Understanding Early-Life Adaptive Immunity to Guide Interventions for Pediatric Health

Abstract

Infants are capable of mounting adaptive immune responses, but their ability to develop long-lasting immunity is limited. Understanding the particularities of the neonatal adaptive immune system is therefore critical to guide the design of immune-based interventions, including vaccines, in early life. In this review, we present a thorough summary of T cell, B cell, and humoral immunity in early life and discuss infant adaptive immune responses to pathogens and vaccines. We focus on the differences between T and B cell responses in early life and adulthood, which hinder the generation of long-lasting adaptive immune responses in infancy. We discuss how knowledge of early life adaptive immunity can be applied when developing vaccine strategies for this unique period of immune development. In particular, we emphasize the use of novel vaccine adjuvants and optimization of infant vaccine schedules. We also propose integrating maternal and infant immunization strategies to ensure optimal neonatal protection through passive maternal antibody transfer while avoiding hindering infant vaccine responses. Our review highlights that the infant adaptive immune system is functionally distinct and uniquely regulated compared to later life and that these particularities should be considered when designing interventions to promote pediatric health.

Keywords: adaptive immunity; adjuvants; infant immunity; maternal antibody transfer; neonatal B cells; neonatal T cells; pediatric infectious diseases; vaccines.

Figure 1

Summary of the T cell compartment in early life. This overview of the infant T cell compartment summarizes evidence from human studies unless otherwise stated. Infants rely on “innate-like” CD4+ and CD8+ T cells, which are more likely to be RTEs and to signal through innate immune pathways such as complement receptor and TLR signaling, promote inflammation, and respond with antimicrobial peptides rather than classic antigen-specific adaptive immune responses. T helper type 1 (Th1) cells are generated in response to certain pathogens and vaccines in early life; however, epigenetic regulation of cytokine loci may limit these responses. T helper type 2 (Th2) cells are generated in response to allergens and common environmental antigens encountered in early life and only rarely in response to pathogens or vaccines. Regulatory T cells (Tregs) maintain fetal immunotolerance in utero and are present in higher numbers and proportions in early life blood and peripheral tissues, which may aid in promoting tolerance to microbial colonization but may impair mucosal and systemic T cell activation and adaptive immune responses. T follicular helper cell (T_FH) responses are impaired in neonatal murine models but have not been studied extensively in human neonates. The restricted function of T_FH cells in early life may be due to immaturity in co-activation signals required for B and T cell crosstalk and may impair generation of germinal center responses. *data shown in mice. RTEs, recent thymic emigrants; CMV, cytomegalovirus; RSV, respiratory syncytial virus; P. falciparum, plasmodium falciparum; T. cruzi, Trypanosoma cruzi.

Figure 2

Summary of the B cell compartment and antibody responses in early life. Dampened germinal center reaction is generally observed in infants, and differentiation of activated B cells is skewed toward short-lived memory B cells over plasma cells. Bone marrow in early life is unable to provide an optimal niche for the differentiation of long-lasting plasma cells. Transplacental maternal antibodies influence the neonatal B cell-mediated response by the illustrated mechanisms. *data shown in mice. FDC, follicular dendritic cell.