Journal of Adolescent Health
Volume 37, Issue 6 , Pages 517.e1-517.e5, December 2005

Immunogenicity and reactogenicity of a reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine in healthy Taiwanese children and adolescents

  • Li-Min Huang, MD, PhD

      Affiliations

    • Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
    • ,
  • Luan-Yin Chang, MD, PhD

      Affiliations

    • Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
    • ,
  • Haiwen Tang, MD, PhD

      Affiliations

    • GlaxoSmithKline Biologicals, Rixensart, Belgium
    • ,
  • Hans L. Bock, MD

      Affiliations

    • GlaxoSmithKline Biologicals, Rixensart, Belgium
    • ,
  • Chun-Yi Lu, MD

      Affiliations

    • Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
    • ,
  • Fu-Yuan Huang, MD

      Affiliations

    • Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
    • ,
  • Tzou-Yien Lin, MD

      Affiliations

    • Chang Gung Children’s Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan
    • Corresponding Author InformationAddress correspondence to: Dr. Tzou-Yien Lin, Chang Gung Children’s Hospital, No. 5, Fu-shin St, Kweishang, Taipei, Taiwan.
    • ,
  • Chin-Yun Lee, MD

      Affiliations

    • Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

Received 3 May 2005; accepted 10 August 2005.

Article Outline

Abstract 

Purpose

Disease caused by Bordetella pertussis is increasingly being identified among older children and adults in immunized populations, indicating a waning of the vaccine-induced immunity. These findings suggest the need for booster immunization of older children and adults. Modern acellular reduced-antigen-content vaccines have been developed, which can be given as a booster in individuals more than 4 years of age. This study was to assess the immunogenicity and reactogenicity of Boostrix™, GlaxoSmithKline Biologicals’ reduced-antigen-content diphtheria-tetanus acellular pertussis (dTpa) vaccine, when administered as a booster in healthy subjects previously primed with DTP vaccine.

Methods

Healthy Taiwanese children and adolescents aged 6–8 years and 15–20 years, previously primed with DTP vaccine, were enrolled. All received one dose of Boostrix™. Two blood samples were taken from each of them, one before vaccination and one at 1 month after vaccination. Serum antibodies to diphtheria and tetanus toxoids and immunoglobulin G (IgG) antibodies against the pertussis components PT, FHA and PRN were measured by enzyme-linked immunosorbent assay (ELISA) technique. Adverse reactions following vaccination were recorded.

Results

A total of 180 subjects were recruited. The vaccine response rates to the pertussis antigens ranged between 89.0–100%. There were no serious adverse events reported during the study period.

Conclusions

The results of this study suggest that Boostrix™ may be safely and effectively administered as a booster dose to children previously primed with DTP vaccine.

Keywords:  Reduced-antigen-content dTpa vaccine , Bordetella pertussis , Taiwan , Booster vaccination , Adolescents

 

Universal infant immunization against diphtheria, tetanus, and pertussis is one of the major goals of the World Health Organization (WHO) Expanded Program on Immunization (EPI). Diphtheria-tetanus-pertussis (DTP) primary vaccination of infants followed by a booster dose in the second year of life is almost a universal practice [1].

In the prevaccination era, pertussis infection commonly occurred in early life. The subsequent natural immunity was then maintained by periodic exposure to the organism (Bordetella pertussis), which acted as a natural booster [2]. Childhood immunization against pertussis has been effective in decreasing the incidence of pertussis but has not eliminated the circulation of Bordetella pertussis [3]. Although the incidence of pertussis in young children has been markedly reduced since the successful implementation of infant immunization programs, there has been a subsequent increase in the incidence in older children, adolescents and adults in immunized populations [3], [4], [5], [6], [7], [8], [9], [10].

Neither vaccination-acquired nor natural immunity from pertussis is life long. An increasing number of adults and adolescents with waning immunity, especially in well-vaccinated populations where natural boosting has been reduced, are now susceptible to pertussis reinfection [8], [11], [12], [13], [14]. The major cause for concern is the potential for older infected family members to serve as reservoir of infection to young infants, which has been shown in several household studies [11], [12], [14], [15], [16], [17], [18].

Furthermore, because the symptoms are generally atypical in adults [19], adult infection is often difficult to diagnose [20] and this situation creates the potential for further spread. Treatment with antibiotics is effective in clearing the organism and limiting spread of the disease only within the first three weeks after onset of symptoms [21].

