Vaccine Information: PENTACEL (Page 3 of 5)

14 CLINICAL STUDIES

The efficacy of Pentacel is based on the immunogenicity of the individual antigens compared to separately administered vaccines. Serological correlates of protection exist for diphtheria, tetanus, poliomyelitis, and invasive disease due to H. influenzae type b. [See Clinical Pharmacology (12.1).] The efficacy against pertussis, for which there is no well established serological correlate of protection, was based, in part, on a comparison of pertussis immune responses following Pentacel in US children to responses following DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) manufactured by Sanofi Pasteur Limited) in an efficacy study conducted in Sweden (Sweden I Efficacy Trial). While Pentacel and DAPTACEL contain the same pertussis antigens, manufactured by the same process, Pentacel contains twice as much detoxified PT and four times as much FHA as DAPTACEL.

Immune responses to Pentacel were evaluated in four US studies: Studies 494-01, P3T06, 494-03, and M5A10. The vaccination schedules of Pentacel, Control vaccines, and concomitantly administered vaccines used in Studies 494-01, P3T06, and 494-03 are provided in Table 1. [See Adverse Reactions (6.1).] In Study M5A10, participants were randomized to receive Pentacel or separately administered DAPTACEL, IPOL, and ActHIB at 2, 4, and 6 months of age. 7-valent pneumococcal conjugate (PCV7, Wyeth Pharmaceuticals Inc.) at 2, 4, and 6 months of age, and Hepatitis B vaccine (Merck and Co. or GlaxoSmithKline Biologicals) at 2 and 6 months of age, were administered concomitantly with Pentacel or Control vaccines.

14.1 Diphtheria

The proportions of participants achieving diphtheria antitoxin seroprotective levels one month following three and four doses of Pentacel or DAPTACEL in Study P3T06 are provided in Table 3.

14.2 Tetanus

The proportions of participants achieving tetanus antitoxoid seroprotective levels one month following three and four doses of Pentacel or DAPTACEL in Study P3T06 are provided in Table 3.

Table 3: Study P3T06 Diphtheria Antitoxin and Tetanus Antitoxoid Responses One Month Following Dose 3 and Dose 4 of Pentacel or DAPTACEL + IPOL + ActHIB in US Children Vaccinated at 2, 4, 6, and 15-16 Months of Age
Pentacel DAPTACEL + IPOL + ActHIB
Per Protocol Immunogenicity population.
*
Seroprotection rate following Pentacel vaccine is not inferior to DAPTACEL vaccine (upper limit of 90% CI of the difference DAPTACEL – Pentacel is <10%).
Non-inferiority criteria were not pre-specified.
With the ELISA used in this study, a tetanus antitoxoid level of 1.0 IU/mL is 10 times the protective level.
Post-Dose 3 N = 331-345 N = 1,037-1,099
Diphtheria Antitoxin % ≥0.01 IU/mL * % ≥0.10 IU/mL Tetanus Antitoxoid % ≥0.10 IU/mL 100.0% 98.8% 99.7% 100.0% 98.5% 100.0%
Post-Dose 4 N = 341-352 N = 328-334
Diphtheria Antitoxin % ≥0.10 IU/mL * % ≥1.0 IU/mL Tetanus Antitoxoid % ≥0.10 IU/mL * % ≥1.0 IU/mL 100.0% 96.5% 100.0% 92.9% 100.0% 95.7% 100.0% 99.4%

14.3 Pertussis

In a clinical pertussis vaccine efficacy study conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial), 2,587 infants received DAPTACEL and 2,574 infants received a non-US licensed DT vaccine as placebo at 2, 4, and 6 months of age. (1) The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL against pertussis after 3 doses of vaccine using the World Health Organization (WHO) case definition (≥21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1%, 88.6%). The protective efficacy of DAPTACEL against mild pertussis (≥1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6%, 82.2%). Protection against pertussis by DAPTACEL was sustained for the 2-year follow-up period.

