PEDIATRICS Vol. 123 No. 1 January 2009, pp. 301-312 (doi:10.1542/peds.2007-3317)
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ARTICLE |
Safety and Immunogenicity of a Pentavalent Vaccine Compared With Separate Administration of Licensed Equivalent Vaccines in US Infants and Toddlers and Persistence of Antibodies Before a Preschool Booster Dose: A Randomized, Clinical Trial
a Department of Public Health, San Antonio Metropolitan Health District, San Antonio, Texas
b Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
c Primary Physicians Research, Pittsburgh, Pennsylvania
d Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
e Sanofi Pasteur Inc, Swiftwater, Pennsylvania
f Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
g Elmwood Pediatrics, Rochester, New York
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ABSTRACT |
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OBJECTIVE. Our goal was to compare the safety and immunogenicity of a combination vaccine (DTaP5-IPV-Hib; Pentacel) with that of its separately administered, US-licensed equivalent vaccines (diphtheria, tetanus, 5-component acellular pertussis vaccine [DTaP5; Daptacel], inactivated poliovirus vaccine [IPV; IPOL], and Haemophilus influenzae type b [Hib] vaccine [ActHIB]), when administered to infants and toddlers concomitantly with other routinely recommended vaccines and to assess antibody persistence from the fourth dose in toddlers to the fifth (preschool) DTaP5 dose.
SUBJECTS AND METHODS. In this randomized, multicenter study, 1939 healthy infants were immunized at 2, 4, and 6 months of age with 1 of 3 lots of DTaP5 coadministered with IPV and Hib vaccines or 1 lot of DTaP5-IPV-Hib combination vaccine. Subsequently, 849 of these study participants were given a fourth dose of DTaP5 and Hib vaccines or a fourth dose of DTaP5-IPV-Hib at 1 to 16 months of age. Safety was monitored throughout the study, and blood specimens were obtained to assess antibody responses.
RESULTS. DTaP5-IPV-Hib elicited similar or fewer solicited injection-site and systemic reactions as compared with the separate administration of US-licensed DTaP5, IPV, and Hib vaccines. Seroresponse and seroprotection rates elicited by DTaP5-IPV-Hib were noninferior to US-licensed equivalent vaccines after the infant series and after the fourth dose. Children immunized with DTaP5-IPV-Hib had higher antibody geometric mean concentrations to pertussis toxoid and filamentous hemagglutinin; children immunized with the separate vaccines had higher responses to pertactin. Hib antibody responses to Hib polysaccharide were nearly identical in the DTaP5-IPV-Hib and separate-vaccine groups. Persistence of antibodies to the fifth (preschool) dose was also similar between groups.
CONCLUSIONS. DTaP5-IPV-Hib combination vaccine was shown to be immunogenic and well tolerated. No clinically important differences in the safety or immunologic profiles were noted for DTaP5-IPV-Hib versus the separately administered, US-licensed equivalent vaccines. DTaP5-IPV-Hib is a suitable replacement for separately administered DTaP, IPV, and Hib vaccines.
Key Words: diphtheria-tetanus-acellular pertussis vaccines • Haemophilus influenzae vaccines • poliovirus vaccine inactivated • vaccines combined
Abbreviations: DTaP5—diphtheria-tetanus-5-component acellular pertussis vaccine • IPV—inactivated poliovirus vaccine • Hib—Haemophilus influenzae type b • DTaP5-IPV-Hib—diphtheria-tetanus-5-component acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b vaccine combined • PCV7—pneumococcal conjugate vaccine • HepB—hepatitis B vaccine • GMC—geometric mean concentration • PRP—polyribosylribitol phosphate • PRP-T—polyribosylribitol phosphate capsular polysaccharide of Hib conjugated to tetanus toxoid • PT—pertussis toxoid • FHA—filamentous hemagglutinin • FIM—fimbriae types 2 and 3 • SAE—serious adverse event • LOQ—limit of quantitation • HHE—hyposreponsive episode
The recommended childhood immunization schedule in the United States has grown increasingly complex, calling for as many as 23 separate injections in the first 18 months of life, with up to 5 injections possible at a single visit.1 The American Academy of Pediatrics, the American Academy of Family Physicians, and the Advisory Committee on Immunization Practices all recommend the use of combination vaccines to minimize the number of injections and to increase compliance with the immunization schedule.2 The use of combination vaccines is preferred over separate injection of their equivalent component vaccines.3 However, a combination vaccine formulation may have an unacceptable safety profile or provide reduced protection against disease as compared with administration of the separate licensed vaccines.4 Consequently, the US Food and Drug Administration recommends that clinical studies compare the safety and immunogenicity of combination vaccines with the separate but simultaneously administered individual vaccines they are designed to replace.5
