Published online April 3, 2006
PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1084-1093 (doi:10.1542/peds.2005-1759)
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Pertussis (Whooping Cough)
Diphtheria
Tetanus (Lockjaw)

Acellular Pertussis Vaccine Booster Combined With Diphtheria and Tetanus Toxoids for Adolescents

Michael E. Pichichero, MDa, Mark M. Blatter, MDb, William A. Kennedy, MDc, James Hedrick, MDd, Dominique Descamps, MDe and Leonard R. Friedland, MDf

a University of Rochester Medical Center, Rochester, New York
b Primary Physicians Research, Pittsburgh, Pennsylvania
c University of California Los Angeles Center for Vaccine Research, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California
d Kentucky Pediatric Research, Inc, Bardstown, Kentucky
e GlaxoSmithKline, Rixensart, Belgium
f GlaxoSmithKline, King of Prussia, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND. The incidence of pertussis is increasing, especially in adolescents, attributed in part to waning of immunity after childhood immunization. Recently licensed in the United States for use in adolescents, acellular pertussis vaccines will provide an immunogenic and safe option for booster immunization against pertussis.

METHODS. This prospective, randomized, observer-blinded, multicenter, comparative study evaluated the safety and immunogenicity of a vaccine formulated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis antigens (Tdap) compared with tetanus and diphtheria toxoids vaccine (Td) for booster immunization in adolescents. There were 4114 healthy adolescents aged 10 to 18 years who completed childhood vaccination against diphtheria, tetanus, and pertussis who were enrolled, randomized, and received study vaccine.

RESULTS. Local and general symptoms were comparable between the Tdap and Td groups. The immune response of Tdap was comparable with Td vaccine for tetanus and diphtheria seroprotection and booster responses. In addition, geometric mean concentrations of antibody to pertussis antigens, pertussis toxoid, filamentous hemagglutinin, and pertactin exceeded the antibody response elicited after infant immunization with diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP) that had proven efficacy against pertussis.

CONCLUSIONS. In adolescents, the studied Tdap was safe and immunogenic and induced pertussis antibodies that were higher than those associated with efficacy in infants.

Key Words: pertussis • diphtheria • tetanus • vaccine • adolescents

Abbreviations: Tdap—tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine • DTaP—diphtheria and tetanus toxoids and acellular pertussis vaccine • DTP—diphtheria and tetanus toxoid and pertussis vaccine • Td—tetanus and diphtheria toxoids vaccine • Lf—limit of flocculation • PT—pertussis toxoid • FHA—filamentous hemagglutinin • PRN—pertactin • ELISA—enzyme-linked immunosorbent assay • EL.U.—enzyme-linked immunosorbent assay units • CI—confidence interval • ATP—according to protocol • GMC—geometric mean concentration • DTwP—diphtheria and tetanus toxoids and whole-cell pertussis vaccine

Reported pertussis incidence in the United States increased from 1010 cases in 1976 to 25827 cases in 2004.1,2 The increase primarily occurred in infants aged <6 months and those ≥10 years, with most cases in adolescents.2–5 Recent prospective, population-based studies of cough illness in adolescents and adults estimated the incidence of pertussis in the United States to be much higher than reported, possibly >1 million cases per year.6,7

Increased disease recognition, improved diagnostic techniques, and active surveillance have contributed to the reported increase in pertussis among adolescents and adults. There is less opportunity for natural pertussis boosting because of widespread childhood immunization and waning vaccine-induced immunity within 5 to 10 years.1,4,8,9 Pertussis can cause significant morbidity, impact quality of life, and incur substantial costs in time and money.9–14 Health economists and public health officials indicate that pertussis immunization of adolescents would be beneficial and cost-effective.15–18

