A, Participant disposition and safety population. B, Participant disposition
and immunogenicity population.
A, Solicited reactions of erythema, swelling, pain, and fever for adolescents
and adults who provided severity measurements of mild to severe. For the percentages
of participants reporting these reactions, the upper limit of the 95% confidence
interval around the difference between Tdap and Td was less than 10% for all
age groups and reactions, except pain in adolescents (10.72%). B, Increases
in circumference of the limb injected with Tdap or Td, measured at the midpoint
of the upper arm. No differences between the 2 vaccine groups were observed
for adolescents or adults.
Pichichero ME, Rennels MB, Edwards KM, Blatter MM, Marshall GS, Bologa M, Wang E, Mills E. Combined Tetanus, Diphtheria, and 5-Component Pertussis Vaccine for Use in Adolescents and Adults. JAMA. 2005;293(24):3003-3011. doi:10.1001/jama.293.24.3003
Author Affiliations: University of Rochester
Medical Center, Rochester, NY (Dr Pichichero); University of Maryland, Baltimore
(Dr Rennels); Vanderbilt University, Nashville, Tenn (Dr Edwards); Primary
Physicians Research, Pittsburgh, Pa (Dr Blatter); University of Louisville,
Louisville, Ky (Dr Marshall); Sanofi Pasteur Limited, Toronto, Ontario (Drs
Bologa, Wang, and Mills).
Context Increasing reports of pertussis among US adolescents, adults, and their
infant contacts have stimulated vaccine development for older age groups.
Objective To assess the immunogenicity and reactogenicity of a tetanus-diphtheria
5-component (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae
types 2 and 3) acellular pertussis vaccine (Tdap) in adolescents and adults.
Design, Setting, and Participants A prospective, randomized, modified double-blind, comparative trial
was conducted in healthy adolescents and adults aged 11 through 64 years from
August 2001 to August 2002 at 39 US clinical centers.
Interventions A single 0.5-mL intramuscular dose of either Tdap or tetanus-diphtheria
Main Outcome Measures Antibody titers to diphtheria and tetanus toxoids for Tdap and Td were
measured in sera collected from subsets of adolescents and adults, before
and 28 days after vaccination. For pertussis antigens, titers in sera from
Tdap vaccinees were assessed vs those from infants who received analogous
pediatric diphtheria-tetanus-acellular pertussis vaccine (DTaP) in a previous
efficacy trial. Safety was assessed via solicited local and systemic reactions
for 14 days and adverse events for 6 months following vaccination.
Results A total of 4480 participants were enrolled. For both Tdap and Td, more
than 94% and nearly 100% of vaccinees had protective antibody concentrations
of at least 0.1 IU/mL for diphtheria and tetanus, respectively. Geometric
mean antibody titers to pertussis toxoid, filamentous hemagglutinin, pertactin,
and fimbriae types 2 and 3 exceeded (by 2.1 to 5.4 times) levels in infants
following immunization at 2, 4, and 6 months with DTaP. The incidence of solicited
local and systemic reactions and adverse events was generally similar between
the Tdap and Td groups.
Conclusions This Tdap vaccine elicited robust immune responses in adolescents and
adults to pertussis, tetanus, and diphtheria antigens, while exhibiting an
overall safety profile similar to that of a licensed Td vaccine. These data
support the potential routine use of this Tdap vaccine in adolescents and
Conclusions Published online June 2, 2005 (doi:10.1001/jama.293.24.3003).
In 2003, 11 647 cases of pertussis, many in adolescents and adults,
were reported to the US Centers for Disease Control and Prevention (CDC).1,2 Preliminary CDC data for 2004 indicate
an increase to 18 957 cases.3 Although
increased awareness and improved diagnostic methods may increase reporting,
factors such as the variable efficacy of whole-cell pertussis vaccines previously
used in the United States,4,5 undervaccination
in childhood, and waning immunity in adolescents and adults may also explain
an increase in incidence. Incompletely immunized infants and toddlers have
the highest susceptibility to pertussis, the most severe disease manifestations,
and highest risk of mortality.6,7 Reported
cases of pertussis decline after completion of the primary infant immunization
series and remain low until early adolescence, when the number of cases increases.
