Adacel (Tetanus Diphtheria Pertussis Vaccine) - Description and Clinical Pharmacology

Adacel^®

Tdap

Rx only

DESCRIPTION

Adacel^®, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap), is a sterile liquid suspension of tetanus and diphtheria toxoids and acellular pertussis components adsorbed onto aluminum phosphate, for intramuscular administration. After shaking, the vaccine is a white, homogenous, cloudy suspension.

Each dose of Adacel vaccine (0.5 mL) contains the following active ingredients:

Acellular Pertussis
Detoxified Pertussis Toxin (PT)	2.5 µg
Filamentous Hemagglutinin (FHA)	5 µg
Pertactin (PRN)	3 µg
Fimbriae Types 2 and 3 (FIM)	5 µg
Tetanus Toxoid (T)	5 Lf
Diphtheria Toxoid (d)	2 Lf

Other ingredients per dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, ≤5 µg residual formaldehyde, <50 ng residual glutaraldehyde and 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative). The antigens are the same as those in DAPTACEL^®, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP); however, Adacel vaccine is formulated with reduced quantities of d and detoxified PT.

The acellular pertussis vaccine components are obtained from Bordetella pertussis cultures grown in Stainer-Scholte medium (1) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and co-purified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde, FHA is treated with formaldehyde, and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed onto aluminum phosphate.

Corynebacterium diphtheriae is grown in modified Mueller's growth medium. (2) After purification by ammonium sulfate fractionation, diphtheria toxin is detoxified with formaldehyde and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (3) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The adsorbed diphtheria, tetanus and acellular pertussis components are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection.

Tetanus and diphtheria toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The tetanus component induces at least 2 neutralizing units/mL of serum and the diphtheria component induces at least 0.5 neutralizing units/mL of serum. The potency of the acellular pertussis vaccine components is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA).

CLINICAL PHARMACOLOGY

Background

Tetanus

Tetanus is an acute and often fatal disease caused by an extremely potent neurotoxin produced by C tetani. The toxin causes neuromuscular dysfunction, with rigidity and spasms of skeletal muscles. The muscle spasms usually involve the jaw (lockjaw) and neck and then become generalized.

Spores of C tetani are ubiquitous. Serological tests indicate that naturally acquired immunity to tetanus toxin does not occur in the US. Thus, universal primary immunization, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect all age groups. Following immunization, protection generally persists for at least 10 years. (4)

Diphtheria

C diphtheriae may cause both localized and generalized disease. The systemic intoxication is caused by diphtheria exotoxin, an extracellular protein metabolite of toxigenic strains of C diphtheriae. Both toxigenic and nontoxigenic strains of C diphtheriae can cause disease, but only strains that produce toxin can cause severe manifestations such as myocarditis and neuritis. Toxigenic strains are more often associated with severe or fatal respiratory infections than with cutaneous infections.

Complete immunization significantly reduces the risk of developing diphtheria and immunized persons who develop disease have milder illness.

Immunization with diphtheria toxoid does not, however, eliminate carriage of C diphtheriae in the pharynx, nose, or on the skin. Following immunization, protection lasts at least 10 years. (4)

Pertussis

Pertussis (whooping cough) is a disease of the respiratory tract, most often caused by B pertussis. This gram-negative coccobacillus produces a variety of biologically active components, though their role in pathogenesis is not clearly defined.

Mechanism of Action

Protection against disease attributable to C tetani is due to the development of neutralizing antiboides to tetanus toxin. A serum antitoxin level of ≥0.1 IU/mL is considered protective, although a level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (5) Protection against disease attributable to C diphtheriae is due to the development of neutralizing antibodies to diphtheria toxin. A serum 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. (6) Levels of 1.0 IU/mL have been associated with long-term protection. (7)

The mechanism of protection from B pertussis disease is not well understood. However, the pertussis components in Adacel vaccine (i.e., detoxified PT, FHA, PRN and FIM) have been shown to prevent pertussis in infants in a clinical trial with DAPTACEL vaccine. (See Clinical Studies.)

Clinical Studies

The efficacy of the tetanus toxoid and diphtheria toxoid used in Adacel vaccine was based on the immune response to these antigens compared to a US licensed Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine manufactured by Sanofi Pasteur Inc., Swiftwater, PA. The primary measures of immunogenicity were (a) the percentage of participants attaining an antibody level of at least 0.1 IU/mL and (b) the percentage of participants achieving a rise in antibody concentration after vaccination (booster response). The demonstration of a booster response depended on the antibody concentration to each antigen prior to immunization. Threshold or "cut-off" values for antibody concentrations to each antigen were established based on the 95^th percentile of the pre-vaccination antibody concentrations observed in previous clinical trials. A booster response was defined as a four-fold rise in antibody concentration if the pre-vaccination concentration was equal to or below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value.

The efficacy of the pertussis antigens used in Adacel vaccine was inferred based on a comparison of pertussis antibody levels achieved in recipients of a single booster dose of Adacel vaccine with those obtained in infants after three doses of DAPTACEL vaccine. In the Sweden I Efficacy Trial, three doses of DAPTACEL vaccine were shown to confer a protective efficacy of 84.9% (95% CI: 80.1%, 88.6%) against WHO defined pertussis (21 days of paroxysmal cough with laboratory-confirmed B pertussis infection or epidemiological link to a confirmed case). The protective efficacy against mild pertussis (defined as at least one day of cough with laboratory-confirmed B pertussis infection) was 77.9% (95% CI: 72.6%, 82.2%). (8) (9) In addition, the ability of Adacel vaccine to elicit a booster response to the pertussis antigens following vaccination was evaluated. The acellular pertussis formulations for Adacel and DAPTACEL vaccines differ only in the amount of detoxified PT (2.5 µg in Adacel vaccine versus 10 µg in DAPTACEL vaccine).

