Applying contemporary immunology to elucidate heterologous effects of infant vaccines and to better inform maternal-infant immunization practices.

This series of publications “Understanding the Ontogeny of the Immune System to Promote Immune-Mediated Health for Life” in Frontiers in Immunology provides a timely summary of the many recent advances in knowledge regarding the immune response of the mother, fetus, newborn, and young infant. This basic information provides the foundation from which new approaches to foster a smooth transition from the relatively insular and protected in utero environment – where bidirectional tolerance between mother and fetus is the over-arching goal – to the postnatal environment – where tolerance to self and the acquired microbiota must be balanced against the threat of pathogen invasion. But to truly address the theme inherent in the title of the Immunotherapies and Vaccines section of Frontiers in which these publications appear, knowledge is only the beginning. As Abu Bakr implied, the far greater (and more important) challenge is for immunologists to bridge between the separate siloes in which they and vaccinologists traditionally operate, then together to work effectively with microbiologists, systems, computational and structural biologists, bioengineers, and formulation chemists to translate emerging biological knowledge into new products and solutions to further reduce the global burden of infectious diseases. Although there has been a gratifying 49% decrease since 1990 in global mortality under the age of 5 years to a rate of ~6.3 million/year in 2013, the rate remains too high; moreover, the rate of decline in neonatal mortality has been less (40%), with the result that 45% of all under five mortality now occurs in the first month of life (http://data. unicef.org/child-mortality/). Collectively, preterm birth and infection are believed to account for approximately one-third and 20% of these neonatal deaths, respectively, with a fraction of preterm birth itself related to infection. These numbers indicate the remaining unmet need to more effectively and efficiently apply existing vaccines and to develop new vaccines to further reduce the burden of infectious diseases in early life. Active immunization of infants and young children – along with improvements in hygiene and nutrition – appears to have been an important factor in this reduction in under-five mortality. And while extending these benefits of vaccines more broadly throughout the world and developing new vaccines against major pathogens for which effective vaccines are not yet available are clear priorities going forward, this Opinion will focus on knowledge gaps in two areas, which if addressed could inform approaches by which to further reduce under-five mortality through immunization. The first need is to better define the heterologous effects of vaccines and vaccine schedules in humans and thereby to provide an evidence-base from which vaccine regimens might be further optimized to protect against target pathogens, while promoting potential for heterologous benefits where possible. The other gap lies in the knowledge needed to design a harmonized program of maternal and infant immunization to protect newborns and young infants from diseases in addition to tetanus, such that protective antibodies acquired by the infant through immunization of the mother do not unduly impede the responses of the infant to those vaccines. Beginning with the pioneering studies by Mackeness in the 1960s, an extensive body of research from mouse and other model systems has shown that immunization with BCG, infection with heterologous pathogens, and exposure to microbial products can “non-specifically” increase, and in other contexts decrease, host resistance to other infectious agents, cancer, and autoimmunity (1–3). Similarly, the impact of antibodies acquired from the mother on postnatal immunization of their infants has been evaluated in model systems, as reviewed in this series by Niewisk (4). This information provides supporting biological rationale and illustrates principles that are likely relevant to humans. Herein, the focus is on human evidence and evidence gaps, which if addressed would illuminate the degree to which those principles apply to human infants and inform ways be which they might be translated into appropriate action.