Pneumococcal conjugate vaccination at birth in a high-risk setting: no evidence for neonatal T-cell tolerance

Abstract

Concerns about the risk of inducing immune deviation-associated "neonatal tolerance" as described in mice have restricted the widespread adoption of neonatal vaccination. The aim of this study was to demonstrate the immunological feasibility of neonatal pneumococcal conjugate vaccination (PCV) which could potentially protect high-risk infants in resource poor countries against severe pneumococcal disease and mortality in the early critical period of life. Papua New Guinean infants were randomized to be vaccinated with the 7-valent PCV (7vPCV) at birth, 1 and 2 months (neonatal group, n=104) or at 1, 2 and 3 months of age (infant group, n=105), or to not receive 7vPCV at all (control group, n=109). Analysis of vaccine responses at 3 and 9 months of age demonstrated persistently higher type-1 (IFN-γ) and type-2 (IL-5 and IL-13) T-cell responses to the protein carrier CRM(197) and IgG antibody titres to 7vPCV serotypes in children vaccinated with 7vPCV according to either schedule as compared to unvaccinated children. In a comprehensive immuno-phenotypic analysis at 9 months of age, no differences in the quantity or quality of vaccine-specific T cell memory responses were found between neonatal vaccinations versus children given their first PCV dose at one month. Hospitalization rates in the first month of life did not differ between children vaccinated with PCV at birth or not. These findings demonstrate that neonatal 7vPCV vaccination is safe and not associated with immunological tolerance. Neonatal immunisation schedules should therefore be considered in high-risk areas where this may result in improved vaccine coverage and the earliest possible protection against pneumococcal disease and death.

Fig. 1

CRM₁₉₇-specific type-1 and type-2 recall responses at 3 and 9 months of age. (A) Geometric means and standard errors of geometric means of CRM₁₉₇-induced IFN-γ (T helper 1), IL-5 and IL-13 (T helper 2) protein responses at 3 and 9 months (○, neonatal n = 48; ■, infant, n = 46; ▴, control, n = 38). The letters indicate significant differences (p < 0.05) for each time point between (a) the neonatal vs. infant group, (b) the neonatal vs. control group and (c) the infant vs. control group, and within groups for 3 compared to 9-month responses for the (d) infant and (e) control group (no statistical differences were found within the neonatal group). (B) Pneumococcal vaccine serotype-specific IgG antibody responses in the neonatal (white bar, n = 44), infant (grey bar, n = 40) and control group (black bar, n = 32). A level of 0.35 μg/ml or more is considered a clinical correlate of protection against invasive pneumococcal disease .

Fig. 2

Immunophenotypic analysis of recall T cell responses at 9 months following neonatal or infant immunisation. (A) Background-adjusted protein cytokine responses to CRM₁₉₇ in the neonatal (white bar; n = 65) and infant groups (grey bar; n = 62) at 9 months. (B) Proportion of children responding with an exclusive Th1 (IFN-γ) (black), mixed Th1/Th2 (IFN-γ, and IL-5 and/or IL-13) (dark grey), exclusive Th2 (IL-5 and/or IL-13) (light grey), or no protein cytokine response to CRM₁₉₇ (positive response ≥ 4 times the background) (white). (C) Microarray-assessed log₂-fold differential gene expression (mean and standard error of the mean) in CRM₁₉₇-stimulated cells compared to that in un-stimulated cells in the neonatal (white bar, n = 5 × 5 pooled PBMC) and infant groups (grey bar, n = 5 × 5 pooled PBMC). (D) Quantitative RT-PCR based relative mRNA expression in CRM₁₉₇-stimulated compared to that in un-stimulated PBMC in the neonatal (○, n = 20) and infant group (, n = 20), normalized against the constantly expressed gene eukaryotic translation elongation factor 1 a 1 (EEF1A1). CSF2, colony stimulating factor 2; CXCL9, Chemokine (C-X-C motif) ligand 9; GZMB, Granzyme B; IFNG, interferon-γ; Interleukin, IL; LIF, Leukemia inhibitory factor; LTA, lymphotoxin A.

Fig. 3

Bystander T cell cytokine responses. Background adjusted in vitro cytokine responses to tetanus toxoid (neonatal, n = 40; infant, n = 28; control, n = 31), measles lysate (neonatal, n = 43; infant, n = 33; control, n = 37) or phytohemagglutinin (PHA) (neonatal, n = 74; infant, n = 74; control, n = 72) at 9 months of age. (a) indicates significant difference in the neonatal compared to infant group.