Developmental biology of the innate immune response: implications for neonatal and infant vaccine development

Abstract

Molecular characterization of mechanisms by which human pattern recognition receptors (PRRs) detect danger signals has greatly expanded our understanding of the innate immune system. PRRs include Toll-like receptors, nucleotide oligomerization domain-like receptors, retinoic acid inducible gene-like receptors, and C-type lectin receptors. Characterization of the developmental expression of these systems in the fetus, newborn, and infant is incomplete but has yielded important insights into neonatal susceptibility to infection. Activation of PRRs on antigen-presenting cells enhances costimulatory function, and thus PRR agonists are potential vaccine adjuvants, some of which are already in clinical use. Thus, study of PRRs has also revealed how previously mysterious immunomodulators are able to mediate their actions, including the vaccine adjuvant aluminum hydroxide that activates a cytosolic protein complex known as the Nacht domain leucine-rich repeat and pyrin domain-containing protein 3 inflammasome leading to interleukin-1beta production. Progress in characterizing PRRs is thus informing and expanding the design of improved adjuvants. This review summarizes recent developments in the field of innate immunity emphasizing developmental expression in the fetus, newborn, and infant and its implications for the design of more effective neonatal and infant vaccines.

Figure 1. Mechanisms of innate immune activation induced by vaccine adjuvants

TLR agonists found in multiple neonatal vaccines (Table 1) activate either cell associated or intracellularly located TLRs or NODs. These PRRs then interact with specific adaptor molecules culminating in NF-κB or IRF activation. Viral-derived products (dsRNA or ssRNA) can also activate endosomal TLRs, along with RLRs (such as RIG-I), which induce type-I IFN production. The vaccine adjuvant Alum activates the cytosolic NALP3/inflammasome leading to proIL-1β cleavage into bioactive IL-1β.

Figure 2. TLR8 agonists activate human APCs and reverse human Treg function

TLR8 agonists, such as R848, ssRNA and stabilized immune modulatory RNA (SIMRA) strongly activate human APCs via TLR8-dependent and TLR8-independent mechanisms including activation of the NALP3 inflammasome inducing IL-1β production. Exposure of human neonatal APCs to TLR8 agonists induces robust phosphorylation of p38 MAP kinase and profound/prolonged disappearance of IkB-κ, resulting in robust induction of protective Th1-type immune responses, including production of IL-12 and up-regulation of the co-stimulatory molecule CD40. TLR8 agonists also reverse suppression mediated by human Treg cells, via both direct action on Treg as well as by induction of APC production of IL-6, a cytokine that renders Tresponder cells refractory to Treg-mediated inhibition.