These findings suggest the need for booster immunizations of older children and adults, with the goal of preventing transmission of B. pertussis from these age groups to infants. Pertussis vaccine boosters have not previously been recommended after seven years of age, mainly due to the high reactogenicity of traditional whole-cell pertussis vaccines [22] in older children and the belief that pertussis is both uncommon and mild in older children, adolescents and adults.

Although combined diphtheria-tetanus-pertussis (DTPa) vaccines, which are less reactogenic than whole-cell vaccines [23], [24], have become routine pediatric vaccines in many countries, their reactogenicity increases with successive doses, making the pediatric formulation less suitable for older individuals [25].

The recent development of a reduced-antigen-content diphtheria-tetanus acellular pertussis vaccine (dTpa) provides health practitioners with a new option. In many countries, immunity to diphtheria and tetanus is currently maintained by booster vaccination at 5- to 10-year intervals. A reduced-antigen-content diphtheria-tetanus (Td) vaccine is used to improve tolerability while eliciting an adequate immune response. Utilizing a reduced antigen dTpa vaccine would provide the added benefit of boosting waning pertussis antibodies in addition to maintaining immunity to diphtheria and tetanus.

This article reports the immunogenicity and reactogenicity of Boostrix™, GlaxoSmithKline Biologicals’ reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, when administered as a booster vaccination to healthy Taiwanese children six to eight years of age and adolescents and young adults aged 15 to 20 years, all of whom were previously primed with DTP vaccine.

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Materials and Methods 

Subjects and ethics 

Sixty healthy children six to eight years of age and 120 healthy young adolescents and adults 15 to 20 years of age who were previously primed with four doses of DTP vaccine according to local schedule, were enrolled.

This study was conducted at the National Taiwan University Hospital and Chang Gung Children’s Hospital in Taiwan. The conduct of this study followed the Declaration of Helsinki and Good Clinical Practice guidelines, with approval of the respective ethical review committee and with witnessed written parental informed consent before the start of the study.

Children and adolescents/young adults were excluded from the study if they had a history of allergic reaction to any of the vaccine components, had a history of diphtheria or tetanus disease or a history of confirmed pertussis disease within the previous five years, had any chronic or neurological illness, or had received any blood products.

Vaccine 

Reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) vaccine—, Boostrix™ (GlaxoSmithKline Biologicals, Rixensart, Belgium), was used in this study. One dose (0.5 mL) contained diphtheria toxoid (≥2 International Units, IU), tetanus toxoid (≥20 IU), Pertussis toxin (PT; 8 μg), filamentous haemagglutinin (FHA; 8 μg), and pertactin (PRN; 2.5 μg). The same manufacturer’s lot of the dTpa vaccine was used in both studies.

Study design 

An open label design was used. All subjects received a single booster dose of dTpa vaccine intramuscularly in the deltoid region.

Data collection 

Diary cards provided by the investigator were used by parents/guardians to record solicited local reactions at the injection site (pain, redness and swelling) and systemic (general) symptoms (axillary temperature, headache, fatigue and gastrointestinal symptoms) on the day of vaccination and for the 14 subsequent days (15-day follow-up period).

Symptoms were graded from 1 to 3 in intensity with total (any symptom irrespective of intensity and relationship to vaccination) and Grade 3 (symptoms that prevented normal activities) incidence being reported here. Grade 3 pain was defined as “spontaneously painful.” For local swelling and redness, the largest diameter was measured and a diameter of >50 mm was defined as intensity Grade 3. Fever was defined as axillary temperature ≥37.5°C, and intensity Grade 3 as a temperature >39.0°C. Unsolicited symptoms reported during the 30-day follow-up period after the vaccine dose and serious adverse events (SAEs) reported during the entire study period were also recorded.

Immunological assays 

Blood samples were collected before the vaccine dose (pre) and one month after the vaccine dose (post). Serum antibodies to diphtheria and tetanus toxoids and immunoglobulin G (IgG) antibodies against the pertussis components PT, FHA and PRN were measured by enzyme-linked immunosorbent assay (ELISA) technique.

