Volume 11, Issue 2 , Pages 129-136, March 2007
A fully liquid diphtheria–tetanus–five component acellular pertussis–inactivated poliomyelitis–Haemophilus influenzae type b conjugate vaccine: immunogenicity and safety of primary vaccination in Taiwanese infants☆
Article Outline
Summary
Objective
To assess the immunogenicity of a fully liquid diphtheria–tetanus–five component acellular pertussis–inactivated poliomyelitis–Haemophilus influenzae type b (DTaP–IPV–Hib) conjugate vaccine compared to DTaP–IPV and lyophilized Hib conjugate vaccines given simultaneously at separate sites as a three-dose primary vaccination in Taiwanese infants.
Methods
Two hundred infants were randomized to receive either DTaP–IPV–Hib or DTaP–IPV plus Hib vaccine at 2, 4, and 6 months of age. Both combined vaccines contained the same five pertussis antigens: pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN), fimbriae 2 and 3 (FIM 2&3). Antibody concentrations were measured before the first and after the third dose. Reactogenicity was evaluated from parental reports. All subjects received hepatitis B vaccine at 0, 1, and 6 months of age following the national vaccination schedule of Taiwan.
Results
The immunogenicity after the third dose was high for each vaccine antigen in both groups, and the vaccines had low reactogenicity. Statistical analysis showed no differences in the immune responses to the fully liquid DTaP–IPV–Hib vaccine compared with those to the DTaP–IPV plus Hib control vaccines, notably the anti-PRP (polyribose ribitol phosphate capsular polysaccharide) response, with 97–99% of infants having concentrations ≥1.0
μg/mL. Approximately 95% of all infants developed seroprotective levels of anti-hepatitis B surface antigen (HBs) antibodies (≥10mIU/mL).
Conclusions
Both combination vaccines had similar high immunogenicity for each antigen, and both were well tolerated. Thus, inclusion of a Haemophilus influenzae type b conjugate vaccine in the combination did not result in clinically significant decrease in the PRP response or increase reactogenicity. The fully liquid pentavalent vaccine has the advantages of not requiring reconstitution and of administration as a single injection.
Keywords: Acellular pertussis, Fully liquid combination vaccine, Haemophilus influenzae type b, Pentavalent vaccine
Introduction
The increasing complexity and inconvenience of childhood vaccination programs may reduce acceptance of, and compliance with, recommended schedules. The completion of all the vaccine doses in a routine childhood immunization schedule requires a great deal of commitment from the child's parents and physicians. Development of highly immunogenic and safe multivalent combinations based on acellular pertussis (DTaP (diphtheria–tetanus–acellular pertussis)) vaccines is a key step towards more realistic childhood immunization schedules that are mutually acceptable to the recipient, their parents, and healthcare professionals. The use of combination vaccines decreases the number of visits required, the number of injections required at each visit, and may also reduce reactogenicity compared with individually administered vaccines. The resulting simplification of immunization schedules may enable caregivers to improve vaccination coverage, dispense a less time-consuming vaccination schedule, and may also decrease administration costs.
Combination vaccines containing acellular pertussis antigens are safe, immunogenic, and effective in preventing pertussis in infants.1 One such vaccine (Tripacel™, or Daptacel™, Sanofi Pasteur) containing five pertussis antigens – pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae 2 and 3 (FIM2&3) – was found to have better reactogenicity and similar immunogenicity when compared to whole cell pertussis vaccines in controlled clinical studies, and was 85% effective in preventing pertussis in large field trials.2, 3, 4, 5 The vaccines evaluated in this study contain the same five acellular pertussis antigens.
The formulation of new vaccines in which several components are combined in a single injection is complex, because the combination of different antigens must not adversely affect the immunogenicity of each component or the safety profile. Consequently, it is important to determine that each component included in a combination vaccine is immunogenic and safe when administered according to the recommended national schedule for routine infant immunization. Pediacel™ (Sanofi Pasteur), the pentavalent vaccine evaluated in this study, is a fully liquid combination, and unlike other similar products, does not require the reconstitution of a lyophilized Hib conjugate vaccine (PRP∼T, polyribose ribitol phosphate conjugated to tetanus protein) with liquid DTaP immediately before injection. It is thus possible to protect infants against five diseases with a single injection. Eliminating the need for Hib vaccine reconstitution decreases the overall time required for administration, and avoids potential errors in preparation, mixing, and injection of the vaccine. Pediacel™ has been licensed in the UK, Canada, and other countries, including the Philippines and Malaysia.
