The Maturing Immune System: Implications for Development and Testing HIV-1 Vaccines for Children and Adolescents

Neonatal Immunity

Immaturity of the newborn immune system leads to a 'physiological immunodeficiency' that encompasses all arms of the host response as reflected by the increased susceptibility of young children to infections by both viral and bacterial pathogens. Differences in innate immunity have been described, including neutrophil, toll-like receptor (TLR)-dependant, and dentritic cell (DC) immune function ( Table 1 ). The humoral immune system remains relatively underdeveloped, with the neonate initially being almost entirely dependent upon passively acquired maternal antibody ( Table 1 ). Maternal immunoglobulin (Ig)-G is actively transported across the placenta during gestation, predominantly during the third trimester, and is present at levels as high as those in adults. Maternal IgA is acquired from breast milk.^[25] Passively acquired antibodies can alter the humoral and antibody-dependant response to immunogens for up to 18 months in infants of infected or immunized mothers; in contrast, cellular immune responses appear unaffected by maternal antibody (Fig. 1).^[26,27]

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The effects of maternity antibody on vaccine responses in the neonate. Reproduced with permission from lambert et al.[62]

In addition to quantitative differences in antibody production during early life versus adulthood, there are also qualitative differences. IgG and IgA responses to pathogens, although inducible, are relatively weak during the first year of life, being short-lived and of low avidity.^[25] Immunogens have been described as thymus-dependant (TD) versus thymus-independent (TI).^[28] TI antigens include high molecular weight polymers, including polysaccharides and polynucleotides. Immune responses to TI antigens develop late in infancy by about 18 months.^[28] This has important implications when developing vaccines that include highly glycosylated proteins such as those that are present in the HIV envelope.

The T-cell repertoire of the developing immune system is less obviously impaired. However, neonates have fewer antigen-specific T-cell precursors than adults^[29] and quantitative differences in most T-cell subsets are detectable throughout childhood and adolescence.^[30] Qualitative differences in cytokine profiles also exist ( Table 1 ). Neonates and children produce less interleukin (IL)-2, IL-4, IL-6 and IL-10 in response to mitogens.^{[20,21,31,32,33]} In the presence of endogenous antigen presenting cells (APC), human cord-blood T cells proliferate poorly and are poor producers of certain cytokines. Overall, the neonatal cytokine profile is thought to be polarized towards a T-helper type 2 (T_H2) response to antigen.^[34,35,36] However, an overall deficiency of certain cytokines may also explain why neonatal CD4 cells nevertheless have diminished capacity to provide help for Ig synthesis.^[37,38]

Induction of CTL is age-dependant and is impaired in infants ( Table 1 ). For example, fewer infants under 5 months develop CTL responses to respiratory syncytial virus (RSV) compared to those 6-24 months of age.^[39] Conversely, promising evidence suggests that it may be possible to induce very early cytotoxic responses in infancy as demonstrated by CD8 cell interferon (IFN)-γ responses to autologous envelope (Env) peptides in infants vertically infected with HIV.^[40] High frequencies of cytomegalovirus (CMV)-specific CD8 T cells have been detected as early as 28 weeks of gestation.^[41] These findings raise the prospect that it may be possible to induce immune responses to HIV immunogens by vaccination immediately post-partum.

Little is known about neonatal gut mucosal immunology. The mucosal surface is exposed to a huge antigenic challenge and the immature mucosal immune system must learn to distinguish when a tolerogenic versus an immunogenic response is most appropriate.^[42] The neonatal gut is an important portal of entry for HIV, the mechanisms of which have not been elucidated.

AIDS. 2006;20(4):483-494. © 2006  Lippincott Williams & Wilkins
Lippincott Williams & Wilkins

Cite this: The Maturing Immune System: Implications for Development and Testing HIV-1 Vaccines for Children and Adolescents - Medscape - Feb 28, 2006.