Understanding Antibody Responses in Early Life: Baby Steps towards Developing an Effective Influenza Vaccine

Abstract

The immune system of young infants is both quantitatively and qualitatively distinct from that of adults, with diminished responsiveness leaving these individuals vulnerable to infection. Because of this, young infants suffer increased morbidity and mortality from respiratory pathogens such as influenza viruses. The impaired generation of robust and persistent antibody responses in these individuals makes overcoming this increased vulnerability through vaccination challenging. Because of this, an effective vaccine against influenza viruses in infants under 6 months is not available. Furthermore, vaccination against influenza viruses is challenging even in adults due to the high antigenic variability across viral strains, allowing immune evasion even after induction of robust immune responses. This has led to substantial interest in understanding how specific antibody responses are formed to variable and conserved components of influenza viruses, as immune responses tend to strongly favor recognition of variable epitopes. Elicitation of broadly protective antibody in young infants, therefore, requires that both the unique characteristics of young infant immunity as well as the antibody immunodominance present among epitopes be effectively addressed. Here, we review our current understanding of the antibody response in newborns and young infants and discuss recent developments in vaccination strategies that can modulate both magnitude and epitope specificity of IAV-specific antibody.

Keywords: B cell; Tfh; antibody; influenza virus; newborn; vaccine.

Figure 1

Induction of the germinal center response. Initiation of an affinity matured antibody response requires the coordinated activation and localization of several key immune subsets. Improvements in any of these, including T and B cell activation, differentiation, and homing to lymphoid organs, promote a greater magnitude and diversity of antibody. GC formation in young infants must also overcome defects in the structural framework of the GC that results from FDC immaturity. Increased innate immune stimulation via adjuvants has been shown to confer global benefits for the early steps of the GC formation. Adjuvants in blue have demonstrated effects in newborns or young infants, while those in green have been shown to work in adults. Whether they can work to modulate the indicated responses in young infants is yet to be explored.

Figure 2

Persistence of GC-derived humoral responses. Prolongation of the germinal center reaction is associated with higher rates of SHM, increased differentiation of LLPCs, and improved generation of broadly neutralizing antibody. Extending the availability of antigen in the GC appears to sustain the GC reaction; if B cells have no antigen to present, they cannot obtain T cell help. Even after successful induction of GC responses, young infants are particularly prone to transient reactions. Once these differentiated B cells exit the germinal center, they face the challenge of continued survival, which is particularly difficult for newborn LLPCs colonizing the immature bone marrow (BM) niche. Adjuvants in blue have demonstrated effects in newborns or young infants, while those in green have been shown to work in adults. Whether they can modulate the indicated responses in young infants is yet to be explored.