Tetanus Toxoid Conjugate

Mechanism Of Action

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective.13 Levels of 1.0 IU/mL have been associated with long-term protection.14

Tetanus

Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level.13,15 A tetanus antitoxoid level ≥ 0.1 IU/mL as measured by the ELISA used in clinical studies of Pentacel vaccine is considered protective.

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

Poliomyelitis

Polioviruses, of which there are three serotypes (Types 1, 2, and 3) are enteroviruses. The presence of poliovirus type-specific neutralizing antibodies has been correlated with protection against poliomyelitis.16

Invasive Disease Due to H influenzae Type b

H influenzae type b can cause invasive disease such as meningitis and sepsis. Anti-PRP antibody has been shown to correlate with protection against invasive disease due to H influenzae type b. Based on data from passive antibody studies17 and an efficacy study with H influenzae type b polysaccharide vaccine in Finland,18 a post-vaccination anti-PRP level of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with Hinfluenzae type b polysaccharide vaccine in Finland indicate that a level > 1.0 mcg/mL 3 weeks after vaccination predicts protection through a subsequent one-year period.19,20 These levels have been used to evaluate the effectiveness of Haemophilus b Conjugate Vaccines, including the ActHIB vaccine component of Pentacel vaccine.

Clinical Studies

The efficacy of Pentacel vaccine 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] 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 vaccine in US children to responses following DAPTACEL vaccine (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 vaccines contain the same pertussis antigens, manufactured by the same process, Pentacel vaccine contains twice as much detoxified PT and four times as much FHA as DAPTACEL vaccine.

Immune responses to Pentacel vaccine were evaluated in four US studies: Studies 494-01, P3T06, 494-03, and M5A10. The vaccination schedules of Pentacel vaccine, Control vaccines, and concomitantly administered vaccines used in Studies 494-01, P3T06, and 494-03 are provided in Table 1. [See ADVERSE REACTIONS).] In Study M5A10, participants were randomized to receive Pentacel vaccine or separately administered DAPTACEL, IPOL, and ActHIB vaccines at 2, 4, and months of age. 7-valent pneumococcal conjugate vaccine (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 vaccine or Control vaccines.

Diphtheria

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

Tetanus

The proportions of participants achieving tetanus antitoxoid seroprotective levels one month following three and four doses of Pentacel vaccine or DAPTACEL vaccine 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 Vaccine or DAPTACEL + IPOL + ActHIB Vaccines in US Children Vaccinated at 2, 4, 6, and 15-16 Months of Age

Post-Dose 3	Pentacel Vaccine N = 331-345	DAPTACEL + IPOL + ActHIB Vaccines N = 1,037-1,099
Diphtheria Antitoxin
% ≥ 0.01 IU/mL *	100.00%	100.00%
% ≥ 0.10 IU/mL†	98.80%	98.50%
Tetanus Antitoxoid
% ≥ 0.10 IU/mL †	99.70%	100.00%
Post-Dose 4	N = 341-352	N = 328-334
Diphtheria Antitoxin
% ≥ 0.10 IU/mL*	100.00%	100.00%
% ≥ 1.0 IU/mL†	96.50%	95.70%
Tetanus Antitoxoid
% ≥ 0.10 IU/mL*	100.00%	100.00%
% ≥ 1.0 IU/mL †‡	92.90%	99.40%
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.

Pertussis

In a clinical pertussis vaccine efficacy study conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial), 2,587 infants received DAPTACEL vaccine 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 vaccine 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 vaccine against mild pertussis ( ≥ 1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6%, 82.2%). Protection against pertussis by DAPTACEL vaccine was sustained for the 2-year follow-up period.