The present article reports on the safety and tolerability of this fully liquid DTaP–IPV–PRP∼T combination as well as the immunogenicity of all the antigenic valences when given to Taiwanese infants at 2, 4, and 6 months of age. The results are compared with those obtained for DTaP–IPV vaccine (Quadracel™) and PRP∼T conjugate (ActHib™) control vaccines given concomitantly at different injection sites, and which have confirmed high immunogenicity and safety.6
Methods
This open, randomized, and controlled study recruited and enrolled subjects who visited a healthy baby clinic at the Chang-Gung Children's Hospital, Taoyuan, Taiwan for routine vaccinations. The study was conducted in accordance with the Declaration of Helsinki Good Clinical Practice and applicable International Conference on Harmonization (ICH) guidelines. Witnessed, written informed consent was obtained from the parents or guardians of all subjects before study entry. The study protocol, amendments, and consent form were approved by the study center Ethical Review Committee before initiation of the study. As the DTaP–IPV–PRP∼T and DTaP–IPV plus PRP∼T vaccines were not marketed in Taiwan, the study file was also submitted for approval by the Taiwanese health authorities.
Subjects
Eligible subjects were healthy infants eight weeks of age or older who had received hepatitis B vaccine at birth and also at one month of age. Exclusion criteria included known or suspected disease of the immune system, including human immunodeficiency virus (HIV) infection; major congenital malformation or condition; serious illness or malignancy; history of neurological disorders or seizures; mother with known or suspected liver disease; any known allergies or reactions likely to be exacerbated by any component of the study vaccines; treatment with immunosuppressive therapies (excluding inhaled and topical steroids) for more than 14 days; current or planned receipt of immunoglobulins or any blood-derived products; previous immunization against diphtheria, tetanus, pertussis, Hib, or poliomyelitis; and prior vaccination other than Bacillus Calmette–Guerin (BCG) and hepatitis B.
Vaccines and vaccine schedule
Subjects were randomized equally to receive either a fully liquid DTaP–IPV–PRP∼T conjugate vaccine (Pediacel™) or a DTaP–IPV vaccine (Quadracel™) plus PRP∼T vaccine (Act-HIB™) given concomitantly at separate sites, at 2, 4, and 6 months of age. Subjects were allocated one of the two study arms in a balanced block format, using a computer-generated list of random numbers.
The study vaccines were produced and supplied by Sanofi Pasteur (formerly Aventis Pasteur), and were administered by intramuscular injection into the left (DTaP–IPV–PRP∼T and DTaP–IPV vaccines) or right (PRP∼T vaccine) anterior aspect of the thigh. Both acellular pertussis vaccines contained 20μg pertussis toxoid (PT), 20μg filamentous hemagglutinin (FHA), 5μg fimbrial antigens FIM2&3, and 3μg pertactin (PRN). The inactivated poliovirus (IPV) vaccine in the fully liquid vaccine is produced in Vero cells, and the IPV in the DTaP–IPV combination is produced in MRC5 human diploid cell culture. All infants had received two doses of a commercially available recombinant hepatitis B vaccine (Engerix-B®, GlaxoSmithKline) separately from the study vaccines, at birth and at one month of age before inclusion in the study; all subjects received a third dose of hepatitis B vaccine by intramuscular injection concomitantly with the study vaccine, into the right thigh at six months of age. The hepatitis vaccine used was not specified in the study protocol, and was chosen at the discretion of the investigator.
Immunology
Blood samples for antibody determination were collected from each subject before immunization, and at one month after the third vaccination at approximately seven months of age. Frozen sera were transported to Sanofi Pasteur in Lyon, France for serologic analysis. Antibodies to hepatitis B surface antigen (HBs), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA), anti-pertussis fimbrial agglutinogens 2 and 3 (FIM2&3) and anti-pertactin (PRN), were determined by enzyme-linked immunosorbent assay (ELISA). Anti-polyribose ribitol phosphate capsular polysaccharide (PRP) was measured by a Farr-type radioimmunoassay, as previously described.7 Anti-diphtheria antitoxin was measured by seroneutralization; anti-tetanus antitoxin, by ELISA; and antibodies to poliovirus types 1, 2, and 3, by seroneutralization. Predefined seroprotection (SP) levels were: anti-PRP ≥0.15 and ≥1.0μg/mL; anti-polio ≥8(1/dil); anti-diphtheria and tetanus ≥0.01IU/mL; and anti-HBs ≥10mIU/mL. Since there are no known correlates of cut-off values for seroprotection for pertussis antibodies, seroconversion/vaccine response rates were assessed as a four-fold increase in antibody concentration from pre- to post-primary vaccination.