Because no booster pertussis vaccine is currently available for adolescents
or adults, these persons become increasingly vulnerable to the disease.8
The role of adolescents and adults in the spread of pertussis is critical.
Disease may be characterized by nonclassical symptoms, making diagnosis more
difficult, particularly given the limitations of available diagnostic tests.
However, adolescents and adults who contract pertussis do experience significant
morbidity and complications.9,10 Delayed
treatment and increased transmission,8,11 most
significantly to unvaccinated or undervaccinated infants, are of concern.12,13 Vaccination of adolescents and adults
with acellular pertussis vaccines might reduce both the morbidity associated
with the disease in these populations and transmission to their household
and other contacts, especially infants. We describe the immunogenicity and
reactogenicity of a new 5-component acellular pertussis vaccine combined with
tetanus and diphtheria toxoids (Tdap; Adacel, Sanofi Pasteur Limited, Toronto,
Ontario) in adolescents and adults.
We examined the immunogenicity and reactogenicity of booster doses of
Tdap vs those of licensed tetanus and diphtheria toxoids adsorbed for adult
use (Td, Sanofi Pasteur Inc, Swiftwater, Pa). The trial was conducted following
the principles outlined in the Declaration of Helsinki. Written informed consent
was obtained from participants, their parents, or guardians before study procedures
were initiated. Written informed assents were obtained for underage adolescents,
as required by institutional review boards (IRBs). Appropriate IRBs approved
study documents at each center. A data and safety monitoring board monitored
study data throughout. A contract research organization (CRO) performed some
study monitoring under the supervision of the sponsor.
Eligible participants were between 11 and 64 years of age, in good health,
with a temperature of less than 38.0°C. Exclusion criteria included receipt
of any pertussis, diphtheria, or tetanus-containing vaccines within 5 years;
diagnosis of pertussis within 2 years; allergy or sensitivity to any vaccine
component, including previous vaccine reactions; acute respiratory illness;
daily use of oral nonsteroidal, anti-inflammatory drugs; receipt of blood
products or immunoglobulins within 3 months; and any immunodeficiency, malignancy,
significant underlying disease, neurological impairment, or pregnancy.
This phase 3, randomized, controlled, modified double-blind trial was
conducted at 39 US clinical centers (Figure 1). To maintain blinding, study center personnel who administered
vaccines did not perform study assessments, while those who performed assessments
remained blinded to study vaccines. Study sponsor personnel, who did not participate
further in the trial, provided a computer-generated randomization list, including
designation of random assignments to provide serum samples, to a central randomization
center at the CRO. Vaccine allocation codes were obtained from an interactive
voice response system at the CRO; an allocation code list was provided in
a sealed envelope by the sponsor. The success of blinding at each site was
evaluated during routine monitoring. Participants were randomized to receive
Tdap or Td (3:2 for adolescents; 3:1 for adults). To ensure adequate distribution
across groups, enrollment was stratified by age (11-13, 14-17, 18-28, 29-48,
and 49-64 years; block size was 10 for adolescents and 8 for adults). Serum
samples were collected immediately prior to and 28 to 42 days following study
vaccination from randomly selected participant subsets representing 50% of
Tdap recipients, 75% of adolescent Td recipients, and 100% of adult Td recipients.
Participants were observed for 30 minutes following vaccination for immediate
reactions; reports of solicited local and systemic reactions were collected
for 14 days following vaccination. Unsolicited adverse event reports were
collected for 6 months.
Tdap contained 2.5 μg of pertussis toxoid; 5 μg of filamentous
hemagglutinin; 3 μg of pertactin; 5 μg of fimbriae types 2 and 3;
2 Limit of flocculation (Lf) of diphtheria toxoid; 5 Lf of tetanus toxoid;
1.5 mg of aluminum phosphate (0.33 mg aluminum); and 0.6% 2-phenoxyethanol
per 0.5-mL dose. The control vaccine, Td, was a licensed product containing
2 Lf of diphtheria toxoid; 5 Lf of tetanus toxoid; 1.5 mg of aluminum phosphate
(0.33 mg aluminum); and 0.01% thimerosal as a preservative per 0.5-mL dose.