Despite record levels of overall vaccination coverage in the United States, a recent study by the Centers for Disease Control and Prevention found that only 17% of 24- to 35-month-old children were vaccinated with 6 recommended vaccines on time, and 37% experienced a delay of >6 months for at least 1 vaccine.6 Delays and omissions in childhood vaccination pose risks, especially with diseases such as pertussis, whose reported incidence has risen among infants and children under 5 years of age.6–9 Among children diagnosed with pertussis in 2005–2006 with available vaccination histories, 
54% of 6- to 11-month-olds and 20% of 1- to 4-year-olds had not yet received 3 doses of pertussis vaccine (Pamela Srivastava, MS, Centers for Disease Control and Prevention, Pertussis Surveillance Report [final data] 2005, written communication, 2006; and Pamela Srivastava, MS, Centers for Disease Control and Prevention, Pertussis Surveillance Report [final data] 2006, written communication, 2008) These cases were potentially preventable with on-time vaccinations. Combination vaccines have been shown to improve coverage rates and timeliness of vaccinations compared with separately administered vaccines.10–12
DTaP5-IPV-Hib is a combination vaccine incorporating diphtheria-tetanus-5-component acellular pertussis (DTaP5), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) vaccines (Pentacel; Sanofi Pasteur Limited, Toronto, Ontario, Canada).13–17 This combination vaccine was licensed in Canada in 1997 and has been routinely given to Canadian children at 2, 4, 6, and 18 months of age.
The objective of this study was to compare the safety and immunogenicity of DTaP5-IPV-Hib combination vaccine with separately administered US-licensed equivalent vaccines.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSTRIAL INFORMATIONREFERENCES |
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Study Design
The study was conducted at 31 centers in the United States from May 2001 through January 2004 and was approved by the institutional review boards of each center. Parents or legal guardians of all subjects provided written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Infant Series
Healthy infants were eligible if they were 2 months (
42 to 
84 days) of age, were at least 37 weeks' gestation at delivery, and had received a single dose of monovalent hepatitis B vaccine (HepB) at least 28 days before the first dose of study vaccine. At the time of enrollment, subjects were evenly randomized among groups in a balanced block format by using a computer-generated allocation schedule generated by the sponsor.
The infant-series portion of the study was designed to evaluate the consistency of manufacturing based on immunogenicity outcomes from 3 lots of DTaP5 (Daptacel; Sanofi Pasteur Ltd., Toronto, Ontario, Canada) and to compare the safety and immunogenicity of DTaP5-IPV-Hib (Pentacel) with those of the separately administered, licensed-equivalent vaccines DTaP5, IPV, (IPOL; Sanofi Pasteur SA, Lyon, France), and Hib (ActHIB; Sanofi Pasteur SA, Lyon, France). A total of 1939 infants previously given 1 dose of HepB were enrolled and assigned randomly to 1 of 4 groups: 3 consistency lots of DTaP5 administered along with IPV and Hib vaccines (herein identified as DTaP5, IPV, and Hib group or control group), or 1 lot of DTaP5-IPV-Hib at 2, 4, and 6 months of age (herein identified as DTaP5-IPV-Hib group). All infants also received pneumococcal conjugate vaccine (PCV7 [Prevnar; Wyeth Pharmaceuticals, Philadelphia, PA]) at 2, 4, and 6 months of age and hepatitis B vaccine (HepB [Recombivax HB; Merck and Co, Inc, Whitehouse Station, NJ]) at 2 and 6 months of age. Blood samples were collected before dose 1 and 1 month after dose 3. Because the safety and immunogenicity profiles for the 3 DTaP5 lots were found to fulfill the preestablished statistical criteria of equivalency based on fever incidence, seroresponse rates (90% confidence intervals [CIs] of the difference <10%) and geometric mean concentration (GMC) ratios (90% CI of the GMC ratio <1.5; to be reported elsewhere), those results were pooled for the purposes of this report.
