Abstract
Infections are most common and most severe at the extremes of age, the young and the elderly. Vaccination can be a key approach to enhance immunogenicity and protection against pathogens in these vulnerable populations, who have a functionally distinct immune system compared to other age groups. More than 50% of the vaccine market is for pediatric use, yet to date vaccine development is often empiric and not tailored to molecular distinctions in innate and adaptive immune activation in early life. With modern vaccine development shifting from whole-cell based vaccines to subunit vaccines also comes the need for formulations that can elicit a CD8+ T cell response when needed, for example, by promoting antigen cross-presentation. While our group and others have identified many cellular and molecular determinants of successful activation of antigen-presenting cells, B cells and CD4+ T cells in early life, much less is known about the ontogeny of CD8+ T cell induction. In this review, we summarize the literature pertaining to the frequency and phenotype of newborn and infant CD8+ T cells, and any evidence of induction of CD8+ T cells by currently licensed pediatric vaccine formulations. In addition, we review the molecular determinants of antigen cross-presentation on MHC I and successful CD8+ T cell induction and discuss potential distinctions that can be made in children. Finally, we discuss recent advances in development of novel adjuvants and provide future directions for basic and translational research in this area.
Highlights
British physician Edward Jenner marked the beginning of vaccinology when he developed the world’s first vaccine for smallpox in 1796 [1]
Subunit vaccines are comprised of purified protein or polysaccharide antigens, often combined with adjuvants, immune potentiators that are capable of stimulating the immune system [24]
We address the key concept of how adjuvants can activate CD8+ T cell responses and discuss their ability to regulate key molecular pathways relating to antigen crosspresentation in early life [46]
Summary
British physician Edward Jenner marked the beginning of vaccinology when he developed the world’s first vaccine for smallpox in 1796 [1]. Human neonatal APCs show distinct features in terms of expression of costimulatory molecules, and it has been proposed that these cells require a higher level of activation than their adult counterparts in order to create similar CD8+ T cell responses [201]. Considering these data, once a human neonatal APC is activated, it could still be entirely competent to induce an adaptive effector response In support of this notion, Gold et al found no defect in human neonatal DCs to process and present particulate antigen and concluded that crosspresentation is fully functional in human newborn DCs. as previously described, Kollman et al observed otherwise [195]. This is, because it has been speculated that TLR ligands potentially use the vacuolar pathway [58], while alum-based adjuvants seem to follow the cytosolic pathway Activating both routes of cross-presentation may enhance MHC class I restricted presentation and, promote CD8+ T cell mediated immunity. Even though alum-adjuvants are probably less suitable candidates in early life, because of their propensity to be Th2 skewing, combinations of alum with TLR adjuvants have shown promise, as described above
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