Antibody assays were performed in a blinded manner at the clinical immunology
laboratories of Sanofi Pasteur Limited in Toronto, Ontario (for pertussis
antigens) or Sanofi Pasteur Inc in Swiftwater, Pa (for tetanus and diphtheria
toxoids) using validated methods.14- 16 Antipertussis,
anti–filamentous hemagglutinin, anti–fimbriae types 2 and 3, antipertactin
IgG, and antitetanus antibody titers were determined by an enzyme-linked immunosorbent
assay (ELISA) method. Results for pertussis antibodies were calculated in
ELISA units per milliliter (EU/mL) by comparison with in-house standard antisera
of assigned unitage, calibrated to the US Human Reference Lots 3 or 4. Pertussis
antibody response comparisons were made using serum samples collected at 7
months of age, following immunization at 2, 4, and 6 months of age, from infant
participants in an efficacy trial using analogous pediatric diphtheria-tetanus
5-component-acellular pertussis vaccine (DTaP; Daptacel, Sanofi Pasteur Limited).4 The infant serum samples from this reference trial
were concurrently tested in the same laboratory, under the same conditions,
and using the same assay as samples from adolescents and adults. Antitetanus
titers were calculated by comparison with an international standard, Lot TE-3,
available from the World Health Organization (WHO). Antidiphtheria antibody
responses were measured by the ability of test sera to protect Vero cells
from a diphtheria toxin challenge. Results were reported by comparison with
a calibrated WHO reference serum and were determined by the highest serum
dilution that allowed cell metabolism in the presence of the challenge dose
of diphtheria toxin.
Immediate reaction data were recorded in the clinic. Local solicited
reactions of erythema, swelling, pain, axillary node swelling, and limb circumference
(at the midpoint between shoulder and elbow of the injected limb) and systemic
solicited reactions of fever (temperature ≥38°C), vomiting, headache,
diarrhea, nausea, chills, rash, generalized body ache or muscle weakness,
tiredness or decrease in energy level, and sore or swollen joints were recorded
daily on a study-provided diary card for 14 days. Unsolicited adverse events
were recorded for 14 days. Erythema, swelling, and fever were rated as mild,
moderate, or severe, based on size (0-9 mm, 10-34 mm, or ≥35 mm) or temperature
(38.0°C-38.7°C, 38.8°C-39.4°C, or ≥39.5°C). Pain was
rated as mild to severe, based on the level of incapacitation experienced.
After the initial 14-day period, any adverse event that required a medical
contact—including change of medication, telephone call, office visit,
emergency department visit, or hospitalization—was recorded. Participants
were contacted by telephone 6 months after immunization to ensure completeness
of reporting. Serious adverse events were recorded throughout the study and
rated by investigators for relationship to study vaccine.
Planned enrollment was 4400 participants, 1000 in each adolescent age
stratum (11-13, 14-17 years) and 800 in each adult age stratum (18-28, 29-48,
and 49-64 years). The overall population for serum analysis was based on a
sample size of 200 participants per stratum for adults receiving Td and 300
per stratum for adolescents in each treatment group and for adults receiving
Tdap. Assuming 10% attrition, the power to test each individual immunogenicity
hypothesis was at least 80%. The sample size for safety had sufficient power
to rule out 2-fold increases of fever occurring at a rate of 3% in the control
group among 11- to 17-year-olds. All sample size calculations were performed
using nQuery version 3.0 (Statistical Solutions, Sagus, Mass) or in-house
SAS version 8.2 (SAS Institute Inc, Cary, NC). Statistical analyses were performed
by Red River Statistics Inc of Shreveport, La, and independently by biostatistians
at the University of Rochester Medical Center, Rochester, NY.