Safety
All infants were monitored for 30minutes after each injection for any immediate local or systemic reactions. Parents or guardians recorded solicited local reactions (injection site redness, swelling, and pain/tenderness) or solicited systemic events (fever (rectal temperature ≥38°C), drowsiness, unusual fussiness, unusual crying, loss of appetite, vomiting, and diarrhea) on diary cards daily for eight days after each vaccination. Any unsolicited local or systemic reactions that occurred during the 30 days after each vaccination were recorded (including date of onset, date of resolution, and intensity). Temperature was monitored daily following the eight-day period after vaccination if the child remained feverish.
Solicited and unsolicited local and systemic reactions were graded as mild, moderate, or severe. Crying when the limb was moved indicated severe injection site tenderness. Rectal temperature >40°C and continuous crying for more than three hours were also criteria for severe reactions.
Statistical analysis
For each vaccine group the seroprotection/seroconversion/vaccine response rates one month after the third dose of vaccine and their 95% confidence intervals (CIs) were calculated. Antibody concentrations or titers were further described by geometric mean concentrations (GMCs), or geometric mean titers (GMTs) in the case of polio, with respective 95% CIs and reverse cumulative distribution curves (RCDC). The primary study outcome was the percentage of subjects with seroprotective anti-PRP antibody concentrations (≥15μg/mL) one month after the third dose of study vaccine. Based on previous experience with these DTaP–IPV and PRP∼T vaccines a rate of 98% was expected in the present study.6 The clinically relevant difference in seroprotection rate was set at 10%, and the one-sided type one error, α, was set at 2.5%. Based on the above defined seroprotection rates, the clinical acceptable difference, the type I error, and on a power of 90%, an optimal sample size of 80 subjects per group was required for a one-sided equivalence test. Estimating that up to 20% of subjects might be excluded from a per protocol analysis, it was planned to enroll 200 subjects.
Statistical evaluation of seroprotection or seroconversion/vaccine response rates for each antigen one month following the primary series was descriptive, using the 95% CI of the between-group differences. The primary objective was reached if the lower limit of the 95% CIs of the difference between subjects receiving DTaP–IPV–PRP∼T minus those receiving DTaP–IPV and PRP∼T concomitantly at separate sites was above the pre-specified clinical limit of −10% (one-sided equivalence test, α=2.5%).
Results
Study population
As planned, a total of 200 subjects were randomized equally to the two study groups. All subjects completed the study. No subject discontinued the trial. The study population included 93 males (46.5%) and 107 females (53.5%). There were slightly more females (62%) in the group given DTaP–IPV–PRP∼T and slightly more males (55%) among those receiving DTaP–IPV and PRP∼T concomitantly. The mean age at enrolment was 10 weeks.
Immunogenicity
The study vaccines in both groups were highly immunogenic with respect to all antigens, diphtheria, tetanus, pertussis (PT, FHA, PRN, and FIM 2&3), the three polio antigens, and PRP, with no significant differences in vaccine response or seroprotection rate to any antigen observed between the groups (Table 1). Seroprotection, seroconversion/vaccine response rates (4-fold increase in antibody concentrations from pre- to post-primary vaccination), were at least 93%. A total of 97% of subjects in the DTaP–IPV– PRP∼T group and 99% in the DTaP–IPV plus PRP∼T group had seroprotective levels of anti-PRP ≥1.0μg/mL one month after completing the three-dose primary vaccination schedule. Seroprotection rates for hepatitis B were between 94% and 96%.
