Pentacel® is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis, poliomyelitis and invasive disease due to Haemophilus influenzae type b. Pentacel vaccine is approved for use as a four dose series in children 6 weeks through 4 years of age (prior to fifth birthday).
2. DOSAGE AND ADMINISTRATION
. Immunization Series
Pentacel vaccine is to be administered as a 4 dose series at 2, 4, 6 and 15-18 months of age. The first dose may be given as early as 6 weeks of age. Four doses of Pentacel vaccine constitute a primary immunization course against pertussis. Three doses of Pentacel vaccine constitute a primary immunization course against diphtheria, tetanus, H influenzae type b invasive disease, and poliomyelitis; the fourth dose is a booster for diphtheria, tetanus, H influenzae type b invasive disease, and poliomyelitis immunizations. [See 14 Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5).]
Mixed Sequences of Pentacel Vaccine and DTaP Vaccine
While Pentacel and DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [DTaP], Sanofi Pasteur Limited) vaccines contain the same pertussis antigens, manufactured by the same process, Pentacel vaccine contains twice the amount of detoxified pertussis toxin (PT) and four times the amount of filamentous hemagglutinin (FHA) as DAPTACEL vaccine. Pentacel vaccine may be used to complete the first 4 doses of the 5-dose DTaP series in infants and children who have received 1 or more doses of DAPTACEL vaccine and are also scheduled to receive the other antigens of Pentacel vaccine. Children who have completed a 4-dose series with Pentacel vaccine should receive a fifth dose of DTaP vaccine using DAPTACEL at 4-6 years of age. However, data are not available on the safety and immunogenicity of mixed sequences of Pentacel vaccine and DAPTACEL vaccine for successive doses of the DTaP series.
Data are not available on the safety and immunogenicity of using mixed sequences of Pentacel vaccine and DTaP vaccine from different manufacturers.
Mixed Sequences of Pentacel Vaccine and IPV Vaccine
Pentacel vaccine may be used in infants and children who have received 1 or more doses of another licensed IPV vaccine and are scheduled to receive the antigens of Pentacel vaccine. However, data are not available on the safety and immunogenicity of Pentacel vaccine in such infants and children.
The Advisory Committee on Immunization Practices (ACIP) recommends that the final dose in the 4-dose IPV series be administered at age ≥4 years. (1) When Pentacel vaccine is administered at ages 2, 4, 6, and 15-18 months, an additional booster dose of IPV vaccine should be administered at age 4-6 years, resulting in a 5-dose IPV series. (1)
Mixed Sequences of Pentacel Vaccine and Haemophilus b Conjugate Vaccine
Pentacel vaccine may be used to complete the vaccination series in infants and children previously vaccinated with one or more doses of Haemophilus b Conjugate Vaccine (either separately administered or as part of another combination vaccine), who are also scheduled to receive the other antigens of Pentacel vaccine. However, data are not available on the safety and immunogenicity of Pentacel vaccine in such infants and children. If different brands of Haemophilus b Conjugate Vaccines are administered to complete the series, three primary immunizing doses are needed, followed by a booster dose.
. Administration
Just before use, thoroughly but gently shake the vial of DTaP-IPV component, withdraw the entire liquid content and inject into the vial of the lyophilized ActHIB vaccine component. Shake the vial now containing Pentacel vaccine thoroughly until a cloudy, uniform, white to off-white (yellow tinge) suspension results. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If these conditions exist, Pentacel vaccine should not be administered.
Withdraw and administer a 0.5 mL dose of Pentacel vaccine intramuscularly. Pentacel vaccine should be used immediately after reconstitution. Refer to Figures 1, 2, 3, 4 and 5.
Pentacel Vaccine: Instructions For Reconstitution of ActHIB Vaccine Component With DTaP-IPV Component
In infants younger than 1 year, the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for injection. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk.
Do not administer this product intravenously or subcutaneously.
Pentacel vaccine should not be mixed in the same syringe with other parenteral products.
3. DOSAGE FORMS AND STRENGTHS
Pentacel vaccine is a suspension for injection (0.5-mL dose) supplied as a liquid vaccine component that is combined through reconstitution with a lyophilized vaccine component, both in single dose vials. [See Dosage and Administration (2.2) and How Supplied/Storage and Handling (16).]
4. CONTRAINDICATIONS
. Hypersensitivity
A severe allergic reaction (eg, anaphylaxis) after a previous dose of Pentacel vaccine or any other diphtheria toxoid, tetanus toxoid, or pertussis-containing vaccine, inactivated poliovirus vaccine or H influenzae type b vaccine, or any ingredient of this vaccine is a contraindication to administration of Pentacel vaccine. [See Description (11).]
. Encephalopathy
Encephalopathy (eg, coma, decreased level of consciousness, prolonged seizures) within 7 days of a previous dose of a pertussis containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis-containing vaccine, including Pentacel vaccine.
. Progressive Neurologic Disorder
Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy is a contraindication to administration of any pertussis-containing vaccine including Pentacel vaccine. Pertussis vaccine should not be administered to individuals with such conditions until a treatment regimen has been established and the condition has stabilized.
5. WARNINGS AND PRECAUTIONS
. Management of Acute Allergic Reactions
Epinephrine hydrochloride solution (1:1,000) and other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.