Based on comparisons of the immune responses to DAPTACEL vaccine 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 vaccine 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 vaccine 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 vaccine (Table 4). Available stored sera from infants who received DAPTACEL vaccine in the Sweden I Efficacy Trial and sera from children who received PCV7 concomitantly with the first three doses of Pentacel vaccine 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 vaccine in the subset of infants from the Sweden I Efficacy Trial and one month following Dose 3 and Dose 4 of Pentacel vaccine 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 vaccine relative to Dose 3 of DAPTACEL vaccine. The non-inferiority criterion for anti-PRN seroconversion following Dose 4 of Pentacel vaccine relative to Dose 3 of DAPTACEL vaccine 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 vaccine in US children relative to Dose 3 of DAPTACEL vaccine in Swedish infants correlates with diminished efficacy of Pentacel vaccine against pertussis is unknown.

Table 4: FHA, PRN and FIM Antibody Responses One Month Following Dose 3 of DAPTACEL Vaccine 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 Vaccine 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 Vaccine Sweden I Efficacy Trial N = 80	Post-Dose 3 Pentacel Vaccine* US Study 494-01 N = 730-995	Post-Dose 4 Pentacel Vaccine † US Study 494-01 N = 507-554
Anti-FHA
% achieving 4-fold rise‡	68.8	79.8	91.7§
GMC (EU/mL)	40.70	71.46	129.85§
Anti-PRN
% achieving 4-fold rise‡	98.8	74.4	89.2**
GMC (EU/mL)	111.26	38.11	90.82§
Anti-FIM
% achieving 4-fold rise‡	86.3	86.5	91.5§
GMC (EU/mL)	339.31	265.02	506.57§
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%].

In a separate study, Study P3T06, US infants were randomized to receive either Pentacel vaccine or DAPTACEL + IPOL + ActHIB vaccines 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 vaccine 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 vaccine relative to Dose 3 of DAPTACEL vaccine. Following Dose 4 of Pentacel vaccine relative to Dose 4 of DAPTACEL vaccine, 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 vaccine relative to Dose 4 of DAPTACEL vaccine in US children correlates with diminished efficacy of Pentacel vaccine against pertussis is unknown.

Table 5: Pertussis Antibody Responses One Month Following Doses 3 and 4 of Pentacel Vaccine or DAPTACEL + IPOL + ActHIB Vaccines in US Infants Vaccinated at 2, 4, 6, and 15-16 Months of Age in Study P3T06

	Post-Dose 3 Pentacel Vaccine N = 143	Post-Dose 3 DAPTACEL +IPOL + Act HIB Vaccines N = 481-485	Post-Dose 4 Pentacel Vaccine N = 113	Post-Dose 4 DAPTACEL + ActHIB Vaccines N = 127-128
Anti-PT
% achieving 4-fold rise*	95.8†	87.3	93.8‡	91.3
GMC (EU/mL)	102.62†	61.88	107.89‡	100.29
	N = 218-318	N = 714-1,016	N = 230-367	N = 237-347
Anti-FHA
% achieving 4-fold rise*	81.9§	60.9	88.4**	79.3
GMC (EU/mL)	73.68§	29.22	107.94**	64.02
Anti-PRN
% achieving 4-fold rise*	74.2§	75.4	92.7**	98.3
GMC (EU/mL)	36.05§	43.25	93.59††	186.07
Anti-FIM
% achieving 4-fold rise*	91.7§	86.3	93.5**	91.6
GMC (EU/mL)	268.15§	267.18	553.39**	513.54
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].

Poliomyelitis

In Study P3T06 (Table 1), in which infants were randomized to receive the first three doses of Pentacel vaccine or DAPTACEL + IPOL + ActHIB vaccines at 2, 4, and 6 months of age, one month following the third dose of study vaccines, ≥ 99.4% of participants in both groups (Pentacel: N = 338-350), (DAPTACEL + IPOL + ActHIB: N = 1,050-1,097) achieved neutralizing antibody levels of ≥ 1:8 for Poliovirus types 1, 2, and 3.

In Study 494-01 (Table 1), in which infants were randomized to receive Pentacel vaccine or HCPDT + POLIOVAX + ActHIB vaccines, GMTs (1/dil) of antibodies to Poliovirus types 1, 2, and 3 one month following Dose 4 of Pentacel vaccine (N = 851-857) were 2,304, 4,178, and 4,415, respectively, and one month following Dose 4 of POLIOVAX vaccine (N = 284-287) were 2,330, 2,840, and 3,300, respectively.

