Malaria in pregnancy is estimated to affect greater than 12 million women leading to a multitude of adverse birth outcomes including low-birth weight, stillbirths, maternal anemia, and intrauterine growth restriction. The only currently available malaria vaccine has been limited by poor immunogenicity in children living in malaria-endemic settings. Children born to mothers with placental malaria have been reported to have an increased risk of malaria in the first years of life. Recent studies have revealed intriguing evidence of fetal tolerance to malaria antigens, suggesting a potential immunologic mechanism for this association. Altered innate and adaptive immune responses after birth have been demonstrated following in utero malaria exposure. A tolerant, or immunoregulatory, T cell phenotype has been described in the cord blood of placental malaria-exposed infants. Additionally, some studies have found that infants born to mothers with placental malaria have decreased response to routine childhood vaccinations. Therefore, prevention of placental malaria-induced immune tolerance through enhanced chemoprevention has the potential to augment longitudinal malaria-specific and global immunity during early childhood. The goal of this K23 proposal is to test the hypothesis that in utero malaria infection induces tolerogenic fetal malaria-specific and global immune responses that are inhibited by enhanced prenatal malaria chemoprevention. We will determine the immunologic consequences of in utero malaria exposure through the following three aims: 1) To determine the effect of in utero malaria exposure and prenatal chemoprevention on malaria-specific T-cell immune responses in early childhood. 2) To determine the effect of in utero malaria exposure and prenatal chemoprevention on innate immune responses during malaria infection in early childhood 3) To assess the impact of in utero malaria exposure on the immune response to routine vaccination. To achieve these aims we will leverage existing infrastructure and samples from a cohort of mother-infant pairs enrolled in an ongoing randomized clinical trial of highly effective artemisinin-based prenatal malaria chemoprevention in Uganda. The studies proposed in this application will build on the candidate's preliminary findings suggesting the development of cord blood immunoregulatory responses among in utero malaria-exposed infants.