Table 1. Seroprotection/vaccine response rates for all vaccine antigens, and differences between the groupsa
| Antibody | Seroprotection/vaccine response | Difference | |
|---|---|---|---|
| DTaP–IPV–PRP∼T | DTaP–IPV+PRP∼T | DTaP–IPV+PRP∼T minus DTaP–IPV–PRP∼T | |
| % (95% CI) | % (95% CI) | % (95% CI) | |
| PRP≥0.15μg/mL | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| PRP≥1.0μg/mL | 97.0 (91.5; 99.4) | 99.0 (94.6; 100) | 2 (2.9; −7.5) |
| D≥0.01IU/mL | 100 (96.4; 100) | 99.0 (94.6; 100) | 0 (3.7; −3.7) |
| T≥0.01IU/mL | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| PT 4-fold increase | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| FHA 4-fold increase | 94.0 (87.4; 97.8) | 93.0 (86.1; 97.1) | −1 (8.5; −6.4) |
| PRN 4-fold increase | 98.0 (93.0; 99.8) | 97.0 (91.5; 99.4) | −1 (6.6; −4.4) |
| FIM 2&3 4-fold increase | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| Polio type 1≥8 1/dil | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| Polio type 2≥8 1/dil | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| Polio type 3≥8 1/dil | 100 (96.4; 100) | 100 (96.4; 100) | 0 (3.7; −3.7) |
| HBs≥10mIU/mL | 95.7 (89.2; 98.8) | 94.4 (87.5; 98.2) | −1.3 (8.5; −5.8) |
aVaccine administered at 2, 4, and 6 months of age. All subjects received hepatitis B vaccination at 0, 1, and 6 months of age. |
The 95% CIs of the between-group differences demonstrates the non-inferiority of group DTaP–IPV–PRP∼T to group DTaP–IPV plus PRP∼T following primary vaccination in terms of seroprotection, and seroconversion/vaccine response to all antigens. Indeed, the observed differences in immune response between the groups were all between 2% (95% CI: 2.9; −7.5) for anti-PRP ≥1.0μg/mL and −1.3% (95%: 8.5; −5.8) for anti-HBs ≥10mIU/mL.
Pre- and post-primary vaccination GMCs (GMTs for anti-polio antibodies) are summarized in Table 2. Anti-PRP GMCs were high in both groups (at least 11.4μg/mL) following vaccination. Anti-polio GMTs were at least 10821/dil for type 1, 25041/dil for type 2, and 16071/dil for type 3. Anti-HB antibody concentrations were over 600IU/mL in both study groups. The reverse cumulative distribution curves (RCDCs) in Figure 1, Figure 2 show similar anti-pertussis and anti-poliovirus antibody titers in both study groups after primary immunization.
Table 2. Geometric mean concentrations of antibodies to study vaccine antigens
| DTaP–IPV–PRP∼T | DTaP–IPV+PRP∼T | |||
|---|---|---|---|---|
| Prevaccination | Post-primary | Prevaccination | Post-primary | |
| GMC (95% CI) | GMC (95% CI) | GMC (95% CI) | GMC (95% CI) | |
| Anti-PRP (μg/mL) | 0.065 (0.051; 0.083) | 11.4 (9.35; 14.0) | 0.056 (0.046; 0.069) | 21.7 (17.3; 27.2) |
| Anti-PT (EU/mL) | 3.42 (3.04; 3.85) | 221 (200; 245) | 3.62 (3.16; 4.16) | 216 (193; 243) |
| Anti- FHA (EU/mL) | 3.96 (3.34; 4.69) | 117 (104; 132) | 4.33 (3.57; 5.26) | 104 (93.4; 116) |
| Anti-PRN (EU/mL) | 1.84 (1.66; 2.04) | 82.3 (71.8; 94.2) | 1.98 (1.76; 2.24) | 98.8 (86.3; 113) |
| Anti FIM2&3 (EU/mL) | 9.15 (8.54; 9.80) | 823 (726; 934) | 9.14 (8.59; 9.73) | 799 (684; 933) |
| Anti-polio type 1 (1/dil) | 6.07 (4.77; 7.71) | 1082 (892; 1314) | 6.66 (5.20; 8.54) | 1218 (957; 1550) |
| Anti-polio type 2 (1/dil) | 12.6(9.94; 15.9) | 2504 (2091; 2999) | 9.72 (7.76; 12.2) | 3180 (2686; 3766) |
| Anti-polio type 3 (1/dil) | 7.60 (6.04; 9.56) | 1607 (1357; 1903) | 6.42 (5.20; 7.92) | 1920 (1578; 2335) |
| Anti-tetanus (IU/mL) | 0.136 (0.096; 0.192) | 5.66 (5.13; 6.23) | 0.101 (0.071; 0.146) | 6.41 (5.63; 7.29) |
| Anti-diphtheria (IU/mL) | 0.005 (0.004; 0.006) | 2.37 (1.97; 2.85) | 0.005 (0.004; 0.006) | 1.59 (1.32; 1.90) |
| Anti-HBs (IU/mL) | 16.6 (10.5; 26.1) | 633 (405; 989) | 17.3 (11.0; 27.2) | 611 (373; 1002) |
Figure 1.