Invasive Disease Due To H influenzae Type b

Anti-PRP seroprotection rates and GMCs one month following Dose 3 of Pentacel vaccine or separately administered ActHIB vaccine in studies 494-01, P3T06, and M5A10 are presented in Table 6. In Study 494-01, non-inferiority criteria were not met for the proportion of participants who achieved an anti-PRP level ≥ 1.0 mcg/mL and for anti-PRP GMCs following Pentacel vaccine compared with separately administered ActHIB vaccine. In each of Studies P3T06 and M5A10, the non-inferiority criterion was met for the proportion of participants who achieved an anti-PRP level > 1.0 mcg/mL following Pentacel vaccine compared with separately administered ActHIB vaccine. In Study M5A10, the non-inferiority criterion was met for anti-PRP GMCs following Pentacel vaccine compared with separately administered ActHIB vaccine.

Table 6: Anti-PRP Seroprotection Rates and GMCs One Month Following Three Doses of Pentacel Vaccine or Separate DTaP + IPV + ActHIB Vaccines Administered at 2, 4, and 6 Months of Age in Studies 494-01, P3T06, and M5A10

	Study 494-01
	Pentacel Vaccine N = 1,127	HCPDT + POLIOVAX + ActHIB Vaccines N = 401
% achieving anti-PRP ≥ 0.15 mcg/mL	95.4*	98.3
% achieving anti-PRP ≥ 1.0 mcg/mL	79.1†	88.8
Anti-PRP GMC (mcg/mL)	3.19‡	6.23
	Study P3T06
	Pentacel Vaccine N = 365	DAPTACEL + IPOL +ActHIB Vaccines N = 1,128
% achieving anti-PRP ≥ 0.15 mcg/mL	92.3*	93.3
% achieving anti-PRP ≥ 1.0 mcg/mL	72.1*	70.8
Anti-PRP GMC (mcg/mL)	2.31 §	2.29
	Study M5A10
	Pentacel Vaccine N = 826	DAPTACEL + IPOL +ActHIB Vaccines N = 421
% achieving anti-PRP ≥ 0.15 mcg/mL	93.8**	90.3
% achieving anti-PRP ≥ 1.0 mcg/mL	75.1**	74.8
Anti-PRP GMC (mcg/mL)	2.52††	2.38
Per Protocol Immunogenicity population for all studies. IPV indicates Poliovirus Vaccine Inactivated. *Percent achieving specified level following Pentacel vaccine not inferior to ActHIB vaccine [upper limit of 90% CI for difference in rates (ActHIB minus Pentacel) < 10%]. † Non-inferiority criterion not met for percent achieving anti-PRP ≥ 1.0 mcg/mL following Pentacel vaccine relative to ActHIB vaccine [upper limit of 90% CI for difference in rates (ActHIB minus Pentacel), 12.9%, exceeds the non-inferiority criterion < 10%]. ‡ Non-inferiority criterion not met for GMC following Pentacel vaccine relative to ActHIB vaccine [upper limit of 90% CI of GMC ratio (ActHIB/Pentacel), 2.26, exceeds the non-inferiority criterion < 1.5]. § Non-inferiority criterion not pre-specified. ** Percent achieving specified level following Pentacel vaccine not inferior to ActHIB vaccine [upper limit of 95% CI for difference in rates (ActHIB minus Pentacel) < 10%]. †† GMC following Pentacel vaccine not inferior to ActHIB vaccine [upper limit of 90% CI of GMC ratio (ActHIB/Pentacel) < 1.5].

In Study 494-01, at 15 months of age prior to receipt of Dose 4 of study vaccines, 68.6% of Pentacel vaccine recipients (N = 829) and 80.8% of separately administered ActHIB vaccine recipients (N = 276) had an anti-PRP level ≥ 0.15 mcg/mL. Following Dose 4 of study vaccines, 98.2% of Pentacel vaccine recipients (N = 874) and 99.0% of separately administered ActHIB vaccine recipients (N = 291) had an anti-PRP level ≥ 1.0 mcg/mL.

