The decline in measles mortality after the first year of life suggests a critical maturation of immune function between 6 and 12 months of age. We propose to use measles immunization to investigate developmental changes in the infant host response to viruses, with emphasis on age-related differences in the capacity of infants to develop T-lymphocyte recognition and cytokine responses to specific measles proteins. This model will permit the analysis of essential issues related to immunogenicity of live viral vaccines in infancy, including (i) failure of the young infant's immune system to develop clonal expansion of T-cells that recognize immunodominant viral proteins, (ii) generalized immunosuppressive effects of vaccine virus, and (iii) neutralization of infectious vaccine virus or immune interference by other mechanisms due to passively acquired maternal antibodies. Our first objective is to determine whether there are age- related, developmental changes in the induction of measles antigen- specific CD4+ T-cell proliferation and Th1 and Th2-like cytokine responses following measles immunization. Cytokine experiments will determine whether there is any shift in the relative predominance of Th1-like (IL-2 and IFN-g) or Th2-like (IL-4 and IL-10) responses in 6 month old infants compared to 12 month old infants or adults given measles vaccine. Secondly, the ontogeny of the infant host response to major measles viral proteins will be examined using purified measles proteins, including hemagglutination (H), fusion (F), matrix (M) and nucleocapsid (N) protein, in assays for T-cell proliferation, cytokine release and antibody production. Cytokine experiments will address whether particular proteins drive Th1 vs. Th2-like CD4+ T-cell responses. The third goal is to determine whether younger infants are more susceptible to the immunosuppressive effects of measles vaccine, measured by effects on mitogen-induced proliferation, spontaneous cytokine production T-cell proliferation to tetanus antigen. The fourth objective is to examine possible interference of passive antibodies with the induction of T-cell recognition of specific measles viral proteins. These experiments will determine whether antibodies detected by neutralization or binding to H, F, M or N proteins by Western blot, diminish or block the induction of T- cell recognition of all or only some viral proteins. Finally, whether younger age at immunization affects the persistence of humoral or cell- mediated immunity to measles proteins or alters the response to re- vaccination in infants at 15 months will be examined. Identifying developmental factors that influence the immunogenicity of measles vaccine is directly relevant to the goal of the Childhood Vaccine Initiative to immunize infants against major pathogens as early in life as possible. Whether primary measles immunization can be accomplished effectively at younger ages is an issue of global importance because measles is associated with annual mortality rates of more than 1 million among young infants in underdeveloped countries. Understanding how developmental changes in basic immunologic responses affect the acquisition of vaccine- induced immunity to measles has direct relevance for optimal design of other viral vaccines for use in infants.