The principal immunogenicity study was a comparative, multi-center, randomized, observer-blind, controlled trial which enrolled 4,480 participants; 2,053 adolescents (11-17 years of age) and 2,427 adults (18-64 years of age). Enrollment was stratified by age to ensure adequate representation across the entire age range. Participants had not received a tetanus or diphtheria toxoid containing vaccine within the previous 5 years. After enrollment participants were randomized to receive one dose of either Adacel vaccine or Td vaccine. A total of 4,461 randomized participants were vaccinated. The per-protocol immunogenicity subset included 1,270 Adacel vaccine recipients and 1,026 Td vaccine recipients. Sera were obtained before and approximately 35 days after vaccination. (Blinding procedures for safety assessments are described in the ADVERSE REACTIONS section.)

Demographic characteristics were similar within age groups and between the vaccine groups. A total of 76% of the adolescents and 1.1% of the adults reported a history of receiving 5 previous doses of diphtheria-tetanus-pertussis containing vaccines. Anti-tetanus and anti-diphtheria seroprotection rates (≥0.1 IU/mL) and booster response rates were comparable between Adacel and Td vaccines. (See Table 1 and Table 2.) Adacel vaccine induced pertussis antibody levels that were non-inferior to those of Swedish infants who received three doses of DAPTACEL vaccine. (See Table 3.) Acceptable booster responses to each of the pertussis antigens were also demonstrated, i.e., the percentage of participants with a booster response exceeded the pre-defined lower limit. (9) (See Table 4.)

Table 1: Pre-vaccination and Post-vaccination Antibody Responses and Booster Response Rates to Tetanus Toxoid Following Adacel Vaccine as Compared to Td Vaccine

			Tetanus Antitoxin (IU/mL)
			Pre-Vaccination		1 Month Post-Vaccination
Age Group (years)	Vaccine	NN = number of participants in the per-protocol population with available data.	% ≥0.10   (95% CI)	% ≥1.0   (95% CI)	% ≥0.10   (95% CI)	% ≥1.0   (95% CI)	% BoosterBooster response is defined as: A four-fold rise in antibody concentration, if the pre-vaccination concentration was equal to or below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value. The cut-off value for tetanus was 2.7 IU/mL.   (95% CI)
11-17	Adacel	527	99.6   (98.6, 100.0)	44.6   (40.3, 49.0)	100.0 1   (99.3, 100.0)	99.6 2   (98.6, 100.0)	91.7   (89.0, 93.9)
	Td 3	516	99.2   (98.0, 99.8)	43.8   (39.5, 48.2)	100.0   (99.3, 100.0)	99.4   (98.3, 99.9)	91.3   (88.5, 93.6)
18-64	Adacel	742- 743	97.3   (95.9, 98.3)	72.9   (69.6, 76.1)	100.0   (99.5, 100.0)	97.8   (96.5, 98.8)	63.1   (59.5, 66.6)
	Td	509	95.9   (93.8, 97.4)	70.3   (66.2, 74.3)	99.8   (98.9, 100.0)	98.2   (96.7, 99.2)	66.8   (62.5, 70.9)

CONCURRENTLY ADMINISTERED VACCINES

Hepatitis B Vaccine

The concomitant use of Adacel vaccine and hepatitis B (Hep B) vaccine (Recombivax HB^®, 10 μg per dose using a two-dose regimen, manufactured by Merck and Co., Inc) was evaluated in a multi-center, open-labeled, randomized, controlled study that enrolled 410 adolescents, 11-14 years of age inclusive. One group received Adacel and Hep B vaccines concurrently (N = 206). The other group (N = 204) received Adacel vaccine at the first visit, then 4-6 weeks later received Hep B vaccine. The second dose of Hep B vaccine was given 4-6 weeks after the first dose. Serum samples were obtained prior to and 4-6 weeks after Adacel vaccine administration, as well as 4-6 weeks after the 2^nd dose of Hep B for all participants. No interference was observed in the immune responses to any of the vaccine antigens when Adacel and Hep B vaccines were given concurrently or separately. (9) (See DOSAGE AND ADMINISTRATION, Concomitant Vaccine Administration.)

Trivalent Inactivated Influenza Vaccine

The concomitant use of Adacel vaccine and trivalent inactivated influenza vaccine (TIV, Fluzone^®, manufactured by Sanofi Pasteur Inc., Swiftwater, PA) was evaluated in a multi-center, open-labeled, randomized, controlled study conducted in 720 adults, 19-64 years of age inclusive. In one group, participants received Adacel and TIV vaccines concurrently (N = 359). The other group received TIV at the first visit, then 4-6 weeks later received Adacel vaccine (N = 361). Sera were obtained prior to and 4-6 weeks after Adacel vaccine, as well as 4-6 weeks after the TIV. The immune responses were comparable for concurrent and separate administration of Adacel and TIV vaccines for diphtheria (percent of participants with seroprotective concentration ≥0.10 IU/mL and booster responses), tetanus (percent of participants with seroprotective concentration ≥0.10 IU/mL), pertussis antigens (booster responses and GMCs except lower PRN GMC in the concomitant group, lower bound of the 90% CI was 0.61 and the pre-specified criterion was ≥0.67) and influenza antigens (percent of participants with hemagglutination-inhibition [HI] antibody titer ≥1:40 IU/mL and ≥4-fold rise in HI titer). Although tetanus booster response rates were significantly lower in the group receiving the vaccines concurrently versus separately, greater than 98% of participants in both groups achieved seroprotective levels of ≥0.1 IU/mL. (9) (See DOSAGE AND ADMINISTRATION, Concomitant Vaccine Administration.)