In Study P3T06, at 15 months of age prior to receipt of Dose 4 of study vaccines, 65.4% of Pentacel vaccine recipients (N = 335) and 60.7% of separately administered ActHIB vaccine recipients (N = 323) had an anti-PRP level ≥ 0.15 mcg/mL. Following Dose 4 of study vaccines, 97.8% of Pentacel vaccine recipients (N = 361) and 95.9% of separately administered ActHIB vaccine recipients (N = 340) had an anti-PRP level ≥ 1.0 mcg/mL.

Concomitantly Administered Vaccines

In Study P3T06, (Table 1) there was no evidence for reduced antibody responses to hepatitis B vaccine (percent of participants with anti-HBsAg ≥ 10 mlU/mL and GMCs) or PCV7 (percent of participants with antibody levels ≥ 0.15 mcg/mL and ≥ 0.5 mcg/mL and GMCs to each serotype) administered concomitantly with Pentacel vaccine (N = 321-325) relative to these vaccines administered concomitantly with DAPTACEL + IPOL + ActHIB vaccines (N = 998-1,029). The immune responses to hepatitis B vaccine and PCV7 were evaluated one month following the third dose.

In Study 494-03, (Table 1) there was no evidence for interference in the immune response to the fourth dose of PCV7 (percent of participants with antibody levels ≥ 0.15 mcg/mL and ≥ 0.5 mcg/mL and GMCs to each serotype) administered at 15 months of age concomitantly with Pentacel vaccine (N = 155) relative to this vaccine administered concomitantly with MMR and varicella vaccines (N = 158). There was no evidence for interference in the immune response to MMR and varicella vaccines (percent of participants with pre-specified seroresponse level) administered at 15 months of age concomitantly with Pentacel vaccine (N = 154) relative to these vaccines administered concomitantly with PCV7 (N = 144). The immune responses to MMR, varicella vaccine and the fourth dose of PCV7 were evaluated one month post-vaccination.

REFERENCES

1. DAPTACEL® [full prescribing information]. Toronto, ON: Sanofi Pasteur; 2011.

13. Department of Health and Human Services, Food and Drug Administration. Biological products; bacterial vaccines and toxoids; implementation of efficacy review; proposed rule. Federal Register 1985;50(240):51002-117.

14. Vitek CR, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: W. B. Saunders; 2008. p. 139-56.

15. Wassilak SGF, et al. Tetanus toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Philadelphia, PA: W.B. Saunders; 2008. p. 805-39.

16. Sutter RW, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, et al. eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences. 1995:289-99.

17. Robbins JB, et al. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 1973;7:103- 10.

18. Peltola H, et al. Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 1977;60:730-7.

19. Kayhty H, et al. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1983; 147:1100.

20. Anderson P. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1984;149:1034.

Before administration of Pentacel vaccine, health-care personnel should inform the parent or guardian of the benefits and risks of the vaccine and the importance of completing the immunization series unless a contraindication to further immunization exists.

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Data From Clinical Studies

Rates of adverse reactions varied by dose number. The most frequent ( > 50% of participants) systemic reactions following any dose were fussiness/irritability and inconsolable crying. The most frequent ( > 30% of participants) injection site reactions following any dose were tenderness and increased circumference of the injected arm.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events.

The safety of Pentacel vaccine was evaluated in four clinical studies in which a total of 5,980 participants received at least one dose of Pentacel vaccine. In three of the studies, conducted in the US, a total of 4,198 participants were enrolled to receive four consecutive doses of Pentacel vaccine. In the fourth study, conducted in Canada, 1,782 participants previously vaccinated with three doses of Pentacel vaccine received a fourth dose. The vaccination schedules of Pentacel vaccine, Control vaccines, and concomitantly administered vaccines used in these studies are provided in Table 1.