Toddler Fourth Dose
For the fourth dose, 1249 toddlers who received 3 doses of separately administered DTaP5 and coadministered vaccines in the infant series were allocated, based on their randomized assignment at the time of infant enrollment, to receive a single lot of DTaP5 according to 1 of 3 schedules. Of the 3 groups, group 1 was prospectively identified as the group to be compared with the Pentacel group (group 4). Group 1 subjects received MMR, varicella, and PCV7 vaccines at 12 months of age and DTaP5 and Hib vaccines at 15 months of age (418 subjects). They did not receive IPV vaccine at 15 months of age as they had already received a complete primary series (3 doses) according to vaccination recommendations in the US. In group 4, 431 toddlers who received 3 doses of DTaP5-IPV-Hib and co-administered vaccines in the infant series received MMR, varicella, and PCV7 vaccines at 12 months of age and DTaP5-IPV-Hib at 15 months of age. Blood samples were collected immediately before vaccination at 15–16 months of age and 1 month after vaccination.
Results from groups 2 and 3, designed to compare various other separate-vaccine schedules, will be reported elsewhere. Subjects in group 2 received DTaP5, Hib, measles-mumps-rubella, varicella, and PCV7 vaccines at 15 months of age (420 subjects), and subjects in group 3 received Hib, MMR, varicella, and PCV7 vaccines at 15 months of age and DTaP5 at 16 months of age (411 subjects).
Immunogenicity Follow-up to Preschool Age
To assess the persistence of antibody up to the time of the next recommended boosting dose at 4 to 6 years of age, 162 preschoolers who received 4 doses of DTaP5-IPV-Hib (toddler group 4) and 487 preschoolers who received 4 doses of DTaP5 (toddler groups 1–3) had antibody titers measured just before their fifth dose of DTaP5 (toddler groups 1–3 were combined for this analysis because the 3 groups all fulfilled the predefined noninferiority criteria 1 month after Dose 4 and had overlapping 95% CIs at pre-Dose 5). These subjects represent a follow-up of at least 33 months after the fourth dose of DTaP5-IPV-Hib or its licensed equivalent vaccines.
Study Vaccines
The composition of each vaccine is shown in Table 1. DTaP5-IPV-Hib is a pentavalent vaccine containing a combination of diphtheria and tetanus toxoids and acellular pertussis antigens adsorbed (DTaP5), inactivated polioviruses types 1, 2, and 3 (IPV), and polyribosylribitol phosphate (PRP) capsular polysaccharide of Hib conjugated to tetanus toxoid (PRP-T). The 5 acellular pertussis antigens in the vaccine are pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin, and fimbriae types 2 and 3 (FIM). Pentacel and Daptacel contain the same diphtheria, tetanus, and pertussis components; Pentacel contains more PT and FHA than Daptacel and the same quantities of pertactin, FIM, and diphtheria and tetanus toxoids. The quantities of the 3 polio serotypes and Hib antigens in Pentacel are the same as in IPOL and ActHIB, respectively.
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Laboratory Methods
All assays were conducted at Sanofi Pasteur by technicians who were blinded to group assignment. Antibodies to tetanus were determined by using an indirect enzyme-linked immunosorbent assay (ELISA) (WHO International Standard lot TE3), and diphtheria antibody titers were determined by the ability of the subject's sera to protect Vero cells from diphtheria toxin challenge (WHO International Standard lots DI-00, DI-01, and DI-03). Antibodies to PT, FHA, pertactin, and FIM were determined by ELISA, and results were expressed in ELISA units (EU)/mL (internal reference standards calibrated to Center for Biologics Evaluation and Research (CBER) reference standard lots 3 and 4). Poliovirus antibody titers were determined by using a serum Vero cell neutralization assay, expressed as the reciprocal titration achieving neutralization (CBER standard lot IIA-4). Antibodies to PRP were determined by using a Farr-type radioimmunoassay and expressed in µg/mL (CBER reference standard lot 1983).
Safety and Reactogenicity Measures
Safety assessments were conducted by parents and study personnel who were blinded to the 3 DTaP5 lots; safety comparisons between the separate vaccine and DTaP5-IPV-Hib groups were unblinded. Study personnel monitored subjects for 30 minutes after each vaccination to detect immediate reactions. Parents or legally authorized representatives were given diary cards and were asked to record the occurrence and intensity (mild, moderate, or severe) of injection-site (ie, redness, swelling, pain; and limb circumference [fourth dose only]), and systemic (eg, fever [38°C], fussiness, crying) reactions from day 0 (evening of immunization) through 7 days after each vaccination.