Based on comparisons of the immune responses to DAPTACEL in US infants (Post-Dose 3) and Canadian children (Post-Dose 4) relative to infants who participated in the Sweden I Efficacy Trial, it was concluded that 4 doses of DAPTACEL were needed for primary immunization against pertussis in US children. (1)

In a serology bridging analysis, immune responses to FHA, PRN and FIM in a subset of infants who received three doses of DAPTACEL in the Sweden I Efficacy Trial were compared to the Post-Dose 3 and Post-Dose 4 responses in a subset of US children from Study 494-01 who received Pentacel (Table 4). Available stored sera from infants who received DAPTACEL in the Sweden I Efficacy Trial and sera from children who received PCV7 concomitantly with the first three doses of Pentacel in Study 494-01 (Table 1) were assayed in parallel. Data on levels of antibody to PT using an adequately specific assay were not available for this serology bridging analysis.

Geometric mean antibody concentrations (GMCs) and seroconversion rates for antibodies to FHA, PRN and FIM one month following Dose 3 of DAPTACEL in the subset of infants from the Sweden I Efficacy Trial and one month following Dose 3 and Dose 4 of Pentacel in a subset of infants from US Study 494-01 are presented in Table 4. Seroconversion was defined as 4-fold rise in antibody level (Post-Dose 3/Pre-Dose 1 or Post-Dose 4/Pre-Dose 1). For anti-FHA and anti-FIM, the non-inferiority criteria were met for seroconversion rates, and for anti-FHA, anti-PRN, and anti-FIM, the non-inferiority criteria were met for GMCs, following Dose 4 of Pentacel relative to Dose 3 of DAPTACEL. The non-inferiority criterion for anti-PRN seroconversion following Dose 4 of Pentacel relative to Dose 3 of DAPTACEL was not met [upper limit of 95% CI for difference in rate (DAPTACEL minus Pentacel) = 13.24%]. Whether the lower anti-PRN seroconversion rate following Dose 4 of Pentacel in US children relative to Dose 3 of DAPTACEL in Swedish infants correlates with diminished efficacy of Pentacel against pertussis is unknown.

Table 4: FHA, PRN and FIM Antibody Responses One Month Following Dose 3 of DAPTACEL in a Subset of Infants Vaccinated at 2, 4, and 6 Months of Age in the Sweden I Efficacy Trial and One Month Following Dose 3 and Dose 4 of Pentacel in a Subset of Infants Vaccinated at 2, 4, 6, and 15-16 Months of Age in US Study 494-01
Post-Dose 3 DAPTACEL Sweden I Efficacy Trial N = 80 Post-Dose 3 Pentacel * US Study 494-01 N = 730-995 Post-Dose 4 Pentacel US Study 494-01 N = 507-554
Analyzed sera were from subsets of the Per Protocol Immunogenicity populations in each study. Data on anti-PT levels using an adequately specific assay were not available.
*
Non-inferiority criteria were not pre-specified for the comparisons of immune responses to Pentacel vaccine Post-Dose 3 vs. DAPTACEL vaccine Post-Dose 3.
Pre-specified non-inferiority analyses compared immune responses to Pentacel vaccine Post-Dose 4 vs. DAPTACEL vaccine Post-Dose 3.
Fold rise was calculated as Post-Dose 3/Pre-Dose 1 antibody level or Post-Dose 4/Pre-Dose 1 antibody level.
§
Percent achieving 4-fold rise or GMC Post-Dose 4 Pentacel vaccine is not inferior to Post-Dose 3 DAPTACEL vaccine [upper limit of 95% CI for difference in rates (DAPTACEL minus Pentacel) <10% and upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) <1.5].
Non-inferiority criterion is not met for percent achieving 4-fold rise in anti-PRN Post-Dose 4 Pentacel vaccine relative to Post-Dose 3 DAPTACEL vaccine [upper limit of 95% CI for difference in rates (DAPTACEL minus Pentacel) = 13.24%, exceeds the non-inferiority criterion of <10%].
Anti-FHA % achieving 4-fold rise GMC (EU/mL) 68.8 40.70 79.8 71.46 91.7§ 129.85§
Anti-PRN % achieving 4-fold rise GMC (EU/mL) 98.8 111.26 74.4 38.11 89.2 90.82§
Anti-FIM % achieving 4-fold rise GMC (EU/mL) 86.3 339.31 86.5 265.02 91.5§ 506.57§

