A nested study within the trial examined the relationship between rotavirus-specific IgA in cord blood, colostrum and breast milk and infant serum IgA response and stool excretion and found no evidence of an association (75). effects. Additional vaccines have been studied at birth including those directed against pertussis, pneumococcus, type B and rotavirus providing important lessons. Current areas of research in neonatal vaccinology include characterization of early life immune ontogeny, heterogeneity in and heterologous effects of BCG vaccine formulations, applying systems biology and systems serology, platforms that model age-specific human immunity and discovery and development of novel age-specific adjuvantation systems. These approaches may inform, de-risk, and accelerate development of novel vaccines for use in early life. Key stakeholders, including the general public, should be engaged in assessing the opportunities and challenges inherent to neonatal immunization. the first 28?days of life. In countries following the EPI schedule, after the neonatal doses of BCG, HBV, and polio vaccines, the next EPI schedule dose is typically given between 6 and 8?weeks of life. PFI-2 As with any vaccine approach, development of neonatal vaccines must take into account potential limitations, including: (a) need to establish safety, (b) lack of effectiveness of some vaccines in early life, (c) challenges of a translational path that typically starts with formulations optimized for adults, rather than generating formulations that are optimal for the young, and (d) potential blunting of neonatal Ab responses after maternal immunization. Nevertheless, the rationale for neonatal immunization is robust and includes: (a) the heavy burden of early life infection; (b) that birth is a practical point of healthcare contact, and pairing immunization with birth may lead to health benefits for both mothers and newborns; (c) immunization at birth may provide earlier protection than existing immunization schedules; (d) the likely benefit of protection to babies born preterm for whom maternal Ab transfer is limited, with an increased risk of serious infections throughout childhood (7); and (e) emerging evidence that the heterologous benefit of the live-attenuated BCG vaccine and other live vaccines may be greatest in early life (8). Lessons from Immune Ontogeny Neonatal immunization occurs in a backdrop of distinct early life immunity. Recent reviews have highlighted that both cellular and soluble aspects of the immune system are distinct at birth (9, 10). Neonatal immunity must not only defend the newborn against a potential onslaught of potential pathogens, but also mediate the acquisition of a colonizing microbiome over the first hours and days of life. In this context, neonatal immune responses are apparently designed to avoid excessive PFI-2 inflammation with a generally reduced production of pro-inflammatory and Th1-polarizing cytokines to microbial components/pattern recognition receptors (PRR) agonists. Age-specific composition of soluble and cellular factors shape neonatal immunity. The distinct composition of human newborn cord blood plasma includes soluble mediators such as maternal Abs, high levels of immunosuppressive adenosine, and low levels of complement, important for triggering adaptive immune Rabbit Polyclonal to PKC alpha (phospho-Tyr657) responses (11). Accordingly, modeling age-specific immunity should take into account distinct composition PFI-2 of age-specific autologous plasma, rather than, for example, fetal bovine serum (9). Distinct cellular immunity in the newborn includes reduced Th1 but robust anti-inflammatory IL-10 responses of antigen-presenting cells to stimulation by PRR agonists, high frequency of na?ve- and regulatory-T cells and CD71+ erythroid precursors that may limit, for example, responses to pertussis immunization (10, 12, 13). Nevertheless, neonatal immunity is capable of mounting antigen-specific effector responses, as demonstrated by BCG-specific IFN production following vaccination at birth (14). Overall, detailed study and modeling of age-specific human immunity may help inform development of vaccine formulations, with or without adjuvants as needed, that may trigger a protective immune response in early life. Proof of Concept: Routine Neonatal Vaccines Bacille CalmetteCGurin Bacille CalmetteCGurin is a live-attenuated strain of heterologous trained immunity (17C19). A CoP is an immune measure that corresponds to vaccine-induced protection from disease (20). Despite substantial efforts to characterize classic adaptive immunity, including multiple studies of polyfunctional CD4 T cells, a clear CoP for BCG has yet to.