Acellular pertussis vaccines are already licensed outside the United States for older individuals, and several countries recommend routine adolescent vaccination.19 In May 2005, a vaccine consisting of acellular pertussis antigens combined with tetanus toxoid and reduced diphtheria toxoid (Tdap; Boostrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) was licensed in the United States for use in adolescents. In June 2005, a second vaccine (Aventis Pasteur Limited, Toronto, Ontario, Canada) also consisting of acellular pertussis antigens combined with tetanus toxoid and reduced diphtheria toxoid was licensed for use in the United States. This article describes the pivotal US safety and immunogenicity trial that led to licensure of the Boostrix Tdap vaccine for booster immunization in adolescents. The studied adolescent Tdap vaccine composition was based on a US-licensed pediatric diphtheria, tetanus, and acellular pertussis vaccine (DTaP)20,21 licensed in the United States in 1997, except with reduced amounts of diphtheria, tetanus, and pertussis antigens to minimize reactogenicity.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Population
The study occurred from November 2002 to December 2003 at 45 US centers after institutional review board approval. Healthy adolescents 10 to 18 years of age who completed routine childhood vaccination against diphtheria, tetanus, and pertussis were enrolled. Written informed assent and/or consent was obtained. Adolescents were ineligible if any of the following were present: diphtheria and tetanus toxoid and pertussis vaccine (DTP) or tetanus and diphtheria toxoids vaccine (Td) within 5 or 10 years, respectively, pertussis disease or household exposure to pertussis within 5 years, immune dysfunction, hypersensitivity to vaccine components, or DTP contraindication.

Study Design
The study was prospective, randomized, observer-blinded, multicenter, and comparative with eligible adolescents receiving 1 of 3 lots of Tdap (to test for manufacturing consistency) or Td in a 1:1:1:1 ratio. A sample size of 3600 adolescents was estimated to be needed for statistical comparisons. Adolescents were stratified such that 75% were 10 to 14 years old, and 25% were 15 to 18 years old. Investigators used a central randomization call-in system on the Internet followed by a randomization blocking scheme (1:1:1:1 ratio) to ensure balance among treatment groups. The primary objectives were evaluated by predefined noninferiority criteria, a statistical method commonly used when a standard of care exists and when the objective is to show that the new treatment is clinically as good as the standard. The power to meet evaluation criteria for each primary objective of the study was >99%. Because of vaccine preparation differences (ie, single versus multiple dose vials), the individual responsible for vaccine preparation and administration was unblinded. All of the other participants were blinded throughout. Adherence to protocol requirements and verification of accurate data generation were achieved through monitoring visits to all of the investigator sites by the sponsor.

Study Vaccines
A single 0.5-mL dose was administered by intramuscular injection in the deltoid muscle of the nondominant arm. Tdap was supplied as single-dose vials containing 2.5 limit of flocculation (Lf) of diphtheria toxoid, 5 Lf of tetanus toxoid, 8 µg pertussis toxoid (PT), 8 µg of filamentous hemagglutinin (FHA), 2.5 µg of pertactin (PRN), and 0.3 mg of aluminum and was free of thimerosal and other preservatives. The US-licensed Td vaccine (Massachusetts Public Health Biological Laboratories, Jamaica Plain, MA) was supplied in multidose vials and contained 2.0 Lf of diphtheria toxoid, 2.0 Lf of tetanus toxoid, 0.45 mg of aluminum, and thimerosal as preservative.

Safety Evaluation
Data on solicited local and general adverse events were collected by the adolescents and their parents/guardians using standardized diaries for 15 consecutive days after vaccination. Local adverse events included pain, redness, and swelling at the injection site and measurement of mid upper–arm circumference. The adolescents were observed for 30 minutes after vaccination and instructed to contact study personnel immediately if they experienced a large injection-site swelling reaction (swelling >100 mm, >50-mm increase in mid upper–arm circumference compared with baseline, or diffuse swelling interfering with or preventing normal activities). General symptoms evaluated included temperature, headache, fatigue, and nonspecific gastrointestinal events (see Table 2 for intensity grading scales). Unsolicited adverse events occurring within 1 month of vaccination were recorded. The adolescents also were monitored for an additional 5-month period for nonroutine medical visits, visits to an emergency department, onset of new chronic illness, and serious adverse events.