For tetanus and diphtheria, antibody levels of at least 0.1 IU/mL are
widely accepted as protective and are thus a primary outcome measure.15,16 Consistent with the US Food and Drug
Administration (FDA) standards regarding demonstration of noninferiority of
new combination products vs licensed or individual products, Tdap was considered
to be at least as immunogenic as Td if the lower bound of a 95% confidence
interval (CI) around the differences in seroprotection rates in participants
vaccinated with Tdap or Td was greater than –10%. For pertussis, Tdap
would be considered at least as immunogenic as DTaP if the lower bound of
the 95% CI around the postvaccination geometric mean titer (GMT) ratio for
Tdap and DTaP was greater than 0.67 (ie, =reciprocal of 1.5, a standard approach
required by FDA for demonstrating noninferiority in vaccine trials). For each
antigen, booster response was a primary outcome measure, defined as a 4-fold
increase if the prevaccination titer was less than or equal to a predefined
cut-off value and a 2-fold increase if the prevaccination titer was greater
than the cut-off value. The cut-off prevaccination values were based on earlier
clinical trial results: 2.56 IU/mL for diphtheria, 2.7 IU/mL for tetanus,
85 EU/mL for pertussis toxoid, 170 EU/mL for filamentous hemagglutinin, 115
EU/mL for pertactin, and 285 EU/mL for fimbriae types 2 and 3.
Baseline variables were compared between groups using the analysis of
variance technique for continuous variables and the χ2 test
or Fisher exact test for categorical variables.
Percentages of participants with immediate, local, or systemic reactions
and those with adverse events or serious adverse events were tabulated. For
the primary safety analysis of erythema, swelling, pain, and fever, Tdap was
considered to be at least as safe as Td if the upper bound of the 95% CI of
the between-vaccine difference in event rates was less than 10%. A post-hoc
analysis for differences in subgroups of vaccinees by sex was performed, as
were post-hoc analyses of rate ratios, with 95% CIs, for erythema, swelling,
pain, and fever.
All participants randomized to provide sera before and after vaccination
who met protocol criteria were included in the per-protocol immunogenicity
analysis. The planned modified intention-to-treat analysis for safety was
to include all participants who received study vaccine, with a corrected allocation
for participants who received the wrong vaccine in error. Data for adolescents
(aged 11-17 years) and adults (aged 18-64 years) were evaluated separately.
No values were imputed to replace missing data; no adjustments were made for
multiplicity. For solicited events, denominators include participants for
whom data were available. For all analyses, nonoverlapping 95% CIs were considered
to be statistically significant.
Between August 2001 and August 2002, 4480 participants were randomized
and underwent study procedures at 39 clinical centers across the United States.
Of these participants, 2053 were adolescents: 1213 received Tdap and 815 received
Td. In the adult group, 2427 enrolled: 1804 received Tdap and 599 received
Td (Figure 1). Vaccination errors were
reported for 5 participants (eg, randomized to Td but vaccinated with Tdap);
these participants were reallocated to the group for which they received vaccine.
All data from 1 site (130 participants total) were excluded from the primary
safety and immunogenicity analyses due to violations of Good Clinical Practices
related to participants’ rights, vaccine administration and accountability,
documentation, and study blinding (Figure 1).
The primary analysis of data omits all data from this study site; for confirmatory
purposes, an additional analysis was performed including these data. Results
were similar in both analyses; accordingly, primary analysis results are presented.
Demographic characteristics by age group are shown in Table 1. Data from 80 infants in a reference DTaP efficacy trial
were included to evaluate pertussis antibody responses; the 80 infant sera
pairs were representative of all 181 pairs tested in the original study, based
on GMT ratios.4
For tetanus and diphtheria, seroprotection rates of at least 0.1 IU/mL,
booster response rates, and 1-month postimmunization GMTs were high and similar
between the Tdap and Td groups for both adolescents and adults. Pertussis
GMTs and proportions of participants with antibody levels consistent with
boosting for each antigen indicated robust responses to Tdap (Table 2).
Pertussis antibody GMTs following 1 dose of Tdap were substantially
higher than those seen among infants following 3 doses of DTaP for all pertussis
antigens in both adults and adolescents (Table
3). In both age groups for diphtheria and tetanus, the lower bounds
of the CIs around the difference in rates between Tdap and Td were greater
than –10%, and for pertussis the lower bounds of the CIs around the
GMT ratios between Tdap and DTaP were above 0.67, meeting the noninferiority
Safety and reactogenicity evaluation outcomes were comparable between
the Tdap and Td groups for both the adolescent and adult populations. Sixteen
participants (11 adolescents and 5 adults) reported immediate reactions within
30 minutes of vaccination. Proportions were similar among Tdap and Td recipients:
approximately 0.5% for adolescents and 0.2% for adults. Most immediate reactions
were nervous system events, such as syncope, dizziness, or vasovagal reaction,
or injection site events, such as pain and erythema.