Parents of participants were contacted by telephone 2–3, 8, and 30 days after each study vaccination, and 60 days after the third and fourth vaccine doses to ensure completeness of reporting and to screen for adverse events (AEs) requiring medical contact (telephone call or office visit), an emergency department visit, or hospitalization. Serious adverse events (SAEs) were recorded throughout the study and rated by investigators for possible relationship to the study vaccines.
For the infant series, the safety data were pooled among children given the 3 DTaP5 consistency lots. For the injection-site reactions among control children, data were pooled from the 3 injection sites, DTaP5, IPV, and Hib for the infant series and 2 injection sites (DTaP5 and Hib) for the fourth dose. Each subject was counted only once, regardless of the number of control injection sites affected. For subjects in both groups, the highest severity of injection-site and systemic reactions was recorded.
Statistical Analysis
The total sample size for this study was 2000 subjects. An attrition rate of 15% during the infant series and an additional 15% for the toddler dose was considered for all statistical power calculations. These sample sizes (360 evaluable subjects per group) provided an overall power of 85% to compare antibody responses to all of the vaccine antigens among study participants for both the infant series and toddler dose. The statistical significance of differences between study groups in demographic characteristics was assessed by a 
2 test. The primary immunogenicity outcomes were compared after the third and fourth dose based on noninferiority criteria. Noninferiority was demonstrated if the upper limit of the 90% CI of the difference in seroresponse rates (DTaP5 + IPV + Hib group – DTaP5-IPV-Hib group) was <10% and if the upper limit of the 2-sided 90% CI of the GMC ratio (DTaP5 + IPV + Hib group/DTaP5-IPV-Hib group) was <.5. No formal statistical comparisons were planned for the immunogenicity data obtained before the booster dose in preschool children. Descriptive observations were made based on the 95% CIs of the GMCs.
All safety analyses were based on the intent-to-treat safety population, defined as all subjects who received at least 1 dose of study vaccine(s). The percentages of participants in each group with immediate, local, or systemic reactions and subjects with AEs or SAEs were tabulated. For descriptive statistical purposes, the proportion of participants in each group experiencing solicited reactions was calculated with exact 95% CIs and compared by Fisher's exact test; P < .05 was considered statistically significant.
The primary immunogenicity analyses were performed on the per-protocol population, defined as subjects who received the full infant series and fourth dose of the appropriately assigned study vaccine(s), had all blood specimens obtained within the time intervals specified in the protocol, and had a valid postvaccination serology test result for at least 1 study vaccine antigen.
Antibody levels at or above the following prespecified thresholds were considered seroprotective: diphtheria and tetanus, 0.01 and 0.1 IU/mL (minimum and standard thresholds, postdose 3) and 0.1 and 1.0 IU/mL (standard and long-term thresholds, postdose 4); polio, 1:8 (1/diluent); and Hib PRP, 0.15 and 1.0 (minimum and long-term protection thresholds).18 For pertussis, for which there are no prespecified serologic threshold levels, vaccine response rates after 3 and 4 doses were defined as postvaccination antibody concentrations 4 times the assay limit of quantitation (LOQ) for the given antigen and greater than the prevaccination concentrations. The assay LOQs for pertussis antigens were PT, 5 EU/mL; FHA, 3 EU/mL; pertactin, 3 EU/mL; and FIM, 17 EU/mL.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSTRIAL INFORMATIONREFERENCES |
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Study Population
A total of 1939 healthy infants were enrolled for the infant series and given at least 1 dose of study vaccine, and 1680 children were enrolled for the fourth dose (849 of whom were enrolled into toddler groups 1 and 4). For the infant series, the safety and immunogenicity populations for the separate-vaccine control group were 1454 and 1167, respectively, and the safety and immunogenicity populations for the subjects in the DTaP5-IPV-Hib group were 485 and 374, respectively. For the fourth dose, the safety and immunogenicity populations for the subjects in the control group (toddler group 1) were 418 and 349, respectively, and the safety and immunogenicity populations for the subjects in the DTaP5-IPV-Hib group (toddler group 4) were 431 and 371, respectively. The study groups were not significantly different (P > .05) with respect to ethnicity, gender, and age (Table 2).