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  		TABLE 2 Overall Incidence of Solicited Local and General Symptoms Reported Within the 72-Hour and 15-Day Postvaccination Periods With Tdap or Td Vaccine (Vaccinated Cohort)

 
Serologic Evaluations
Blood samples were obtained before and 1 month after vaccination. Standardized enzyme-linked immunosorbent assays (ELISAs) were used to assess antibody concentrations to diphtheria and tetanus toxoids, PT, FHA, and PRN. For both anti-diphtheria and anti-tetanus ELISA assays, antibody concentration of 0.1 IU/mL was the lowest quantifiable protective concentration.22,23 Antibody concentrations to each pertussis antigen of ≥5 ELISA units (EL.U.)/mL were prespecified to indicate seropositivity. Booster response definitions (antibody concentrations 1 month after vaccination relative to prevaccination concentrations) to diphtheria, tetanus, and pertussis antigens are provided in Table 3.


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  		TABLE 3 Antibody Responses to Diphtheria and Tetanus Toxoids and Pertussis Antigens After Vaccination With Tdap or Td (ATP Cohort for Immunogenicity)

 
Statistical Analysis
Primary safety analyses were based on the vaccinated cohort. The percentage of adolescents experiencing solicited symptoms within 72 hours or 15 days after vaccination or unsolicited symptoms during 31 days of follow-up, and 2-sided exact 95% confidence intervals (CIs) were computed by symptom and intensity. Differences between groups were compared using 2-sided Fisher's exact test and quantified using standardized asymptotic 95% CIs. A 2-sided P < .05 was considered significant. According to prespecified criteria, Tdap was noninferior to Td if the upper limit of the 2-sided 95% CI on the difference in incidence of grade 3 pain for Tdap – Td was ≤4%.

Primary immunogenicity analyses were based on the according-to-protocol (ATP) cohort, which included adolescents who met eligibility criteria, complied with the protocol, and had antibody results for ≥1 antigen. Prespecified exclusions from the ATP cohort were made by individuals blinded to randomization. Geometric mean concentrations (GMCs) of antibody were calculated for each antigen. The percentages of adolescents with anti-diphtheria and anti-tetanus concentrations ≥0.1 IU/mL (ie, seroprotection rate) and ≥1.0 IU/mL; seropositivity rates to each pertussis antigen; and booster responses to diphtheria, tetanus, and pertussis antigens were calculated with 95% CI. Standardized asymptotic 95% CIs for group differences in anti-diphtheria and anti-tetanus seroprotection rates, antibody concentrations ≥1.0 IU/mL, and booster response rates were calculated. According to prespecified criteria, Tdap was noninferior to Td if the upper limit of the 2-sided 95% CI on the difference for Td – Tdap was ≤10% for both diphtheria and tetanus seroprotection rates and booster responses.

Given the absence of recognized serologic correlates of protection against pertussis, the efficacy of a vaccine against pertussis as demonstrated in infants can be extrapolated to a booster pertussis vaccine in an older age group.24 Therefore, GMCs to PT, FHA, and PRN in the Tdap group were compared with GMCs from a study in which infants received 3 doses of DTaP vaccine (Infanrix, GlaxoSmithKline Biologicals, Rixensart, Belgium)25 with similar composition, albeit higher antigen concentrations, and in which efficacy against World Health Organization-defined pertussis was 88.7%.21 Comparison was made through computation of the 95% CI of the GMC ratio between adolescents who received Tdap and infants who received DTaP. According to prespecified criteria, noninferiority was met if the upper limit of the 95% CI for the GMC ratio of DTaP over Tdap for each antigen was <1.5.

Limited immunogenicity data were available before trial initiation on the control Td vaccine. Therefore, 1 planned interim analysis was performed after the first 400 adolescents were enrolled to confirm the feasibility of the projected sample size to demonstrate noninferiority of Tdap to Td. The analysis was conducted by individuals blinded to randomization, and "stopping rules" were prespecified.