Reverse Cumulative Distribution Curves (RCDC) of anti-pertussis antibody GMCs (EU/mL) following three doses of DTaP–IPV–PRP–T or DTaP–IPV+PRP–T at 2, 4, and 6 months of age.
Figure 2.
Reverse Cumulative Distribution Curves (RCDC) of anti-poliovirus types 1, 2, and 3, antibody GMTs (dil:U) after three doses of DTaP–IPV–PRP–T or DTaP–IPV+PRP–T at 2, 4, and 6 months of age.
Safety and reactogenicity
All study vaccines were safe and well tolerated. Both acellular pertussis-based combined vaccines elicited similar low rates of solicited local and systemic reactions, the large majority of which were transient and mild to moderate. The inclusion of PRP∼T in the combination vaccine did not increase reactogenicity compared with the PRP∼T vaccine given concomitantly (Table 3).
Table 3. Incidence of solicited local or vaccine-related local and systemic adverse reactions within the eight days following injection (regardless of dose)a
| Type of reactionb | DTaP–IPV–PRP∼T | DTaP–IPV+PRP∼T | ||
|---|---|---|---|---|
| n=300 | n=300 | |||
| % | % | % | ||
| Any local | Any | 18.7 | 20.3 | 12 |
| Severe | 0.7 | 1 | 0.3 | |
| Redness | Any | 14.7 | 15 | 9 |
| Severe | 0.3 | 0.3 | 0 | |
| Swelling | Any | 10.7 | 11.7 | 5.3 |
| Severe | 0 | 0.3 | 0 | |
| Pain | Any | 6.7 | 8.3 | 5 |
| Severe | 0.3 | 0.3 | 0.3 | |
| Any systemic | Any | 39.0 | 44.0 | |
| Severe | 6 | 8.3 | ||
| Feverc | Any | 7.0 | 10.3 | |
| Severe | 0 | 0 | ||
| Drowsiness | Any | 12.3 | 17.0 | |
| Severe | 4 | 5.0 | ||
| Fussiness | Any | 14.3 | 16.3 | |
| Severe | 0.3 | 2.7 | ||
| Unusual crying | Any | 18.7 | 15.0 | |
| Severe | 0.3 | 3.0 | ||
| Loss of appetite | Any | 23.3 | 22.0 | |
| Severe | 0.3 | 0 | ||
| Vomiting | Any | 6.3 | 7.7 | |
| Severe | 0.3 | 0 | ||
| Diarrhea | Any | 6.7 | 8.7 | |
| Severe | 1.0 | 0.7 | ||
aVaccine administered at 2, 4, and 6 months of age. All subjects received hepatitis B vaccination at 0, 1, and 6 months of age. |
bHaving a possible, probable, or definite relationship to the vaccination (regardless of intensity). |
cFever |
Serious adverse events
A total of 27 serious adverse events (SAEs) were reported in 21 subjects (13 from the combined vaccine group and eight from the group given concomitant vaccinations). They were all considered by the investigator to be unrelated to vaccination and they all resolved. Most of the SAEs were common events or diagnoses observed in infancy, for example, viral infection, urinary tract infection, bronchiolitis, or gastroenteritis. No cases of hypotonic hyporesponsive episodes or seizures were reported within one month after vaccination. No withdrawals occurred because of SAEs.
Solicited local and systemic reactions
No immediate local or systemic adverse events occurred within 30minutes after vaccination. All study vaccines were associated with a low incidence of solicited local and systemic adverse reactions (Table 3). Most of the symptoms occurred within the 72hours after vaccination and were mild or moderate, and transient in nature. Redness was the most frequent local reaction, observed after 14.7% of doses given in the DTaP–IPV–PRP∼T group, and 15% and 9% of injections in the group given DTaP–IPV plus PRP∼T. Loss of appetite was the most frequent systemic reaction, observed following 23.3% and 22% of DTaP–IPV–PRP∼T and DTaP–IPV plus lyophilized PRP∼T doses, respectively. In only one case was loss of appetite reported as severe. The incidence of fever was low, between 7% and 10.3% with no occurrences of severe fever. The rates of severe solicited local and systemic reactions were very low in both study groups.
