Immunization of pregnant women is increasingly used to protect mothers and/or infants against vaccine- preventable diseases. However, there is little knowledge on the effects of maternal vaccination on infant immune responses. There is growing evidence that infants can develop in utero responses to maternal vaccines. We hypothesized that in utero exposure to maternal influenza vaccine (IIV) antigens may generate infant adaptive responses against influenza in utero that may protect the infant against the disease after maternal antibodies decrease in infant circulation below the threshold of protection. Conversely, in utero immunization also may generate regulatory T cells (Treg) that downregulate the infant responses to childhood vaccines. To address these hypotheses, we formulated the following specific aims: Aim 1. To determine the rate of IIV in utero immunization and the persistence of Flu-specific antibody and cellular immune responses after in utero immunization. IIV-exposed immunized infants will be identified by presence of Flu-specific IgA, T cells, or B cells in cord blood that exceed the 99th percentile of the corresponding markers in IIV-unexposed infants. Persistence will be defined by the presence of Flu-specific IgA antibodies, memory B cells and T cells at 6 to 18 months of age, before the administration of the 1st dose of IIV to the infant. Aim 2. To determine the effect of IIV in utero immunization on subsequent immune responses to pediatric IIV administered at 6 to 18 months of life. We will measure Flu-specific humoral and cellular immune responses to the initial administration of pediatric IIV in IIV-exposed immunized infants primarily by comparison with IIV-unexposed infants. Responses measured in this will consist of Flu-specific antibodies, effector and memory B cells and T cells and their transcription profiles. We will correlate the proportions of Flu-specific Treg before pediatric IIV administration with the magnitude of the adaptive immune responses developed after completion of the 2 doses of IIV in the primary pediatric immunization schedule. Aim 3. To compare the epigenetic profile of Flu-specific T cells generated by in utero immunization or pediatric IIV administration at 6 to 18 months of life. T cells that proliferate after ex vivo Flu stimulation of CBMC of IIV-exposed immunized or infant PBMC from de novo immunized infants will be purified and their epigenetic profile will be compared using ATAC-Seq. The results of this study will determine the quality, durability and the epigenetic characteristics of the fetal immune responses to foreign antigens introduced by maternal vaccination. It will define the effect of in utero immunization on neonatal immunity and inform the practice of vaccination during pregnancy.

Influenza vaccination is recommended for pregnant women. There is evidence that part of the vaccine may cross the placenta into the fetus. We propose to study protection against influenza in infants whose maternal influenza vaccine crossed the placenta. We will also study how these infants respond to the primary pediatric influenza vaccination during the first 18 months of life.