Malaria and Early Life Immunity: Competence in Context

Abstract

Childhood vaccines have been the cornerstone tool of public health over the past century. A major barrier to neonatal vaccination is the "immaturity" of the infant immune system and the inefficiency of conventional vaccine approaches at inducing immunity at birth. While much of the literature on fetal and neonatal immunity has focused on the early life propensity toward immune tolerance, recent studies indicate that the fetus is more immunologically capable than previously thought, and can, in some circumstances, mount adaptive B and T cell responses to perinatal pathogens in utero. Although significant hurdles remain before these findings can be translated into vaccines and other protective strategies, they should lend optimism to the prospect that neonatal and even fetal vaccination is achievable. Next steps toward this goal should include efforts to define the conditions for optimal stimulation of infant immune responses, including antigen timing, dose, and route of delivery, as well as antigen presentation pathways and co-stimulatory requirements. A better understanding of these factors will enable optimal deployment of vaccines against malaria and other pathogens to protect infants during their period of greatest vulnerability.

Keywords: fetal immunity; malaria; neonatal immunity; neonatal vaccination; plasmodium.

Figure 1

Maternal-origin IgG is transported across the syncytiotrophoblast barrier of the placenta to the fetus via FcRn, possibly in the form of immune complexes. In areas of placental villous denudement or necrosis, unbound plasmodial antigen may also cross into the fetal circulation. P. falciparum antigens have been shown to prime fetal αβ T cells and B cells, the location and identity of the antigen-presenting cells remain unknown, but could include fetal Hofbauer cells, dendritic cells, or γδ T cells. Semi-innate Vγ9Vδ2 T cells can be directly activated by plasmodial-derived phosphoantigens via butyrophilin2a1 and butyrophilin3a1, even in the absence of prior antigen exposure. In addition, fetal lymphocytes expressing CD16/FcRγIIIa, including NK cells and possibly γδ T cells, may be activated by maternal IgG bound to antigen. Created with BioRender.com.