Across the four studies, 50.8% of participants were female. Among participants in the three US studies, 64.5% were Caucasian, 9.2% were Black, 12.9% were Hispanic, 3.9% were Asian, and 9.5% were of other racial/ethnic groups. In the two controlled studies, the racial/ethnic distribution of participants who received Pentacel and Control vaccines was similar. In the Canadian fourth dose study, 86.0% of participants were Caucasian, 1.9% were Black, 0.8% were Hispanic, 4.3% were Asian, 2.0% were East Indian, 0.5% were Native Indian, and 4.5% were of other racial/ethnic groups.

Table 1: Clinical Safety Studies of Pentacel Vaccine: Vaccination Schedules

Study	Pentacel	Control Vaccines	Concomitantly Administered Vaccines
494-01	2, 4, 6 and 15 months	HCPDT + POLIOVAX + ActHIB at 2, 4, 6, and 15 months	7-valent pneumococcal conjugate vaccine* (PCV7) at 2, 4, and 6 months in a subset of participants† Hepatitis B vaccine at 2 and 6 months‡
P3T06	2, 4, 6, and 15-16 months	DAPTACEL + IPOL + ActHIB at 2, 4, and 6 months; and DAPTACEL + ActHIB at 15-16 months	PCV7* at 2, 4, and 6 months Hepatitis B vaccine at 2 and 6 months‡
494-03	2, 4, 6, and 15-16 months	None	PCV7* at 2, 4, and 6 months in all participants; and at 15 months in a random subset of participants Hepatitis B vaccine at 2 and 6 months (if a dose was previously administered)‡ or at 2, 4, and 6 months (if no previous dose) Measles, mumps, rubella vaccine§ (MMR) and varicella§ vaccine at 12 or 15 months in random subsets of participants
5A9908	15-18 months **	None	None
HCPDT: non-US licensed DTaP vaccine that is identical to the DTaP component of Pentacel vaccine. POLIOVAX: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur Limited. IPOL: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur SA. *PCV7 manufactured by Wyeth Laboratories. †PCV7 was introduced after the study was initiated, and thus, administered concomitantly with Pentacel vaccine in a subset of participants. ‡ The first dose of hepatitis B vaccine (manufacturer not specified) was administered prior to study initiation, from birth to 21 days of age. Subsequent doses were with hepatitis B vaccine manufactured by Merck and Co. § MMR and varicella vaccines were both manufactured by Merck and Co. ** Study participants previously had received three doses of Pentacel vaccine by 8 months of age.

Solicited Adverse Reactions

The incidence and severity of selected solicited injection site and systemic adverse reactions that occurred within 3 days following each dose of Pentacel or Control vaccines in Study P3T06 is shown in Table 2. Information on these reactions was recorded daily by parents or guardians on diary cards. In Table 2, injection site reactions are reported for the Pentacel vaccine and DAPTACEL vaccine injection sites.

Table 2: Number (Percentage) of Children with Selected Solicited Adverse Reactions by Severity Occurring within 0-3 days of Pentacel Vaccine or Control Vaccines in Study P3T06

