Whole-Cell or Acellular Pertussis Primary Immunizations in Infancy Determines Adolescent Cellular Immune Profiles

Abstract

Introduction: Pertussis is re-emerging worldwide, despite effective immunization programs for infants and children. Epidemiological studies show a more limited duration of protection against clinical pertussis in adolescents primed with acellular pertussis (aP) vaccines during infancy than those who have been primed with whole-cell pertussis (wP) vaccines. This study aimed to determine whether memory immune responses to aP, diphtheria, and tetanus vaccine antigens following booster vaccinations at 4 and 9 years of age differ between wP- versus aP-primed children.

Methods: In a cross-sectional study, blood was collected of DTwP- or diphtheria, tetanus, and aP (DTaP)-primed children before, 1 month, and 2 years after the preschool DTaP booster administered at 4 years of age (n = 41-63 per time point). In a longitudinal study, blood was sampled of DTwP- or DTaP-primed children before, 1 month, and 1 year after a preadolescent Tdap booster at 9 years of age (n = 79-83 per time point). Pertussis, diphtheria, and tetanus vaccine antigen-specific IgG levels, B-cell and T-cell responses were determined.

Results: After the preschool booster vaccination, IgG levels were significantly higher in aP-primed as compared with wP-primed children until 6 years of age. Before the preadolescent Tdap booster vaccination, humoral and cellular immune responses were similar in aP- and wP-primed children. However, the Tdap booster vaccination induced lower vaccine antigen-specific humoral, B-cell, and T-helper 1 (Th1) cell responses resulting in significantly lower Th1/Th2 ratios in aP-primed compared with wP-primed children.

Conclusion: The memory immune profiles at preadolescent age to all DTaP vaccine antigens are already determined by the wP or aP combination vaccines given in infancy, showing a beneficial Th1-dominated response after wP-priming. These immunological data corroborate epidemiological data showing that DTaP-primed adolescents are less protected against clinical pertussis than DTwP-primed children.

Keywords: (pre-)adolescents; T-helper 1/Th2 ratio; immune profiles; infant priming; pertussis.

Figure 1

Overview of the study groups. Schematic overview of the six blood sampling time points. Children were primed with either whole-cell pertussis (wP) or acellular pertussis (aP) combination vaccines in the first year of life (2, 3, 4, and 11 months of age) and received a diphtheria, tetanus, and aP (DTaP) booster vaccination at 4 years of age, all according to the Dutch national immunization program. Groups of children were sampled cross-sectionally pre-booster, 1 month and 2 years (at 6 years of age) post DTaP booster vaccination at 4 years of age (indicated in red) (25). In addition, children 9 years of age, primed with either wP vaccines (26, 27) or with aP vaccines (NTR4089, Figure E1 and Method S1 in Supplementary Material) received an additional Tdap booster vaccination and were sampled longitudinally before, 1 month, and 1 year after the booster (indicated in green).

Figure 2

IgG antibody levels in children 4–9 years of age covering two booster vaccinations. (A) Pertussis toxin (PT), (B) filamentous hemagglutinin (FHA), (C) pertactin (Prn), (D) diphtheria toxoid, and (E) tetanus toxin-specific IgG levels (IU/mL) of 4- to 9-year-old whole-cell pertussis (wP)- (blue circles) or acellular pertussis (aP)-primed (red triangles) children. Blood was sampled cross-sectionally at 4 years of age before, 1 month, and 2 years (6 years of age) after the preschool diphtheria, tetanus, and aP booster and from different children longitudinally at 9 years of age before, 1 month, and 1 year after the preadolescent Tdap booster. Note, black lines indicate geometric mean concentration with 95% confidence interval, *p-value <0.05, and **p-value <0.01. Note, data of PT, FHA, and Prn for wP-primed children aged 4–9 years and aP-primed children aged 4–6 years were previously published (25, 26).

Figure 3

Reverse cumulative distribution curves of IgG antibody levels in children 9 years of age before and after a Tdap booster vaccination. Reverse cumulative distribution curves of (A) pertussis toxin (PT), (B) filamentous hemagglutinin (FHA), (C) pertactin (Prn), (D) diphtheria toxoid, and (E) tetanus toxin-specific IgG levels of whole-cell pertussis (wP)- (blue) and acellular pertussis-primed (red) children 9 years of age before (solid lines), 1 month (striped lines), and 1 year (dotted lines) after a preadolescent Tdap booster vaccination. Note, data of PT, FHA, and Prn for wP-primed children were previously published (26).

Figure 4

Numbers of memory B-cells in children 9 years of age before and after a Tdap booster vaccination. The numbers of (A) pertussis toxin (PT), (B) filamentous hemagglutinin (FHA), (C) pertactin (Prn), and (D) tetanus toxoid-specific IgG producing memory B-cells per 10⁵ IgG producing B-cells of whole-cell pertussis (wP)- (blue circles) or acellular pertussis (aP)-primed (red triangles) children 9 years of age before, 1 month, and 1 year after a preadolescent Tdap booster vaccination. Note, black lines indicate geometric mean numbers, *p-value <0.05, and **p-value <0.01. For all antigens, values of pre versus 1 month, pre versus 1 year, and 1 month versus 1 year were all significantly different within the wP- and aP-primed longitudinal groups of children (all p-values <0.05). Note, data of wP-primed children were previously published (26).

Figure 5

T-helper 1 (Th1)/Th2 ratio in children 9 years of age before and after a Tdap booster vaccination. The interferon-gamma (IFN-γ) (Th1)/interleukin-13 (IL-13) (Th2) ratio in supernatants of (A) pertussis toxin (PT), (B) filamentous hemagglutinin (FHA), (C) pertactin (Prn), or (D) tetanus toxoid-stimulated T-cells of whole-cell pertussis (wP)- (blue circles) and acellular pertussis (aP)-primed (red triangles) children 9 years of age, before, 1 month, and 1 year after a preadolescent Tdap booster vaccination. Note, black lines indicates geometric mean IFN-γ/IL-13 ratio and dotted lines indicates an IFN-γ/IL-13 ratio of 1. *p-Value <0.05 and **p-value <0.01; within the longitudinal study groups, there was only a significant difference for PT-stimulated T-cells between pre- and 1 year post-booster in wP-primed children (p-value <0.05).