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For the infant series, 1 DTaP5-IPV-Hib recipient and 5 separate-vaccine recipients were withdrawn from the study because of AEs. One DTaP5-IPV-Hib recipient died because of accidental asphyxiation 8 days after the fourth dose. None of these events were considered related to the study vaccines by the investigators, except for a case of nonfebrile seizure after the first dose of control vaccines.
Safety Assessment
Immediate Reactions
No anaphylactic or other severe reactions were reported to occur within 30 minutes after any dose of study vaccine.
Injection-Site and Systemic Adverse Reactions
Figs 1 and 2 show the proportions of subjects in the DTaP5-IPV-Hib and control groups who reported solicited injection-site and systemic adverse reactions within 3 days after each of the 4 doses. The most frequently reported solicited local reaction in both groups was injection-site tenderness (Fig 1). The majority of injection-site reactions in both groups were mild and persisted for <3 days. After the fourth dose, the incidence of increased limb circumference among children in the DTaP5-IPV-Hib and in the separate-vaccine groups was similar (33.6% and 37.5%). Only 2 DTaP5-IPV-Hib recipients and 4 separate-vaccine recipients reported a severe increase in limb circumference. Overall, compared with the control vaccines, DTaP5-IPV-Hib exhibited a significant (P < .05) lower rate for redness and tenderness at dose 1 and redness at dose 3. No injection-site reactions were significantly lower in the control group at any dose.
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The most common solicited systemic reactions were crying and fussiness (Fig 2). Most of the fever reactions were mild or moderate in intensity and short in duration. Severe fever (>39.5°C) was reported by 0.3% of DTaP5-IPV-Hib recipients and 0.8% of control vaccine recipients after dose 4. Subjects given DTaP5-IPV-Hib exhibited significantly lower rates of fever after doses 1 and 2 (each P < .05) compared with control vaccines. No systemic reactions were significantly lower in the control group at any dose. No hospitalizations because of fever were reported for subjects in either group.
Seizures and Neurologic Events
No cases of hypotonia or hypotonic hyporesponsive episodes (HHEs) were reported in the DTaP5-IPV-Hib group during the infant series. One case of hypotonia (4 days after the first dose) and 1 case of HHE (16 days after the second dose) were reported in the control group.
No seizures were reported within 60 days after any dose of DTaP5-IPV-Hib. Two infants were reported with nonfebrile seizures within 60 days after vaccination in the control group, 12 hours after the administration of dose 1 (with apnea), and 22 days after dose 1. In addition, 2 children were reported with febrile seizures within 60 days after a dose of control vaccines (30 days postdose 3 and 49 days postdose 4).
Serious Adverse Events
From the time of the first dose to 60 days after the third dose, 75 (5.2%) subjects in the control group and 25 (5.2%) subjects in the DTaP5-IPV-Hib group experienced SAEs. All SAEs were assessed as unrelated to vaccination except for the nonfebrile seizure described earlier. After the fourth dose, 16 subjects experienced SAEs within 60 days of control or DTaP5-IPV-Hib vaccines. None of these SAEs were considered related to study vaccines.
Immunogenicity Assessment
Seroprotection and vaccine response rates for each antigen in the study vaccines are summarized in Table 3, and GMCs are listed in Table 4. In general, seroprotective antibody levels postdose 3, predose and postdose 4, and predose 5 were similar among the DTaP5-IPV-Hib and separate-vaccine groups.
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Diphtheria and Tetanus
After completion of the infant series, nearly all subjects in both the DTaP5-IPV-Hib and control groups achieved protective concentrations of antibodies (
0.1 IU/mL) against diphtheria (98.5% to 98.8%, respectively) and tetanus (99.7% to 100%, respectively) toxoids. After the fourth dose, 100% of subjects achieved tetanus and diphtheria antibody concentrations 0.1 IU/mL. The comparison of postdose 3 and postdose 4 GMCs also fulfilled the predefined noninferiority criteria, except for postdose 4 antitetanus GMCs (upper bound 95% CI of the ratio: 1.74). Immediately before the fifth dose, >98% of subjects in both groups had antibody concentrations to diphtheria and tetanus toxoids 0.01 IU/mL (Table 3).