The frequency and maximum intensity of solicited local reactions of
erythema and swelling were comparable between the Tdap and Td groups for both
adolescents and adults (Figure 2). In
adolescents, pain occurred slightly more frequently with Tdap vs Td. The onset
of solicited local adverse events was highest during days 0 through 3 in both
vaccine groups. Reported increases in limb circumference vs baseline were
similar between the Tdap and Td groups, and most increases were 2 cm or less.
Reported changes from baseline included decreases in limb circumference in
some participants. No cases of whole-arm swelling were reported in either
For adolescents and adults, the frequency and maximum intensity of each
of the solicited systemic reactions were comparable between the Tdap and Td
groups, based on noninferiority testing (Table
4). For adolescents and adults, proportions of participants with
fever were within predefined comparability bounds. The majority of these fevers
were mild, with only 2 of 1170 adolescents in the Tdap group and 1 of 783
adolescents and 1 of 551 adults in the Td group reporting severe fever (temperature
≥39.5°C). Most solicited systemic reactions reported were mild. With
the exception of headache, severe adverse events were uncommon for all solicited
systemic adverse events, occurring in 1.3% or less of all Tdap and Td participants.
Severe headache was reported by 23 of 1175 and 12 of 787 adolescents and 47
of 1698 and 12 of 560 adult Tdap and Td participants for whom severity was
reported, respectively, during postvaccination days 0 through 14. A trend
for higher percentages of females vs males with local reactions was observed
in the Tdap and Td groups, with greater differences in adults than in adolescents.
No significant between-group differences were observed for unsolicited
adverse events (Table 4).
Thirty women, 23 in the Tdap and 7 in the Td group, became pregnant
1 or more times during trial participation; each tested nongravid at study
entry. Five miscarriages in the Tdap group, 1 therapeutic abortion in the
Td group, and 4 early deliveries (2 in each group) were reported. At birth,
23 newborns, including the 4 early deliveries, were reported to be normal.
One Tdap recipient experienced a miscarriage, reconceived, and subsequently
delivered a healthy infant.
Sixty-three of 4301 (1.46%) participants reported 1 or more serious
adverse events: 44 of 2936 (1.50%) in the Tdap group and 19 of 1365 (1.39%)
in the Td group. Only 2 serious adverse events, both in adult Tdap recipients,
were considered possibly related to vaccine by the investigator. A 23-year-old
woman was hospitalized for a severe migraine with unilateral facial paralysis
1 day after vaccination, recovered without sequelae, and was discharged 2
days later. A 49-year-old woman was hospitalized with a diagnosis of nerve
compression 12 days after vaccination; the complaint resolved within 1 day.
Two cases of diabetes (1 in each vaccine group) and 2 cases of seizures in
adolescents with prior history of seizure disorder (1 in each vaccine group)
were among the serious adverse events considered unrelated to study vaccine
In this study, the Tdap vaccine administered was comparable with Td
vaccine with respect to reactogenicity and tetanus-diphtheria immunogenicity,
while providing robust pertussis antibody responses in both adolescents and
adults. The percentages of participants receiving Tdap and having seroprotective
antibody levels of at least 0.1 IU/mL to tetanus and diphtheria were high
and similar to those among Td recipients. Pertussis GMTs to pertussis toxoid,
filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3 after 1 dose
of Tdap exceeded those measured in a subset of infants who had received 3
doses of the analogous DTaP vaccine in an efficacy trial that demonstrated
85% protection against classic pertussis and 78% protection against milder
pertussis (defined as culture-proven pertussis with ≥1 day of cough).4 In comparisons between Tdap and Td for erythema, swelling,
pain, and fever, Tdap was comparable with Td, with the possible exception
of pain in adolescents, for which the results were marginally outside of the
predefined comparability bound. These results support the use of the Tdap
vaccine in adolescents and adults.