All of the analyses and summaries were performed by using SAS 8 (SAS Institute, Inc, Cary, NC). The study was designed and data collected and analyzed by GlaxoSmithKline in coordination with the principal investigator who had access to the data and attests to the accuracy of the data and data analysis.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Population
A total of 4116 adolescents were enrolled and randomized; 2 were not vaccinated, 3080 were randomized to Tdap and 1034 to Td. Approximately 10% in each group was excluded from the ATP cohorts for various reasons unrelated to adverse events (Fig 1). There were no significant differences between groups with respect to age, gender, race, previous DTP history, and prevaccination antibody concentrations to diphtheria and tetanus (Table 1). The type of previous DTP vaccine received was not known for the majority of adolescents. Based on the routine immunization schedule in place when adolescents received their first 3 DTP doses, it is likely that whole-cell DTP (DTwP) was administered, followed by either DTwP or DTaP for subsequent doses. Approximately 98% of adolescents complied with study instructions.


Figure 1
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  		FIGURE 1 Disposition of adolescents enrolled. a Incorrect number of doses (<4 or >5), <5-year interval between previous DTP vaccination and study vaccine, or adolescent was >7 years old at time of previous DTP dose.

 

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  		TABLE 1 Baseline Characteristics of Adolescents in the Vaccinated Cohort

 
Safety
Solicited Local Symptoms
Injection-site pain was the most frequently reported local symptom in both groups at both reporting time frames (Table 2). Any pain was reported significantly more often with Tdap than with Td within 72 hours (75.0% vs 71.4%; P = .02) and 15 days (75.3% vs 71.7%; P = .02) after vaccination, respectively. In addition, grade 2 or 3 pain was reported significantly more often with Tdap than with Td within 72 hours (50.7% vs 42.2%; P < .001) and 15 days (51.2% vs 42.5%; P < .001) after vaccination. The incidence of the primary safety end point of grade 3 pain was low (<5%) and not significantly different between groups (within the limits for noninferiority) at both time frames. There were no significant differences between groups with respect to injection-site redness, swelling, or increase in mid upper–arm circumference. One adolescent in each group reported an episode of large injection-site swelling 3 days after vaccination, which did not involve a large increase in mid upper–arm circumference or the elbow or shoulder and resolved without sequelae.

Solicited General Symptoms
In both groups, the most frequently reported solicited general symptoms within 72 hours and 15 days after vaccination were headache and fatigue (Table 2). There was no significant difference between groups for general symptoms during both follow-up periods, with the exception of a significantly greater rate of grade 2 or 3 headache in the Tdap group within 15 days (15.7% vs 12.7%; P = .02). The incidence of grade 3 solicited general symptoms was low (<4% for each group).

The incidence of adverse events in both groups when analyzed by age (10–14 and 15–18 years), gender, or race was consistent with those of the vaccinated cohort. In adolescents who previously received multiple consecutive DTaP doses, there was no consistent trend toward increased reactogenicity after Tdap administration.

Unsolicited Symptoms
There were 771 of 3034 adolescents (25.4%) in the Tdap group and 248 of 1013 adolescents (24.5%) in the Td group who reported ≥1 unsolicited symptom within 1 month postvaccination. The most commonly reported events were pharyngitis and upper respiratory tract infection. No serious adverse events were reported in either group during this period. At least 97% of the 4114 vaccinated adolescents completed the additional 5-month safety follow-up evaluation (Tdap, n = 3005; Td, n = 1003). During the extended safety follow-up period, the percentages of adolescents reporting a serious adverse event, new onset of a chronic illness, or an adverse event that led to an emergency department or nonroutine office visit were similar and not statistically significantly different in the Tdap and Td groups. Fourteen of the 3005 (0.5%) adolescents in the Tdap group and 2 of the 1003 (0.2%) adolescents in the Td group reported a serious adverse event during the extended safety follow-up period (P = .4). All of the serious adverse events were judged by the investigators to be unrelated to vaccination, and none were of potential autoimmune origin or new onset and chronic in nature.

