Challenges in vaccination of neonates, infants and young children

Abstract

All neonates, infants and young children receive multiple priming doses and booster vaccinations in the 1st and 2nd year of life to prevent infections by viral and bacterial pathogens. Despite high vaccine compliance, outbreaks of vaccine-preventable infections are occurring worldwide. These data strongly argue for an improved understanding of the immune responses of neonates, infants and young children to vaccine antigens and further study of the exploitable mechanisms to achieve more robust and prolonged immunity with fewer primary and booster vaccinations in the pediatric population. This review will focus on our recent work involving infant and young child immunity following routine recommended vaccinations. The discussion will address vaccine responses with respect to four areas: (1) systemic antibody responses, (2) memory B-cell generation, (3) CD4 T-cell responses, and (4) APC function.

Keywords: Antigen presenting cells; B cells; B-cell receptor; CD4 T-cells; Children; Dendritic cells; Haemophilus influenzae; Infants; MHC II; Neonate; Streptococcus pneumoniae; T cells; T-cell receptor; Toll-like receptor; Vaccination; cytokines; immunologic memory; pediatric vaccines.

Figure 1. Proportion of age-matched sOP children (n=34; red color) and non-sOP children (n=34; black color) with antibody protective levels plotted against age of the child

sOP children more frequently had nonprotective levels of antibody but no time gradient for DT, TT, PRN and HepB. The sOP children more frequently had nonprotective levels of antibody for PT, FHA, Polio 3 and Spn 23F, but the group effect varied with age. sOP and non-sOP children responded similarly to Polio 1, Polio 2, PRP, Spn 6B and Spn 14. Solid lines: Generalized estimating equations (GEEs) were used to fit the statistical models as previously described[21].

Figure 2. Correlation of antigen-specific memory B cells and serum IgG titers in LVR versus NOP children

(A) Frequencies of antigen-specific memory B cells (MBCs). (B) Serum immunoglobulin G (IgG) titers to 5 pneumococcal protein antigens. (C) Correlation between PhtD-specific serum antibody titers and PhtD-specific percentages of antigen-specific MBCs. Data are for 10 LVRsOP children and 12 non–otitis prone (NOP) children. Open circles denote otitis prone and closed circles denote non–otitis prone. *P = 0.05; ** P = 0.005.

Figure 3. B cell receives proliferation and differentiation signals through the B cell receptor (BCR) and the co-receptors Igα and Igβ

Following antigen binding to BCR, the co-receptors Igα and Igβ signals to activate downstream molecules phospholipase Cγ2 (PLCγ2) and the phosphoinositide 3-kinase (PI3K) pathway. CD22 is a B cell surface glycoprotein that can negatively regulate BCR signaling. Activation of BCR leads to phosphorylation of CD22, resulting in recruitment of SHP-1 to CD22 by Lyn which finally induces the apoptosis pathway. Defects in PLCγ2 or PI3K impair BCR signaling, class-switching responses and memory B cell formation. CD40 is a co-stimulatory marker expressed on B cells and CD40L (CD154) is the ligand expressed on T cells. CD40-CD40L interaction plays a critical role in T cell-dependent B cell antibody response.

Figure 4. CD4 T-cell responses in young children and adults

We assessed the poly-functional cytokine potential CD4 T-cells (PBMC) responses in young children (<12 months, n=20) and adults (mean age 30yr, n=12) to (A) PT, (B) PRN, (C) FHA, or with (D) SEB stimulation. P values *<0.05 and ***<0.005. (Figure is a regraph of figure 3 in reference[25])

Figure 5. Shortcomings of neonatal and young child T-cells

Various stages in neonatal and young children T-cell activation starting with T-cell receptor (TCR)-mediated activation. T-cells have reduced CD3 sensitivity and lower phosphorylation of several TCR-signaling molecules resulting in low Ca²⁺ flux induction and reduced NFATc2 translocation in the nucleus. After activation, neonates and young children T-cells demonstrate comparable levels of cellular proliferation compared to adult T-cells. However, neonatal and young children T-cells are prone to apoptosis post-activation. The limited frequencies of activated T-cells that result in effector/memory generation do not produce optimal levels of cytokines and lack multi-functionality.

Figure 6. MHC II expression levels on APCs of otitis-prone (OP) and non-otitis-prone (NOP) children

The MHC II levels of the different cell types from peripheral blood were measured using flow cytometry. mDC, myeloid dendritic cells; pDC, plasmacytoid dendritic cells; Mono, monocytes.