The potential benefits of widespread use of an adolescent and adult
pertussis booster vaccine include a reduction in pertussis disease. As the
overall US case counts have grown, so too has the proportion of pertussis
cases in persons at least 10 years old, increasing steadily from 15% in 1977-1979
to 49% in 1997-2000.2 In 2003, the latest year
for which complete data are available, that proportion increased to 64%.1 Waning immunity to pertussis has been demonstrated
in adolescents and adults, indicating increased susceptibility to disease
in these age groups. Increased incidence of disease in older patients is of
public health significance because they serve as the reservoir for Bordetella pertussis infections in infants who are too young to have
completed the primary series of immunization. Pertussis may be severe and
even life-threatening in very young infants.11,13,17 Antimicrobial
therapy, although effective in eradicating the organism from the respiratory
tract,18 does not alter the progression of
disease unless given early, during the catarrhal phase when pertussis is rarely
suspected. Therefore, control of the disease must be based on vaccination.
Tolerability is an important consideration in the development of new
vaccines. Reactogenicity to pediatric formulation DTaP vaccines is associated
with the amount of pertussis or diphtheria toxoid per dose. Formulations with
lower diphtheria and pertussis toxoid concentrations elicit less reactogenicity.19 Therefore, the Tdap studied was formulated to contain
lower quantities of diphtheria and pertussis toxoids than the analogous US-licensed
pediatric DTaP vaccine. Results of this study show a favorable reactogenicity
profile in adolescents and adults, suitable for routine use. Furthermore,
differences in reactogenicity between females and males were observed for
both vaccines, consistent with observations made with the use of other vaccines,
such as influenza vaccine.20
Our study had certain limitations. There was insufficient power to detect
uncommon adverse events. Also, the use of an infant comparison group to evaluate
the immunogenicity of the pertussis component in adolescents and adults may
raise some questions. However, no definitive serological correlates of protection
are available for pertussis, and the efficacy of the infant formulation in
preventing disease is well established. Therefore, this approach has been
endorsed by the FDA’s Vaccines and Related Biological Products Advisory
Committee21 for the purpose of licensing adolescent
and adult acellular pertussis vaccine formulations that are based on infant
vaccines of demonstrated efficacy. Additional experience will be needed to
further define the profile of this vaccine in larger populations.
Booster vaccination with tetanus and diphtheria toxoids every 10 years
has become a standard of care in the United States. Our data indicate that
the Tdap vaccine studied could be used to provide protection for tetanus and
diphtheria, as recommended, while providing additional protection against
pertussis. Evidence to support the introduction of an acellular pertussis
booster in the United States includes a recent Canadian National Advisory
Committee on Immunization statement recommending that all preadolescents and
adolescents be vaccinated with an appropriately formulated acellular pertussis
vaccine.22 The introduction of adolescent and
adult Tdap booster immunization in the United States could enhance immunity
against pertussis, which would be anticipated to decrease the incidence of
pertussis in the population, reduce the reservoir of pertussis, and lessen
transmission from adolescents and adults to infants.
Corresponding Author: Michael E. Pichichero,
MD, University of Rochester Medical Center, Elmwood Pediatric Group, 601 Elmwood
Ave, Rochester, NY 14642 (email@example.com).
Author Contributions: Dr Pichichero had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Pichichero.
Acquisition of data: Pichichero, Rennels, Edwards,
Blatter, Marshall, Bologa, Wang, Mills.
Analysis and interpretation of data: Pichichero,
Rennels, Edwards, Blatter, Bologa, Wang, Mills.
Drafting of the manuscript: Pichichero, Blatter.
Critical revision of the manuscript for important
intellectual content: Pichichero, Rennels, Edwards, Marshall, Bologa,
Statistical analysis: Pichichero.
Obtained funding: Pichichero.
Administrative, technical, or material support:
Rennels, Edwards, Marshall, Bologa.
Study supervision: Edwards, Blatter, Marshall,
Bologa, Wang, Mills.