Immunogenicity
Consistency of the 3 manufacturing lots of Tdap in terms of immunogenicity for all 5 of the antigens was demonstrated (data not shown).

Response to Diphtheria and Tetanus Toxoids
Noninferiority of Tdap compared with Td was demonstrated for anti-diphtheria and anti-tetanus seroprotective rates and booster responses. GMC responses to diphtheria and tetanus were statistically significantly greater in the Td group because the 95% CI of the GMC ratios for Td over Tdap were above and excluded 1.0 (Table 3). One month after vaccination, seroprotective antibody concentrations (≥0.1 IU/mL) against diphtheria and tetanus were achieved by 99.9% and 100% of adolescents in both groups, respectively. Booster response rates to diphtheria were 90.6% with Tdap and 95.9% with Td. Among adolescents seronegative before vaccination, 97.2% and 100%, respectively, in the Tdap and Td groups demonstrated a booster response to diphtheria. Booster response rates to tetanus were 89.7% with Tdap and 92.5% with Td. In both groups, all of the adolescents seronegative before vaccination had a booster response to tetanus.

Response to Pertussis
For all 3 of the pertussis antigens, seropositivity rates 1 month after Tdap vaccination were ≥98.9% (Table 3). Tdap elicited large increases in anti-PT, anti-FHA, and anti-PRN GMCs. The lower limit of the exact 2-sided 95% CI in the percentage of adolescents with a booster response was ≥83.0% for each pertussis antigen, exceeding the predefined criterion of a lower limit of 80% needed to demonstrate a booster response.

Antibody concentrations achieved after Tdap vaccination were higher than those achieved after a 3-dose primary series with infant DTaP where efficacy was demonstrated previously (Table 4). 21,25 Noninferiority of Tdap compared with DTaP was demonstrated for the DTaP over Tdap GMC ratio for each antigen.


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  		TABLE 4 Comparison of Pertussis Immune Responses 1 Month After a Single Dose of Tdap Vaccine in Adolescents With Responses 1 Month After Completion of a 3-Dose Primary Immunization Series With DTaP Vaccine in Infants (ATP Cohort for Immunogenicity)

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
An adolescent Tdap vaccine administered as a single-dose booster to 10- to 18-year-olds was demonstrated to be safe and immunogenic compared with Td vaccine. The Tdap vaccine had a comparable safety profile to that of Td vaccine when administered to adolescents. A higher incidence of any and grade 2 or 3 injection-site pain was reported in the Tdap group compared with Td, which may relate in part to the 3 additional antigens contained in Tdap versus Td. A significant difference in grade 2 or 3 headache was observed within 15 days, but not within 4 days, after vaccination with Tdap versus Td. The significant difference in headache incidence within 15 days after vaccination is only likely to be because of chance alone and not to be clinically relevant. Significant differences between groups for other solicited local or general symptoms were absent. No serious adverse events were reported with either vaccine within 1 month after vaccination. The Tdap sample size allowed for the detection of any adverse event occurring at a rate of >0.1% ({alpha} = 5%).

Large injection-site swelling reactions have been described after booster doses of DTaP, diphtheria and tetanus toxoid vaccine, DTwP, and Td vaccines.26–28 In this study, 1 adolescent in each group reported large injection-site swelling. Most adolescents in this study are assumed to have received DTwP for their primary immunization series, because DTaP was not available until 1996. More data are needed on Tdap safety in adolescents who received only DTaP, although a sizable cohort will be not available in the United States until at least 2007.