Injection Site Reactions	Pentacel Vaccine				DAPTACEL Vaccine
	Dose 1 N = 465-467 %	Dose 2 N = 451 %	Dose 3 N = 438-440 %	Dose 4 N = 387-396 %	Dose 1 N = 1,400-1,404 %	Dose 2 N = 1,358-1,359 %	Dose 3 N = 1,311-1,312 %	Dose 4 N = 376-380 %
Redness
> 5 mm	7. 1	8.4	8.7	17.3	6.2	7.1	9.6	16.4
> 25 mm	2. 8	1.8	1.8	9.2	1	0.6	1.9	7.9
> 50 mm	0.6	0.2	0	2.3	0.4	0.1	0	2.4
Swelling
> 5 mm	7.5	7.3	5	9.7	4	4	6.5	10.3
> 25 mm	3	2	1.6	3.8	1.6	0.7	1.1	4
> 50 mm	0.9	0	0	0.8	0.4	0.1	0.1	1.3
Tenderness *
Any	47.5	39.2	42.7	56.1	48.8	38.2	40.9	51.1
Moderate or Severe	19.6	10.6	11.6	16.7	20.7	12.2	12.3	15.8
Severe	5.4	1.6	1.4	3.3	4.1	2.3	1.7	2.4
Increase in Arm Circumference
> 5 mm	-	-	-	33.6	-	-	-	30.6
> 20 mm	-	-	-	4.7		-	-	6.9
> 40 mm	-	-	-	0.5	-	-	-	0.8
Systemic Reactions	Pentacel Vaccine				DAPTACEL + IPOL + ActHIB Vaccines			DAPTACEL + ActHIB Vaccines
	Dose 1 N = 466-467 %	Dose 2 N = 451-452 %	Dose 3 N = 435-440 %	Dose 4 N = 389-398 %	Dose 1 N = 1,390-1,406 %	Dose 2 N = 1,346-1,360 %	Dose 3 N = 1,301-1,312 %	Dose 4 N = 379-381 %
Fever†‡
≥ 38.0°C	5.8	10.9	16.3	13.4	9.3	16.1	15.8	8.7
> 38.5°C	1.3	2.4	4.4	5.1	1.6	4.3	5.1	3.2
> 39.5°C	0.4	0	0.7	0.3	0.1	0.4	0.3	0.8
Decreased Activity/Lethargy §
Any	45.8	32.7	32.5	24.1	51.1	37.4	33.2	24.1
Moderate or Severe	22.9	12.4	12.7	9.8	24.3	15.8	12.7	9.2
Severe	2.1	0.7	0.2	2.5	1.2	1.4	0.6	0.3
Inconsolable Crying
Any	59.3	49.8	47.3	35.9	58.5	51.4	47.9	36.2
≥ 1 hour	19.7	10.6	13.6	11.8	16.4	16	12.2	10.5
> 3 hours	1.9	0.9	1.1	2.3	2.2	3.4	1.4	1.8
Fussiness/Irritability
Any	76.9	71.2	68	53.5	75.8	70.7	67.1	53.8
≥ 1 hour	34.5	27	26.4	23.6	33.3	30.5	26.2	19.4
> 3 hours	4.3	4	5	5.3	5.6	5.5	4.3	4.5
Any: Mild, Moderate or Severe; Mild: subject whimpers when site is touched; Moderate: subject cries when site is touched; Severe: subject cries when leg or arm is moved. † Fever is based upon actual temperatures recorded with no adjustments to the measurement route. ‡ Following Doses 1-3 combined, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 46.0%, 53.0%, 1.0%, and 0% respectively, for Pentacel vaccine and 44.8%, 54.0%, 1.0%, and 0.1%, respectively, for DAPTACEL + IPOL + ActHIB vaccines. Following Dose 4, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 62.7%, 34.4%, 2.4% and 0.5%, respectively, for Pentacel vaccine, and 61.1%, 36.6%, 1.7% and 0.5%, respectively, for DAPTACEL + ActHIB vaccines. § Moderate: interferes with or limits usual daily activity; Severe: disabling, not interested in usual daily activity.

Hypotonic Hyporesponsive Episodes

In Study P3T06, the diary cards included questions pertaining to HHEs. In Studies 494-01, 494-03, and 5A9908, a question about the occurrence of fainting or change in mental status was asked during post-vaccination phone calls. Across these 4 studies, no HHEs, as defined in a report of a US Public Health Service workshop4 were reported among participants who received Pentacel vaccine (N = 5,979), separately administered HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032) or separately administered DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). Hypotonia not fulfilling HHE criteria within 7 days following vaccination was reported in 4 participants after the administration of Pentacel vaccine (1 on the same day as the 1st dose; 3rd on the same day as the 3 dose) and in 1 participant after the administration of DAPTACEL + IPOL + ActHIB vaccines (4 days following the 1st dose).