Pertussis
As shown in Table 3, DTaP5-IPV-Hib recipients achieved vaccine response rates to all pertussis antigens that were noninferior to those of the licensed-equivalent component DTaP5. Furthermore, DTaP5-IPV-Hib elicited significantly higher vaccine response rates after the infant series than did DTaP5 for PT (P = .0108) and FHA (P < .0001). After the fourth dose, the pertussis response rates achieved with DTaP5-IPV-Hib were also noninferior to those of DTaP5. GMCs (Table 4) in the DTaP5-IPV-Hib group were noninferior to those of the control group after the infant series for all pertussis antigens. Individually, DTaP5-IPV-Hib GMCs were higher for PT (P < .0001) and FHA (P < .0001), slightly lower for pertactin (P = .005), and nearly identical for FIM. After the fourth dose, the GMCs in the DTaP5-IPV-Hib group were noninferior for PT, FHA, and FIM but inferior for pertactin (Table 4). Individually, GMCs were significantly higher in subjects in the DTaP5-IPV-Hib group than in the control group for FHA (P < .0001), lower for pertactin (P < .0001), and comparable (P .05) for PT and FIM. Immediately before receiving the preschool DTaP booster dose, the anti-pertussis GMCs for the 2 groups had overlapping 95%CIs for all pertussis antigens except for the anti-pertactin GMC, which was slightly lower in subjects in the DTaP5-IPV-Hib group than in the control group (9.16 EU/mL and 15.62 EU/mL, respectively).
Polio
Nearly all subjects (99.4%–100%) in both groups achieved seroprotective antibody titers (8 [1/diluent]) against each of the 3 poliovirus serotypes after the infant vaccine series. After the fourth dose of DTaP5-IPV-Hib, 100% of subjects achieved seroprotective titers.
Hib
Seroprotection rates and anti-PRP GMCs elicited by DTaP5-IPV-Hib were noninferior to those elicited by the separately administered control Hib vaccine after the 3-dose primary series and after the booster dose. Similar proportions of DTaP5-IPV-Hib and control vaccine recipients achieved seroprotective antibody concentrations after the infant series (92%–93% 0.15 µg/mL) and after the fourth dose (96%–98% 1.0 µg/mL). Anti-PRP GMCs were also comparable between the groups after the infant series and fourth dose, with a robust anti-PRP response observed after the fourth dose in both groups. Antibody to PRP persisted well to 4 years of age, with >90% of subjects having levels 0.15 µg/mL just before administration of the preschool DTaP and IPV vaccines (Table 3).
Hepatitis B and Pneumococcal Conjugate
The postdose 3 antibody responses to HepB and pneumococcal conjugate vaccines in the DTaP5-IPV-Hib group were noninferior those of the control vaccines group (Tables 5 and 6).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSTRIAL INFORMATIONREFERENCES |
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The present study was conducted to generate data to support licensure of DTaP5-IPV-Hib vaccine in the United States. All of the study vaccines were well tolerated during the infant series and fourth dose, and no unusual events or patterns were observed through the 60-day and 180-day postvaccination safety follow-up periods. The incidence of clinically SAEs remained low in both groups.
During the infant series and fourth dose, DTaP5-IPV-Hib elicited similar or fewer solicited injection-site and systemic reactions when compared with separate administration of US-licensed DTaP5, IPV, and Hib vaccines. Fewer than 1% of reactions were reported as severe after any dose in either group. Fever of any severity was reported at lower (P < .05) rates among DTaP5-IPV-Hib vaccine recipients after dose 1, dose 2, and the overall infant series (not shown). Fever with the first dose is of particular importance, because fever in young infants is often considered as possibly representing sepsis and thus may lead to medical and laboratory evaluations, including a visit to the physician's office or emergency department and diagnostic testing for possible systemic infection.
In general, DTaP5-IPV-Hib recipients achieved higher antibody responses (vaccine response rates and GMCs) to PT and FHA, lower responses to pertactin, and similar responses to FIM compared with the separate vaccine group. It is unlikely that any of the differences in GMCs are of clinical significance, given the high postdose 3 and postdose 4 seroresponse rates observed in both groups. However, assessing clinical relevance of GMC variations in multi-component acellular pertussis vaccines is difficult. The stand-alone DTaP5 vaccine demonstrated an efficacy of 85.2% (95% CI: 80.6%–88.8%) against World Health Organization-defined pertussis (21 consecutive days of paroxysmal cough because of pertussis) in the National Institutes of Health-sponsored prospective, double-blind, placebo-controlled efficacy trial in Sweden.19 Kohberger et al20 used an epidemiologic and mathematical model established by Storsaeter and colleagues21 to demonstrate that a similar efficacy would be expected for DTaP5-IPV-Hib. The statistical model showed predicted efficacies of 83% (95% CI: 65–96) and 82% (95% CI: 64–96) for the DTaP5 and DTaP5-IPV-Hib vaccines, respectively, after Dose 3 and 84% (95% CI: 66–96) and 83% (95% CI: 66–96) for the DTaP5 and DTaP5-IPV-Hib vaccines, respectively, after Dose 4.