Unsolicited reactions
Of all doses administered to the 200 study subjects, three were considered by the investigator to be associated with an unsolicited systemic reaction occurring within 30 days of vaccination. In the DTaP–IPV plus PRP∼T group, one subject had transient gastroenteritis four days after dose three. The gastroenteritis was preceded by one episode of diarrhea that occurred the day after the same dose (recorded as a solicited symptom related to vaccination). One subject given DTaP–IPV–PRP∼T had decreased activity of the left leg, which had received the injection, that resolved within two days. A second infant in the same group had fussiness and irritability beginning four days after the second dose and lasting one day. This was preceded by another episode of fussiness and irritability occurring a day after the same dose, which was recorded as a solicited reaction.
Discussion
The current study was conducted to compare the immunogenicity and safety of the fully liquid DTaP–IPV–PRP∼T vaccine with that of DTaP–IPV plus PRP∼T vaccine given concomitantly at separate sites as a three-dose primary vaccination in healthy Taiwanese infants. A previous investigation in Canadian children confirmed the high immunogenicity of the DTaP–IPV plus PRP∼T vaccines given concomitantly and which were the control vaccines used in this study.6 All infants enrolled in this study also received hepatitis B vaccination at 0, 1, and 6 months of age according to the national vaccination schedule of Taiwan.
Recent studies with other acellular pertussis combination vaccines containing a conjugated Hib antigen have shown significant reductions in the anti-PRP GMCs when the Hib vaccine is combined with the other valences in a single injection.8, 9, 10 In this study, all infants showed high immune responses to all vaccine antigens, with no clinically significant differences in immune response between the DTaP–IPV–PRP∼T study and control vaccines for any of the antigens evaluated. All subjects developed an anti-PRP antibody concentration of at least 0.15μg/mL, which has been established to provide immediate protection against Hib infection, and 97–99% of subjects developed a level of at least 1.0μg/mL, which is considered to indicate long-term protection based on the rate of decline of antibody titers.11, 12 The antibody responses to the other vaccine antigens in both study groups, based on the antibody GMTs and 95% CIs, also show no evidence of interference when the PRP∼T vaccine was included in the fully liquid combination compared with concomitant administration. The convenience of the single injection with DTaP–IPV–PRP∼T is therefore not associated with a lower PRP∼T seroprotective response.
Both the fully liquid vaccine and concomitant vaccination elicited high immunogenicity for each antigenic component. All subjects had antibody concentrations that were above levels considered to be protective against diphtheria and tetanus. All subjects also achieved seroprotective titers for neutralizing antibody to all three poliovirus types with DTaP–IPV–PRP∼T (IPV produced on Vero cell cultures) and with DTaP–IPV (IPV produced on MRC5 cell cultures). Thus, although the IPVs were produced on different cell lines, there were no differences between the two vaccines in the immune responses evaluated.
Although there are no established serological markers of protection against pertussis, the high antibody responses against the five acellular pertussis components, PT, FHA, PRN, and FIM2&3, were comparable with those observed to elicit a protective efficacy of 85% in a Swedish field trial in which the same acellular pertussis components were used, and similar to those observed in a previous study of the DTaP–IPV control vaccine.4, 5 The seroprotection rates against hepatitis B were also high in both groups. Thus, the concomitant administration of these acellular pertussis-based combinations plus PRP∼T vaccine did not affect the immunogenicity of hepatitis B vaccine given according to the Taiwan national schedule at 0, 1, and 6 months of age.
Both acellular pertussis-based combined vaccines elicited similar low rates of solicited local and systemic reactions, the large majority of which were transient and mild to moderate. There were no study withdrawals because of adverse events and no hypotonic hyporesponsive episodes or seizures associated with the vaccinations. The low reactogenicity observed in both study groups shows that inclusion of PRP∼T in the combination vaccine does not increase reactogenicity compared with the PRP∼T vaccine given concomitantly, and reinforces the excellent safety profiles expected of acellular pertussis vaccines.3
The immunogenicity and safety results observed in this clinical study are similar to previous data generated in Taiwan using the same five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) combined, or given concomitantly with PRP∼T vaccine.13 In that study, anti-PRP GMC values were 11.8mg/mL in the combined group compared with 13.0mg/mL in the concomitant group. The data from that study also clearly show that these DTaP and PRP∼T vaccines can be combined without clinically significant interaction. A similar vaccine containing the same five acellular pertussis antigens and PRP∼T, plus IPV produced on MRC5 cell culture, given as a single injection (Pentacel™) has been in routine use in Canada since 1997. National surveillance in Canada between 2001 and 2003 has confirmed the effectiveness of that vaccine against pertussis and invasive Hib disease as well as improved safety compared to the whole cell pertussis combination vaccine that it replaced.14, 15 Concomitant administration of hepatitis B vaccine with the two acellular pertussis-based vaccines in this study was carried out with satisfactory safety and immunogenicity, demonstrating the compatibility of these two vaccines.
