ONTOGENY OF GENERATION OF NEONATAL ANTIBODY DIVERSITY

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DESCRIPTION (Adapted from Applicant's Description): Both premature and full term human neonates generate suboptimal antibody (Ab) responses to vaccines. The overall goal of this proposal is to investigate whether defects in the preimmune Ab repertoire of neonatal B cells and in the diversification of this repertoire after immunization contribute to defective Ab responses and whether immunization during pregnancy is able to alter the immunoglobulin repertoire and B cell memory of the neonate. In Aim 1, the investigators hypothesize that the preimmune repertoire of the neonate is restricted in diversity of the immunoglobulin heavy chain third complementarity determining region (CDR3), which arises from the joining of Ig gene segments and N region addition. To investigate this hypothesis, they will characterize and compare the diversity and structure of the CDR3 regions of preterm and full term neonatal and adult B lymphocytes. They will analyze the potential antigen binding activity of a CDR3 library expressed from each group with a single immunoglobulin heavy chain variable region gene (VH) and light chain gene in a Fab surface phage expression library for binding to self and non-self antigens. In Aim 2, we will investigate the hypothesis that the neonate fails to diversify postimmunization and Ab repertoires with somatic hypermutation of VH by analyzing somatic hypermutation in VH at birth and after immunization of the neonate. To explore the hypothesis that the neonatal B cell repertoire can be altered by maternal immunization during pregnancy with vaccines that induces a high titered clonally restricted IgG Ab response, they will immunize pregnant women in the third trimester of pregnancy with Haemophilus influenzae b vaccines, which generate a high-titered oligoclonal IgG Ab response, and analyze the offspring for evidence of immunologic priming with Ab production and generation of B cell memory. The results of these investigations should provide novel insights into the ontogeny of the neonatal B cell repertoire and in the potential to accelerate of immunity.