A major goal of the Childhood Vaccine Initiative is to provide vaccine induced protection as early in life as possible. H. influenzae PRP- protein conjugate vaccines, which clearly differ in their capacity to elicit efficient antibody responses in the human neonate and infant, will be used as model immunogens: PPR-OMPC induces brisk responses at 2 months of age, but tolerance in neonates; PPR-T induces little or no response in neonates, weak responses in infants and a mature response by 15 months of age. To rationally modify these agents to improve immunogenicity in the neonate and to extrapolate these data to facilitate preparation of future vaccines will require 1) an understanding of the fundamental mechanisms underlying differences in the immune responses of the neonate and infant compared to more mature individuals and 2) a more complete understanding of the molecular and cellular events required for an effective antibody response to conjugate vaccines. The proposal addresses a central hypothesis:A major factor limiting the production of protective antibodies to PPR conjugate vaccine in the neonate is the need for contact dependent T cell help, and the inability of neonatal T cells to provide this help in an efficient manner; this will reflect in part diminished and delayed expression of the CD40 ligand and critical cytokines; it may be compounded by an initial paucity of primed B cells expressing B7 (CD80) antigens. This hypothesis will be tested by determining: 1) The age at which the capacity to express CD40 ligand and lymphokines required for efficient antibody production and Ig class switching matures in humans. 2) The induction of and requirement for CD40 ligand and B7 antigens in response to H. influenzae PRP conjugate vaccines differing in immunogenicity in human infants, as tested in murine model. 3) The basis of the lack of efficacy or induction of tolerance by PRP conjugates in neonates. 4) Whether a transgene that leads to CD40 ligand expression in the initial response of naive T cells in the mouse will enhance antibody responses to PRP conjugate vaccines. These studies will use samples from human infants, neonatal as compared to adult mice, including transgenic mice. Further, the transgenic mice will allow us to determine if altering the capacity of naive T cells to express critical ligands and cytokines ordinarily expressed only by memory T cells, will facilitate an earlier or more robust antibody response. If so, this approach might provide a general strategy to accelerate the capacity of the neonate to response to vaccines.
