structure includes a Clinical Research Core, to enroll and monitor subjects, maintain a centralized data base, and provide biostatistical oversight. Characterizing basic immune mechanisms associated with host containment of HCMV has direct practical significance for designing an effective HCMV vaccine, which was classified as highest priority by the 1999 Institute of Medicine, report on vaccines. More generally, improving our knowledge about the maturation of adaptive immune responses in early childhood will be used for the many major initiatives now aimed at developing new viral vaccines and improving the safety and efficacy of existing vaccines for use in young children.
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