In a separate study, Study P3T06, US infants were randomized to receive either Pentacel or DAPTACEL + IPOL + ActHIB at 2, 4, 6, and 15-16 months of age (Table 1). The pertussis immune responses (GMCs and seroconversion rates) one month following the third and fourth doses were compared between the two groups (Table 5). Seroconversion was defined as a 4-fold rise in antibody level (Post-Dose 3/Pre-Dose 1 or Post-Dose 4/Pre-Dose 1). Data on anti-PT responses obtained from an adequately specific assay were available on only a non-random subset of study participants. The subset of study participants was representative of all study participants with regard to Pre-Dose 1, Post-Dose 3 and Post-Dose 4 GMCs of antibodies to FHA, PRN and FIM. For each of the pertussis antigens, non-inferiority criteria were met for seroconversion rates and GMCs following Dose 3 of Pentacel relative to Dose 3 of DAPTACEL. Following Dose 4 of Pentacel relative to Dose 4 of DAPTACEL, non-inferiority criteria were met for all comparisons except for anti-PRN GMCs [upper limit of 90% CI for ratio of GMCs (DAPTACEL/Pentacel) = 2.25]. Whether the lower anti-PRN GMC following Dose 4 of Pentacel relative to Dose 4 of DAPTACEL in US children correlates with diminished efficacy of Pentacel against pertussis is unknown.

Table 5: Pertussis Antibody Responses One Month Following Doses 3 and 4 of Pentacel or DAPTACEL + IPOL + ActHIB in US Infants Vaccinated at 2, 4, 6, and 15-16 Months of Age in Study P3T06
Post-Dose 3 Pentacel Post-Dose 3 DAPTACEL + IPOL + ActHIB Post-Dose 4 Pentacel Post-Dose 4 DAPTACEL + ActHIB
Per Protocol Immunogenicity population for anti-FHA, anti-PRN, and anti-FIM. Non-random subset of per Protocol Immunogenicity population for anti-PT. See text for further information on the subset evaluated.
*
Fold rise was calculated as Post-Dose 3/Pre-Dose 1 antibody level or Post-Dose 4/Pre-Dose 1 antibody level.
Percent achieving 4-fold rise or GMC Post-Dose 3 Pentacel vaccine not inferior to Post-Dose 3 DAPTACEL vaccine [upper limit of 95% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 95% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
Percent achieving 4-fold rise or GMC Post-Dose 4 Pentacel vaccine not inferior to Post-Dose 4 DAPTACEL vaccine [upper limit of 95% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 95% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
§
Percent achieving 4-fold rise or GMC Post-Dose 3 Pentacel vaccine not inferior to Post-Dose 3 DAPTACEL vaccine [upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 90% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
Percent achieving 4-fold rise or GMC Post-Dose 4 Pentacel vaccine not inferior to Post-Dose 4 DAPTACEL vaccine [upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) <1.5 and upper limit of 90% CI for differences in rates (DAPTACEL minus Pentacel) <10%].
#
Non-inferiority criterion is not met for GMC Post-Dose 4 Pentacel vaccine relative to Post-Dose 4 DAPTACEL vaccine [upper limit of 90% CI for GMC ratio (DAPTACEL/Pentacel) = 2.25, which exceeds the non-inferiority criterion of <1.5].
N = 143 N = 481-485 N = 113 N = 127-12 8
Anti-PT % achieving 4-fold rise * GMC (EU/mL) 95.8 102.62 87.3 61.88 93.8 107.89 91.3 100.29
N = 218-318 N = 714-1,016 N = 230-367 N = 237-347
Anti-FHA % achieving 4-fold rise * GMC (EU/mL) 81.9§ 73.68§ 60.9 29.22 88.4 107.94 79.3 64.02
Anti-PRN % achieving 4-fold rise * GMC (EU/mL) 74.2§ 36.05§ 75.4 43.25 92.7 93.59# 98.3 186.07
Anti-FIM % achieving 4-fold rise * GMC (EU/mL) 91.7§ 268.15§ 86.3 267.18 93.5 553.39 91.6 513.54

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