Noninferiority of Tdap compared with Td was demonstrated for anti-diphtheria and anti-tetanus seroprotective rates and booster responses. There were no predefined criteria for noninferiority of diphtheria and tetanus GMCs. Although the GMC responses were significantly greater in the Td group, the differences are unlikely to be clinically relevant because the antibody concentrations with Tdap exceeded the cutoff for seroprotection by 10-fold (≥1.0 IU/mL) in 97.3% of adolescents for diphtheria and in 99.5% for tetanus, and diphtheria and tetanus antibody concentrations ≥1.0 IU/mL are associated with long-term protection (≥5–10 years) against diphtheria and tetanus disease.22,23,29,30 Both the Tdap and Td vaccines investigated in this study will provide adolescents with long-term protection against diphtheria and tetanus disease.

The pertussis antibody response after Tdap was not inferior to, and in fact exceeded, that after DTaP in infants.21,25 Therefore, 1 booster dose of Tdap should be at least as efficacious as infant DTaP in preventing pertussis.

A limitation of this study relates to persistence of antibody and longer-term protection (eg, 5–10 years) against diphtheria, tetanus, and pertussis. Although such data are not available with this Tdap vaccine, 1 study demonstrated sustained pertussis efficacy to ≥6 years of age after primary immunization with DTaP.31 Although a serologic correlate of protection for pertussis has not been established, the pertussis antibody responses in the adolescents after a single dose of Tdap exceeded those in infants after a 3-dose primary vaccination series with DTaP. The protective efficacy for pertussis infection of Tdap given to adolescents will only really be known based on postmarketing studies. A similar Tdap vaccine with the identical antigens and antigen quantities as the Tdap studied in this clinical trial (marketed outside the United States) given to adolescents and adults sustained seroprotection against diphtheria and tetanus and seropositivity of PT, FHA, and PRN antibodies for 36 months, and all of the antibody concentrations remained higher than prevaccination levels.32,33

Acellular pertussis vaccines without tetanus and diphtheria have been studied in clinical trials in the United States.7 The pertussis vaccine evaluated in this trial will only be available as a combination Tdap booster for the benefit of protection against diphtheria, tetanus, and pertussis in a single injection. In the United States, the current focus of vaccine manufacturers is on combination Tdap vaccines, which, if administered at the recommended routine 11- to 12-year-old adolescent assessment,34 will not require an additional office visit. Furthermore, use of Tdap vaccine may reduce circulating Bordetella pertussis in the general population and reduce the likelihood that susceptible persons in the community will become infected.35 The Tdap vaccine studied in this clinical trial, as well as a different Tdap vaccine were both recently licensed in the United States for use in adolescents. Although there is no head-to-head clinical trial comparing the 2 vaccines, both appear to be safe and immunogenic.36 In June 2005, the Advisory Committee on Immunization Practices recommended that adolescents 11 or 12 years of age receive Tdap in place of the Td booster vaccine currently being given to adolescents. The committee also recommended that Tdap be given to adolescents 13 to 18 years of age who did not receive a Td booster at 11 or 12 years of age and encouraged provision of Tdap to adolescents 11 to 18 years old who have already been vaccinated with Td to further protect them against pertussis.37 The Boostrix Tdap vaccine studied in this clinical trial will help reduce the number of cases of pertussis among adolescents.


   ACKNOWLEDGMENTS
 
The clinical trial was funded by GlaxoSmithKline (identifying code is 776423/001), including design and conduct of the study, collection, management, analysis, and interpretation of the data, and preparation and review of the article. Dr Pichichero received research grant support from GlaxoSmithKline and Sanofi-Aventis. Dr Kennedy received grant support from the National Institutes of Health, the International Vaccine Institute, and GlaxoSmithKline.