Financial Disclosures: Drs Pichichero and Edwards
have received grants from Aventis, GlaxoSmithKline, and MedImmune. Dr Blatter
is on the speakers’ bureau for Aventis. Dr Marshall has received research
contracts, honoraria, and consultancies from Aventis.
Funding/Support: Funding for the study was
provided by Aventis Pasteur, now Sanofi Pasteur. Funding went to the academic
institutions of the authors.
Role of the Sponsor: The authors who are employees
of Aventis Pasteur participated in the design, supervision, and conduct of
the study; performed interpretation of the data; and provided critical review
of the manuscript. The sponsor played a principal role in the design and conduct
of the study. A contract research organization, PPD Development, made site
visits to ensure accuracy and integrity of the data and managed the study.
Independent Statistical Analysis: Jason Roy,
PhD, and Shirley Eberly, MS, of the Department of Biostatistics at the University
of Rochester Medical Center, Rochester, NY, performed a confirmatory statistical
analysis. Shayami Thanabalasundrum and James Trammel of Red River Statistics
Inc, Shreveport, La, as well as Aleksandra Kolenc-Saban, MSc, and James Sloan
of Aventis Pasteur performed data analyses and management. Aventis Pasteur
contracted with Red River Statistics for independent statistical review of
the data. Red River Statistics was not employed by Aventis Pasteur, nor were
there any other arrangements with Aventis Pasteur other than the contracted
arrangement. Analysis of the data was performed by the independent statistics
company and guided by the Food and Drug Administration for data requested
in association with the Biologics License Application (BLA) (presentations
for the BLA occurred on March 15, 2005).
Study Investigators: The following physicians
enrolled participants into the trial and performed study evaluations: Brian
Allen, Onalaska, Wis; Wilson P. Andrews, Jr, Marietta, Ga; Gerald Bader, Vancouver,
Wash; Ladan Bakhtari, Plano, Tex; David Bernstein, Cincinnati, Ohio; Mark
M. Blatter, Pittsburgh, Pa; Kenneth Bromberg, Brooklyn, NY; Daniel Brune,
Peoria, Ill; Timothy Craig, Hershey, Pa; Robert Daum, Chicago, Ill; Cornelia
Dekker, Stanford, Calif; Arnold del Pilar, Jr, South Bend, Ind; Kathryn M.
Edwards, Nashville, Tenn; Bryan D. Evans, Huntsville, Ala; Stephen M. Fries,
Boulder, Colo; David P. Greenberg, Pittsburgh, Pa; Susan A. Keathley, Little
Rock, Ark; Donald J. Kennedy, St Louis, Mo; Erik Lamberth, Sellersville, Pa;
Thomas Latiolais, Bossier City, La; Joseph Leader, Woburn, Mass; Gary Marshall,
Louisville, Ky; Emma E. McCarty, Shreveport, La; Douglas K. Mitchell, Norfolk,
Va; Laurie Peterson, Chippewa Falls, Wis; Michael Pichichero, Rochester, NY;
Sharon E. Prohaska, Kansas City, Mo; Alfredo Quinonez, San Diego, Calif; Margaret
B. Rennels, Baltimore, Md; David Paul Robinson, Columbia, Mo; Kevin G. Rouse,
Jonesboro, Ark; Joseph Saponaro, Jupiter, Fla; Shelly David Senders, University
Heights, Ohio; Charles Sheaffer, Chapel Hill, NC; Marc R. Shepard, Washington,
DC; Peter E. Silas, Layton, Utah; Alex Spyropoulos, Albuquerque, NM; Bradley
Sullivan, Marshfield, Wis; Leonard B. Weiner, Syracuse, NY.
Acknowledgment: We thank William Bartlett,
PhD, and Linda Young, who performed serology analyses; Kathy Heard and Jennifer
Kasztejna, who performed and oversaw trial monitoring; Robert Daum, MD, David
Johnson, MD, and Michael D. Decker, MD, who provided scientific advice; and
Lisa DeTora, PhD, and David Johnson, MD, who are both full-time employees
of Sanofi Pasteur in Swiftwater, Pa, and who assisted in the editing of the
Published Online: June 2, 2005 (doi:10.1001/jama.293.24.3003).