With respect to other antigens, antibody responses elicited by DTaP5-IPV-Hib were statistically noninferior to those of the separate vaccines after the infant series and fourth dose. The higher GMC to tetanus toxoid in the control group after the fourth dose is not considered clinically significant, because 100% of subjects in both groups achieved titers at or above 0.1 IU/mL, the level considered necessary for long-term seroprotection.
Antibody responses to PRP-T elicited by DTaP5-IPV-Hib also were statistically noninferior to the control group. The postdose 3 data in this report are in concordance with other published studies in which either Pentacel or another DTaP5-Hib formulation elicited anti-PRP responses comparable to separately administered Hib vaccine.22
The children in the current study were followed to age 4 to 5 years, at which time a fifth dose of DTaP vaccine is recommended in the US immunization schedule. Blood drawn from subjects immediately before the fifth dose showed that the 2 groups had comparable persistence of antibodies (as assessed by 95% CIs of GMCs) to all vaccine antigens in the DTaP5-IPV-Hib vaccine, except for pertactin. In particular, continued seroprotection against Hib was evident; titers 0.15 µg/mL persisted in >90% of subjects in each group.
The fact that the Hib antibody levels after separate or combined vaccine were similar postdose 3, postdose 4, and predose 5 is noteworthy, because vaccines that combine conjugate Hib vaccines with DTaP vaccines other than DTaP5 have been reported to produce decreased antibody responses to the PRP component, compared with administration of the equivalent separate vaccines.23–31 Using an animal model, Mawas and colleagues32 found reduced PRP responses when conjugate Hib vaccines were combined with DTaP3 (containing PT, FHA, and pertactin), but not when they were combined with DTaP5 vaccine. Subsequently, Mawas and colleagues33 demonstrated that the adjuvant used with the DTaP3 vaccine, Al(OH)3, played an important role in this interference. In contrast, combination vaccines with DTaP5 are unique in using a different adjuvant (AlPO4), for which Mawas et al33 did not find evidence of interference with Hib responses.
A limitation of the current study is that the open-label nature of the safety evaluations could have introduced bias in the parent's assessment of the reactogenicity variables. However, the similarity of the safety data in this study and in other parent-blinded studies of the DTaP5-IPV-Hib combination vaccine makes this particular bias unlikely.22,24 The study was not powered to detect uncommon events, such as HHEs, and therefore it is not possible to make a meaningful comparison of the study groups for these rare events based solely on the results of this study. However, the current results are reassuring and consistent with safety surveillance data in Canada, where for the past decade, the combination vaccine has been the only DTaP-containing vaccine used among infants and toddlers.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSTRIAL INFORMATIONREFERENCES |
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This study supports the conclusion that the DTaP5-IPV-Hib combination vaccine is a suitable replacement for the separately administered licensed-equivalent DTaP5, IPV, and Hib vaccines based on similar safety profiles, postdose 3 and postdose 4 antibody responses to the vaccine antigens, and persistence of antibody up to the age of the preschool fifth booster. By combining the antigens of 3 separate vaccines into 1 combination vaccine, Pentacel would reduce the total number of injections in the first 18 months of life by 7. Minimizing the number of injections in an increasingly complex schedule of recommended immunizations may help to improve compliance and thus optimize protection against vaccine-preventable diseases.2,12
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TRIAL INFORMATION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSTRIAL INFORMATIONREFERENCES |
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This work was presented in part at the annual meeting of the International Congress on Infectious Diseases, March 5, 2004, Cancun, Mexico; and the annual meeting of the Infectious Diseases Society of America, October 6, 2005, San Francisco, CA.
This trial has been registered at www.clinicaltrials.gov (identifier NCT 00662870).