In addition to the authors, the following investigators participated in this clinical trial: Southern California Kaiser Permanente Medical Group, Los Angeles, CA: V. Wong, M. Quan, E. Curry; Pediatric Health Associates/Hunnewell Ground Children's Hospital, Boston, MA: H. Bernstein; Gray Station Primary Care, Gray, TN: S. Combs; Children's Hospital Medical Center of Akron, Akron, OH: B. Congeni; DiscoveResearch, Inc, Bryan, TX: A. Damian; Arkansas Children's Hospital, Little Rock, AR: J. Elser; Tempe Primary Care Associates, PC, Tempe, AZ: T. Fiel; Scott and White Clinic, Temple, TX: M. Gaglani; Norwich Pediatric Group, PC, Norwich, CT: R. Geller; St Joseph Heritage Healthcare, Fullerton, CA: J. Gilbert, Jr; Middlesex Family Physicians/Pro Health Physicians PC, Middletown, CT: M. Good; Boulder Clinical Research, Inc, Boulder, CO: K. Graff; Children's Hospital of Pittsburgh, Pittsburgh, PA (at time of study): D. Greenberg; New West Physicians, Golden, CO: D. Grosser; Radiant Research, Austin, TX: J. Guerrero; Foothill Family Clinic, Salt Lake City, UT: D. Henry; Whitehouse Station Family Medicine, Whitehouse Station, NJ: A. Kelsey; Olentangy Pediatrics, Columbus, OH: K. Koranyi; MetroHealth Medical Center, Cleveland, OH: M. Kumar; Woburn Pediatric Associates, Woburn, MA: J. Leader; 1st Allergy and Clinical Research Center, Centennial, CO : I. Melamed; Center for Pediatric Research, Norfolk, VA: D. Mitchell; Baylor College of Medicine and Affiliated Hospitals, Houston, TX: F. Muñoz; University Hospital, Stony Brook, NY: S. Nachman; Capitol Pediatric and Adolescent Center, Raleigh, NC: M. Ogle; Milford Emergency Associates, Milford, MA: A. Puopolo; Shands Jacksonville, Jacksonville, FL: M. Rathore; Creighton University, Omaha, NE (at time of study): J. Romero; Pennridge Pediatric Associates, Sellersville, PA: E. Rothstein; The Children's Clinic of Jonesboro, Jonesboro, AR: K. Rouse; Dr Senders and Associates, University Heights, OH: S. Senders; St Jude Heritage Medical Group, Yorba Linda, CA: T. Schmidt; Peninsula Research Associates, Rolling Hills Estates, CA: L. Sher; Clinic of Physicians and Surgeons, Ltd, Mesa, AZ: G. Shockey; Edinger Medical Group, Fountain Valley, CA: M. Sperling; Roslindale Pediatric Associates, PC, Boston, MA: R. Stacks; Sylva Pediatrics, Sylva, NC: C. Toledo; Duke Children's Primary Care, Durham, NC: E. Walter; J. Lewis Research, Inc, West Jordan, UT: R. Watson; Children's Memorial Hospital, Chicago, IL: R. Yogev.

Assistance with the article was provided by Una Kistner, RPh (Scientific Therapeutics Information, Inc, Springfield, NJ), and Merry Saba, PharmD (Sparta, NJ). Assistance with data collection, analysis, and reporting was provided by Alix Collard (GlaxoSmithKline, Rixensart, Belgium), Isabelle Maviglia (GlaxoSmithKline, Rixensart, Belgium), Yaela Baine (GlaxoSmithKline, King of Prussia, PA), and Diane Sullivan (GlaxoSmithKline, King of Prussia, PA).


   FOOTNOTES
 
Accepted Sep 14, 2005.

Address correspondence to Michael E. Pichichero, MD, University of Rochester Medical Center, 601 Elmwood Ave, Box 672, Rochester, NY 14642. E-mail: michael_pichichero{at}urmc.rochester.edu

Financial Disclosure: Drs Pichichero and Blatter report having served as a paid consultant or speaker for GlaxoSmithKline and Sanofi-Aventis. Drs Descamps and Friedland are employees of GlaxoSmithKline and report ownership of equity or stock options.

All of the authors had input into study design and participated in the trial, had access to study data, and were involved with article preparation. An independent analysis of the complete clinical study report was performed by the biometrics group at Kendle International Inc, Munich, Germany.

This clinical trial was registered at ClinicalTrials.gov under registration number NCT00109330.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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