Seizures

Across Studies 494-01, 494-03, 5A9908 and P3T06, a total of 8 participants experienced a seizure within 7 days following either Pentacel vaccine (4 participants; N = 4,197 for at least one of Doses 1-3; N = 5,033 for Dose 4), separately administered HCPDT + POLIOVAX + ActHIB vaccines (3 participants; N = 1,032 for at least one of Doses 1-3, N = 739 for Dose 4), separately administered DAPTACEL + IPOL + ActHIB vaccines (1 participant; N = 1,455 for at least one of Doses 1-3), or separately administered DAPTACEL + ActHIB vaccines (0 participants; N = 418 for Dose 4). Among the four participants who experienced a seizure within 7 days following Pentacel vaccine, one participant in Study 494-01 had an afebrile seizure 6 days after the first dose, one participant in Study 494-01 had a possible seizure the same day as the third dose, and two participants in Study 5A9908 had a febrile seizure 2 and 4 days, respectively, after the fourth dose. Among the four participants who experienced a seizure within 7 days following Control vaccines, one participant had an afebrile seizure the same day as the first dose of DAPTACEL + IPOL + ActHIB vaccines, one participant had an afebrile seizure the same day as the second dose of HCPDT + POLIOVAX + ActHIB vaccines, and two participants had a febrile seizure 6 and 7 days, respectively, after the fourth dose of HCPDT + POLIOVAX + ActHIB vaccines.

Serious Adverse Events

In Study P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 19 of 484 (3.9%) participants who received Pentacel vaccine and 50 of 1,455 (3.4%) participants who received DAPTACEL + IPOL + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 5 of 431 (1.2%) participants who received Pentacel vaccine and 4 of 418 (1.0%) participants who received DAPTACEL + ActHIB vaccines experienced a serious adverse event. In Study 494-01, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 23 of 2,506 (0.9%) participants who received Pentacel vaccine and 11 of 1,032 (1.1%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 6 of 1,862 (0.3%) participants who received Pentacel vaccine and 2 of 739 (0.3%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event.

Across Studies 494-01, 494-03 and P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were bronchiolitis, dehydration, pneumonia and gastroenteritis. Across Studies 494-01, 494-03, 5A9908 and P3T06, within 30 days following Dose 4 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were dehydration, gastroenteritis, asthma, and pneumonia.

Across Studies 494-01, 494-03, 5A9908 and P3T06, two cases of encephalopathy were reported, both in participants who had received Pentacel vaccine (N = 5,979). One case occurred 30 days post-vaccination and was secondary to cardiac arrest following cardiac surgery. One infant who had onset of neurologic symptoms 8 days post-vaccination was subsequently found to have structural cerebral abnormalities and was diagnosed with congenital encephalopathy.

A total of 5 deaths occurred during Studies 494-01, 494-03, 5A9908 and P3T06: 4 in children who had received Pentacel vaccine (N = 5,979) and one in a participant who had received DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). There were no deaths reported in children who received HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032). Causes of death among children who received Pentacel vaccine were asphyxia due to suffocation, head trauma,

Sudden Infant Death syndrome, and neuroblastoma (8, 23, 52 and 256 days post-vaccination, respectively). One participant with ependymoma died secondary to aspiration 222 days following DAPTACEL + IPOL + ActHIB vaccines.

Data From Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of Pentacel vaccine worldwide, since 1997. Between 1997 and 2007, Pentacel vaccine was primarily used in Canada. Because these events are reported voluntarily from a population of uncertain size, it may not be possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Pentacel vaccine.

Cardiac Disorders

Cyanosis

Gastrointestinal Disorders

Vomiting, diarrhea

General Disorders and Administration Site Conditions

Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H influenzae type b disease)

Immune System Disorders

Anaphylaxis/anaphylactic reaction, hypersensitivity (such as rash and urticaria)

Infections and Infestations

Meningitis, rhinitis, viral infection

Metabolism and Nutrition Disorders

Decreased appetite

Nervous System Disorders

Somnolence, HHE, depressed level of consciousness

Psychiatric Disorders

Screaming

Respiratory, Thoracic and Mediastinal Disorders

Apnea, cough

Skin and Subcutaneous Tissue Disorders Erythema, Skin Discoloration

Vascular disorders Pallor

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