Trial Centers
(1) Gunderson Clinic, LaCrosse, WI; (2) Pediatric and Adolescent Medicine, Marietta, GA; (3) Primary Physicians Research, Pittsburgh, PA; (4) Radiant Research, Portland, OR; (5) University of Chicago, Department of Pediatric Infectious Disease, Chicago, IL; (6) Norwich Pediatric Group, Norwich, CT; (7) Children's Hospital Medical Center, Cincinnati, OH; (8) Children's Hospital of Pittsburgh, Pittsburgh, PA; (9) San Antonio Metropolitan Health District, San Antonio, TX; (10) Kentucky Pediatric/Adult Research Inc, Bardstown, KY; (11) North Carolina Children's and Adult's Clinical Research Foundation, Chapel Hill, NC; (12) Center for Children and Families, San Antonio, TX; (13) Camcare Health Education/Research Institute, Charleston, WV; (14) ARK-LA-TEX Children's Clinic, Bossier, LA; (15) Utah Valley Pediatrics, Provo, UT; (16) University of Northern Texas, Health Science Center, Fort Worth, TX; (17) Chestnut Grove Pediatrics, Kingsport, TN; (18) Rockwood Clinic, Spokane, WA; (19) Children's Clinic of Jonesboro, Jonesboro, AR; (20) First Allergy and Clinical Research, Englewood, CO; (21) Radiant Research, Austin, TX; (22) Elmwood Pediatrics, Rochester, NY; (23) Pediatric Medical Associates, Norristown, PA; (24) Outpatient Pediatric Center, Orlando, FL; (25) Northwest Arkansas Pediatric Clinic, Fayetteville, AR; (26) Endinger Medical Group, Inc, Fountain Valley, CA; (27) Radiant Research, Bridgeton, MO; (28) Little Rock Children's Clinic, Little Rock, AR; (29) Marshfield Clinic, Marshfield, WI; (30) Advanced Pediatrics, Vienna, VA; and (31) MacGregor Medical Association, Pasadena, TX.
Investigators
(1) Brian Allen, DO; (2) Wilson Andrews, MD; (3) Mark M. Blatter, MD; (4) Frank Calcango, MD; (5) Robert Daum, MD; (6) Richard Geller, MD; (7) Michael Gerber, MD; (8) David P. Greenberg, MD; (9) Fernando Guerra, MD; (10) James Hedrick, MD; (11) Fredrick Henderson, MD; (12) Hal Jenson, MD; (13) Raheel Khan, MD; (14) Thomas Latiolais, MD; (15) Michael Lauret, MD; (16) Marianne Levine, DO; (17) Joseph Ley, MD; (18) Stephen Luber, MD; (19) David Matthews, MD; (20) Isaac Melamed, MD; (21) Beth Nauert, MD; (22) Michael Pichichero, MD; (23) Steven Shapiro, DO; (24) Robert Copper, MD (replaced by Douglas Short, MD); (25) David Smith, MD; (26) Malcolm Sperling, MD; (27) Craig Spiegel, MD; (28) Tracy Stewart, MD; (29) Bradley Sullivan, MD; (30) Richard Schwartz, MD; and (31) Monica Thint, MD.
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FOOTNOTES |
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Accepted Apr 24, 2008.
Address correspondence to Fernando A. Guerra, MD, MPH, Sanofi Pasteur Inc, One Discovery Drive, Swiftwater, PA 18370. E-mail: fernando.noriega{at}sanofipasteur.com
Financial Disclosure: Dr Guerra conducts clinical studies for Sanofi Pasteur, GlaxoSmithKline, Merck, and Novartis and is on the speaker's bureau for Sanofi Pasteur, GlaxoSmithKline, and Merck; Dr Blatter conducts clinical studies for Sanofi Pasteur, GlaxoSmithKline, Merck, Wyeth, and Novartis and is on the speaker's bureau for Sanofi Pasteur and GlaxoSmithKline; Dr Greenberg received research support from and served on the speaker's bureau for Sanofi Pasteur, GlaxoSmithKline, and Merck at the time the study was conducted and is now an employee of Sanofi Pasteur; Dr Pichichero has received research grants from, has consulted with, and has received honoraria from Sanofi Pasteur; and Dr Noriega is an employee of Sanofi Pasteur. This study was sponsored by Sanofi Pasteur Inc.
| What's Known on This Subject DTaP5, IPV, and Hib vaccines administered separately to infants and toddlers have a favorable immunogenicity/safety profile.
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| What This Study Adds When administered in a combination vaccine to infants and toddlers, DTaP5, IPV, and Hib components have similar immunogenicity and safety compared with the individually administered components. The combination vaccine required fewer injections to generate similar levels of immune response.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSTRIAL INFORMATIONREFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2009 by the American Academy of Pediatrics
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