Conclusion
This study shows that DTaP–IPV–Hib provides protection against five diseases in a single, convenient, premixed formulation without compromising safety or tolerability, or the immunogenicity of the individual component antigens. The fully liquid pentavalent vaccine has been shown to be similarly highly immunogenic and as well tolerated as DTaP–IPV plus Hib vaccine; however, in contrast with the latter regimen, no reconstitution is required, and it can be administered as a single injection. The response to Hib PRP antigen as measured by the proportion of subjects with anti-PRP levels ≥1.0μg/mL was not reduced in DTaP–IPV–Hib compared with the DTaP–IPV plus Hib vaccine combination, so the convenience of the single injection with DTaP–IPV–Hib is not at the expense of lessened protection against Hib disease.
Acknowledgements
The authors wish to acknowledge the assistance of Tanja Shen, Sanofi Pasteur Taiwan for study monitoring, and Christèle Deroche, Sanofi Pasteur France for analysis of study data.
Conflict of interest: Esteban Ortiz and Pascale Chavand are employees of Sanofi Pasteur, Lyon, France, which provided support for the conduct of this study.
References
- . Pertussis vaccine. In: Plotkin SA, Orenstein WA editor. Vaccines. 4th ed.. Philadelphia, Pa: Saunders; 2004;p. 471–528
- Comparison of 13 acellular pertussis vaccines: overview and serologic response. Pediatrics. 1995;96:548–557
- Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics. 1995;96:557–566
- . A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med. 1996;334:349–355
- . Randomised controlled trial of two-component, three component, and five component acellular pertussis vaccines compared with whole-cell pertussis vaccine. Lancet. 1997;350:1569–1577
- Safety and immunogenicity of a combined five-component pertussis–diphtheria–tetanus–inactivated poliomyelitis–Haemophilus B conjugate vaccine administered to infants at two, four and six months of age. Vaccine. 1998;16:576–585
- . A quantitative immunochemical measure of the primary interaction between I125 BSA and antibody. J Infect Dis. 1958;103:239–269
- . Randomized trial of the effect of co–administration with acellular pertussis DTP vaccine on immunogenicity of Haemophilus influenzae type b conjugate vaccine. Lancet. 1996;348:1688–1692
- . Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria–tetanus–pertussis containing acellular pertussis. Lancet. 1999;354:2063–2068
- Vaccine antigen interactions after a combination diphtheria–tetanus toxoid–acellular pertussis/purified capsular polysaccharide of Haemophilus influenzae type b–tetanus toxoid vaccine in two-, four- and six-month infants. Pediatr Infect Dis J. 1997;16:863–870
- . The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1983;147:1100
- . The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1984;149:1034–1035
- An evaluation of the safety and immunogenicity of a five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) when combined with a Haemophilus influenzae type b–tetanus toxoid conjugate vaccine (PRP–T) in Taiwanese infants. Pediatrics. 1999;103:25–30
- . Invasive Haemophilus influenzae type b infections in vaccinated and unvaccinated children in Canada. CMAJ. 2005;172:53–56
- . Decrease in hospital admissions for febrile seizures and reports of hypotonic–hyporesponsive episodes presenting to hospital emergency departments since switching to acellular pertussis vaccine in Canada: a report from IMPACT. Pediatrics. 2003;112:348–353
☆ Presented at the 11th International Congress on Infectious Diseases, Cancun, Mexico, March 5–7, 2004 as “Immunogenicity and safety of a fully liquid DTaP–IPV–Hib vaccine given as a three-dose primary vaccination in Taiwanese infants”.
PII: S1201-9712(06)00057-9
doi:10.1016/j.ijid.2005.10.014
© 2006 International Society for Infectious Diseases. Published by Elsevier Inc. All rights reserved.
Volume 11, Issue 2 , Pages 129-136, March 2007
