Th2-associated local reactions to the acellular diphtheria-tetanus-pertussis vaccine in 4- to 6-year-old children

Abstract

Acellular vaccines against diphtheria-tetanus-pertussis (acellular pertussis) (DTaP) are being progressively introduced into vaccination programs worldwide, with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis (whole-cell pertussis) (DTwP) vaccine. The DTaP vaccine has an improved safety profile in infants, but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses. We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4- to 6-year-old children primed during infancy with DTaP (n = 30) or DTwP (n = 16) and by correlating these parameters, in particular cytokine responses, with expression of local side effects at the injection site. Large local reactions (> or =50-mm diameter) 24 to 72 h after receiving the DTaP booster occurred in 43% of exclusively DTaP-primed children, in contrast to 6% of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 (IL-5), IL-6, and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically "high Th2 responders" as detected by in vitro responsiveness to polyclonal mitogen. Our findings suggest that priming during infancy with DTaP promotes stable, boostable Th2-polarized immunity against vaccine antigens, which in a significant subset of children is subsequently associated with local reactions at the booster site. The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory.

Figures

FIG. 1.

Anti-TT IgG and IgE in DTaP-R-, DTaP-NR-, and DTwP-primed groups. Serum samples taken from 4- to 6-year-old children at the time of (prebleed) and 4 weeks after (postbooster) vaccination with DTaP were assayed for TT-specific IgG (in 103 units per liter [kU/L]) and IgE (IU/ml). The children have been classified as DTaP-primed reactive (DTaP-R) (those with a ≥50-mm-diameter redness at the site of the vaccine), DTaP-primed nonreactive (DTaP-NR) (those with smaller or no reaction), and DTwP-primed (DTwP). Data are expressed as scatter plots, with the solid line representing the median value. Below each graph, P values are shown, which were determined by the Wilcoxon matched-pair signed-rank test.

FIG. 2.

TT-specific cytokine production by PBMC. PBMC isolated from children at the time of (prebleed) vaccination with DTaP were cultured for 96 h alone or together with TT (0.5 Lf/ml). Supernatant levels of IL-5, IL-6, IL-10, IL-13, and IFN-γ were determined by time-resolved fluorometry, and IL-5, IL-6 and IL-13 data are shown here as picograms per milliliter. The change in values (treatment control) for each individual was calculated, and the pooled data were then expressed as box plots for DTaP-R-, DTaP-NR-, and DTwP-primed groups described in the legend to Fig. 1. The limits of the boxes represent the 25th and 75th percentiles of the results, the black line in the box represents the median (50th percentile), and the whiskers represent the 5th and 95th percentiles. Significant differences between each of the groups are shown and were determined by the Mann-Whitney U test for unpaired responses.