For anti-diphtheria and anti-tetanus antibodies, titres above the assay cut-offs were considered to be seroprotective. For pertussis antigens, subjects with antibody titres above the assay cut-off were termed as seropositive. Furthermore, because there is no defined serological correlate of protection for B. pertussis, a vaccine response was defined as post-vaccination antibody titres above the assay cut-off value in initially seronegative subjects, and as at least a twofold increase in antibody titres from prevaccination to postvaccination in initially seropositive subjects.

Statistical analysis 

All analyses performed to assess the antibody response and reactogenicity of a single dose of GSK Biologicals’ dTpa vaccine were descriptive. At each blood sampling time point (pre- and postbooster), seroprotection rates against diphtheria and tetanus toxoids, vaccine response rates to pertussis antigens, and geometric mean concentrations (GMCs) with 95% confidence intervals (CI) were tabulated for all antibodies.

The incidences of local and general adverse events (solicited/unsolicited after the vaccine dose) were calculated with exact 95% CI, in addition to tabulating intensity and relationship. Serious adverse events and discontinuation due to adverse events were described.

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Results 

Demographics 

The mean age of the enrolled children was six years, with a standard deviation of ±.13 years in the group of six- to eight-year-olds. All 60 children completed the study. All were Asian and the male-to-female ratio was approximately 1:1. All 60 were included in the reactogenicity analysis and 59 were included in the immunogenicity analysis (one subject was outside of the accepted age range).

The mean age in the group of 15- to 20-year-olds was 17 years (SD ± 1.64 years). All subjects were Asian and the male-to-female ratio was approximately .5: 1. Of the 120 subjects enrolled, 119 were vaccinated and included in the analyses. One subject did not return for the postvaccination blood sampling.

Immunogenicity 

One month after the vaccine dose, all subjects in both age groups had seroprotective anti-diphtheria and anti-tetanus antibody titres and a vaccine response against the pertussis antigens was elicited in most subjects (90.9–100%) (Table 1).

Table 1. Immunogenicity results following reduced-antigen dTpa vaccine administered to children and adolescents
Vaccine antigenSubjects nAge (years)Response (%)a95% CIGMC95% CI
Diphtheria596–810093.9–1004.73.6–6.2
11915–2010096.9–10011.710.1–13.7
Tetanus596–810093.9–10020.316.5–25.1
11915–2010096.9–1002.42.0–3.0
PT596–894.985.9–98.989.268.7–115.9
11915–2090.884.1–95.353.343.4–65.4
FHA596–898.390.9–100572.2469.9–696.8
11915–2010096.9–100780.6681.4–894.2
PRN596–896.688.3–99.6223.7159.4–313.8
11915–2099.285.4–100350.8257.6–477.7

a Vaccine response definition: diphtheria and tetanus: post-vaccination antibody titer > 0.1IU/mL by ELISA; pertussis antibodies: initially seronegative participants before vaccination with postvaccination antibody titer > 5 EL.U/mL; initially seropositive participants with post-vaccination antibody titer at least twofold higher than prevaccination titer.

GMCs increased significantly from prebooster to postbooster vaccination in both groups (data not shown). In the group of six- to eight-year-olds, there was a >22-fold increase for anti-diphtheria and a >52-fold for anti-tetanus concentrations. Anti-PT and anti-FHA concentrations increased >24-fold and anti-PRN increased >25-fold. In the group of 15- to 20-year-olds, GMC of anti-diphtheria increased >19-fold, anti-tetanus increased >23-fold, anti-PT increased >10-fold, anti-FHA ≥32-fold, and anti-PRN >34-fold.

Reactogenicity 

In both groups, local reactions were reported more frequently than were general symptoms (approximately three times more often in the six- to eight-year-olds and twice as often in the 15- to 20-year-olds). For both groups, pain at injection site and fatigue were the most frequently reported solicited local and general symptoms, respectively (Table 2). No Grade 3-solicited local or general symptoms were reported by the six- to eight-year-old group; two cases were reported in the older age group, both of which resolved by Day 18 postvaccination without sequelae. No cases of fever were reported by the younger children. The six cases reported in the 15- to 20-year-olds were assessed by the investigator as being unrelated to vaccination. The majority of the solicited local and general symptoms had an onset within 48 hours after vaccination. No unsolicited symptoms were reported in the younger age group. Seven of the 15- to 20-year-olds reported an unsolicited symptom within 30 days after vaccination and were assessed as having a probable or suspected relationship to vaccination. These included injection site reaction, pain, diarrhea, upper respiratory tract infection, pharyngitis, rhinitis and lymphadenopathy.

