Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from <1 ml of blood, a volume readily obtained from newborns. Indexing to baseline and applying innovative integrative computational methods reveals dramatic changes along a remarkably stable developmental trajectory over the first week of life. This is most evident in changes of interferon and complement pathways, as well as neutrophil-associated signaling. Validated across two independent cohorts of newborns from West Africa and Australasia, a robust and common trajectory emerges, suggesting a purposeful rather than random developmental path. Systems biology and innovative data integration can provide fresh insights into the molecular ontogeny of the first week of life, a dynamic developmental phase that is key for health and disease.

troponin T 10a, aldolase and superoxide dismutase. By contrast, the activities (V max ) of enzymes involved in aerobic performance, phosphofructokinase, hexokinase, pyruvate kinase and cytochrome c oxidase, did not increase in the flight muscles of hive bees, young foragers, mature foragers and old foragers. However, citrate synthase activity was found to increase with foraging experience. Hence, our results suggest plasticity in both structural and metabolic components of flight muscles with foraging experience.

e HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following the WHO extended program on immunization (EPI).Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.

These observations indicate that initiation of maternal ART before pregnancy reduces the susceptibility of HEU infants born in a HIC to severe infections and that this effect could be related to the prevention of immune alterations during fetal life.

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Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-Guérin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (∼50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces "heterologous" protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed "trained immunity." In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TBspecific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCG's innate immune activation, suggesting that aspects of BCG's effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines.

BackgroundSusceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination.ObjectiveDetermine whether differences in innate immune responses exist among infants from different continents of the world.MethodsWe determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe).ResultsWe found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs.ConclusionsSubstantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world.

The transfer of maternal immune factors to the newborn is critical for protection from infectious disease in early life. Maternally acquired passive immunity provides protection until the infant is beyond early life’s increased susceptibility to severe infections or until active immunity is achieved following infant’s primary immunization. However, as reviewed here, human immunodeficiency virus (HIV) infection alters the transfer of immune factors from HIV-infected mothers to the HIV-exposed newborns and young infants. This may relate to the immune activation in HIV-infected pregnant women, associated with the production of inflammatory cytokines at the maternofetal interface associated with inflammatory responses in the newborn. We also summarize mother-targeting interventions to improve the health of infants born to HIV-infected women, such as immunization during pregnancy and reduction of maternal inflammation. Maternal immunization offers the potential to compensate for the decreased transplacentally transferred maternal antibodies observed in HIV-exposed infants. Current data suggest reduced immunogenicity of vaccines in HIV-infected pregnant women, possibly reducing the protective impact of maternal immunization for HIV-exposed infants. Fortunately, levels of antibodies appear preserved in the breast milk of HIV-infected women, which supports the recommendation to breast-feed during antiretroviral treatment to protect HIV-exposed infants.