Table 2. Reactogenicity: incidence of solicited local and general symptoms reported within the 15-day follow-up period after vaccination
Adverse event6 to 8-year-olds (n = 60)15 to 20-year-olds (n = 119)
%95% CI%95% CI
Local injection site reactions
Pain
Total66.753.3–78.379.971.5–86.6
Grade 30—2.0.2–6.9
Redness
Total3523.1–48.425.217.7–34.0
Grade 30—0—
Swelling
Total4027.6–53.521.814.8–30.4
Grade 30—2.9.6–8.4
General symptoms6 to 8 year olds15 to 20 year olds
Fever
Total0—6.72.9–12.8
Grade 30—0—
Fatigue
Total16.78.3–28.524.417.0–33.1
Grade 30—0—
Gastrointestinal
Total6.71.8–16.211.86.6–19.0
Grade 30—0—
Headache
Total103.8–20.512.67.2–19.9
Grade 30—0—

n = Overall number of subjects with diary cards completed and returned.

No serious adverse events were reported and no child or adolescent/young adult experienced an adverse event that led to discontinuation from the study.

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Discussion 

Vaccination of older children, adolescents and adults against pertussis is now being proposed by some authorities to manage the recently observed epidemiological shift in the incidence of the disease to older age groups [8], [26]. To achieve long-term protection, it is possible that subsequent doses of pertussis vaccine are required at regular intervals throughout life, irrespective of both past immunization history and exposure to the natural infection [27]. As is the case for most vaccine-preventable diseases, high vaccination coverage must be achieved before herd immunity can be acquired and control of infection is afforded the entire population [28]. Combination with an already routinely used booster vaccine such as the diphtheria-tetanus vaccine (Td) is generally accepted as not only the most efficient, but also the most cost-effective means of achieving high coverage [29], [30].

However, it is important to ensure that neither the immunogenicity nor the reactogenicity profile of the combined vaccine is compromised. The assessment of immune response assumes greater significance in the case of dTpa vaccine, in which the diphtheria toxoid and pertussis antigen contents have been reduced to improve greater tolerability [31].

Earlier studies [26], [32], [33], [34], [35], [36], [37], [38] have demonstrated safety, good tolerability, and immunogenicity of DTPa vaccines as compared with DTPw vaccines when administered as booster doses in infants, preschool children and adults. However, the reactogenicity of DTPa vaccines is higher when used as a booster dose as compared with primary immunization [37], [39]. This can be circumvented by using a reduced-antigen-content dTpa vaccine.

Historical data have shown that reduced-antigen-content dTpa vaccines elicit immunogenicity profiles comparable with DTPa vaccines when administered as a booster dose [40]. Findings from other historical data indicate that vigorous booster responses can be elicited by reduced quantities of vaccine antigens in previously primed subjects [41]. The reduction of diphtheria toxoid and pertussis antigen contents did not have a deleterious effect on the immunogenicity of the vaccine when administered as a booster dose.

The results of these dTpa vaccine studies are consistent with these earlier results as demonstrated by seroprotection/vaccine response to all antibodies in a majority of the subjects and absence of Grade 3-solicited symptoms, unsolicited symptoms or serious adverse events.

In conclusion, these studies suggest that the reduced-antigen-content dTpa vaccine may be safely and effectively administered as a booster dose to children aged six to eight years and adolescents/young adults aged 15 to 20 years who were previously primed with DTP vaccine. The dTpa combination vaccine offers the benefits of lower reactogenicity as compared with the DTPa vaccines, satisfactory immunogenicity profile, and increased compliance.

Given the recent epidemiological data showing an increase in the susceptibility of older age groups to pertussis and the apparent lack of protection against diphtheria, there is a need for harmonized, universal primary vaccination followed by a booster policy [31]. A reduced-antigen-content dTpa vaccine, with its improved tolerability and the ability to boost titres against all three diseases, meets the growing need for a booster vaccine by offering protection against pertussis infection and providing the opportunity for control of the disease in these age groups.

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Acknowledgment 

This study was funded by a grant from GlaxoSmithKline Biologicals, Rixensart, Belgium.

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PII: S1054-139X(05)00392-7

doi:10.1016/j.jadohealth.2005.08.009

Journal of Adolescent Health
Volume 37, Issue 6 , Pages 517.e1-517.e5, December 2005

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