. Adverse Reactions Following Prior Pertussis Vaccination
If any of the following events occur within the specified period after administration of a pertussis vaccine, the decision to administer Pentacel vaccine should be based on careful consideration of potential benefits and possible risks.
- Temperature of ≥40.5°C (≥105°F) within 48 hours, not attributable to another identifiable cause.
- Collapse or shock-like state (hypotonic-hyporesponsive episode (HHE)) within 48 hours.
- Persistent, inconsolable crying lasting ≥3 hours within 48 hours.
- Seizures with or without fever within 3 days.
. Guillain-Barré Syndrome and Brachial Neuritis
A review by the Institute of Medicine (IOM) found evidence for a causal relation between tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome. (2) If Guillain-Barré syndrome occurred within 6 weeks of receipt of prior vaccine containing tetanus toxoid, the decision to give Pentacel vaccine or any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks.
. Infants and Children with a History of Previous Seizures
For infants or children with a history of previous seizures, an appropriate antipyretic may be administered (in the dosage recommended in its prescribing information) at the time of vaccination with a vaccine containing acellular pertussis antigens (including Pentacel vaccine) and for the following 24 hours, to reduce the possibility of post-vaccination fever.
. Limitations of Vaccine Effectiveness
Vaccination with Pentacel vaccine may not protect all individuals.
. Altered Immunocompetence
If Pentacel vaccine is administered to immunocompromised persons, including persons receiving immunosuppressive therapy, the expected immune response may not be obtained. [See Drug Interactions (7.2).]
6. ADVERSE REACTIONS
. 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 |
|---|
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. |
|
| 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 |
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 |
0.6 |
1.9 |
7.9 |
| >50 mm |
0.6 |
0.2 |
0.0 |
2.3 |
0.4 |
0.1 |
0.0 |
2.4 |
| Swelling |
|
|
|
|
|
|
|
|
| >5 mm |
7.5 |
7.3 |
5.0 |
9.7 |
4.0 |
4.0 |
6.5 |
10.3 |
| >25 mm |
3.0 |
2.0 |
1.6 |
3.8 |
1.6 |
0.7 |
1.1 |
4.0 |
| >50 mm |
0.9 |
0.0 |
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 |
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 |
16.0 |
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 |
68.0 |
53.5 |
75.8 |
70.7 |
67.1 |
53.8 |
| ≥1 hour |
34.5 |
27.0 |
26.4 |
23.6 |
33.3 |
30.5 |
26.2 |
19.4 |
| >3 hours |
4.3 |
4.0 |
5.0 |
5.3 |
5.6 |
5.5 |
4.3 |
4.5 |
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 workshop (3) 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; 3 on the same day as the 3rd 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
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
7. DRUG INTERACTIONS
. Concomitant Administration with Other Vaccines
In clinical trials, Pentacel vaccine was administered concomitantly with one or more of the following US licensed vaccines: hepatitis B vaccine, 7-valent pneumococcal conjugate vaccine, MMR and varicella vaccines. [See Adverse Reactions (6) and Clinical Studies (14).] When Pentacel vaccine is given at the same time as another injectable vaccine(s), the vaccine(s) should be administered with different syringes and at different injection sites.
. Immunosuppressive Treatments
Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Pentacel vaccine. [See Warnings and Precautions (5.6).]
. Drug/Laboratory Test Interactions
Antigenuria has been detected in some instances following receipt of ActHIB vaccine. Urine antigen detection may not have definite diagnostic value in suspected H influenzae type b disease within one week following receipt of Pentacel vaccine. (4)
8. USE IN SPECIFIC POPULATIONS
. Pregnancy
Pregnancy Category C
Animal reproduction studies have not been conducted with Pentacel vaccine. It is also not known whether Pentacel vaccine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.
. Pediatric Use
The safety and effectiveness of Pentacel vaccine was established in the age group 6 weeks through 18 months on the basis of clinical studies. [See Adverse Reactions (6.1) and Clinical Studies (14).] The safety and effectiveness of Pentacel vaccine in the age group 19 months through 4 years is supported by evidence in children 6 weeks through 18 months. The safety and effectiveness of Pentacel vaccine in infants less than 6 weeks of age and in children 5 to 16 years of age have not been established.
11. DESCRIPTION
Pentacel vaccine consists of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus (DTaP-IPV) component and an ActHIB® vaccine component combined through reconstitution for intramuscular injection. ActHIB vaccine (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]), consists of H influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]) covalently bound to tetanus toxoid (PRP-T). The DTaP-IPV component is supplied as a sterile liquid used to reconstitute the lyophilized ActHIB vaccine component to form Pentacel vaccine. Pentacel vaccine is a uniform, cloudy, white to off-white (yellow tinge) suspension.
Each 0.5 mL dose contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens [20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)], inactivated polioviruses [40 D-antigen units (DU) Type 1 (Mahoney), 8 DU Type 2 (MEF-1), 32 DU Type 3 (Saukett)] and 10 mcg PRP of H influenzae type b covalently bound to 24 mcg of tetanus toxoid (PRP-T).
Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm by calculation), ≤5 mcg residual formaldehyde, <50 ng residual glutaraldehyde, ≤50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative), <4 pg of neomycin and <4 pg polymyxin B sulfate.
Corynebacterium diphtheriae is grown in modified Mueller's growth medium. (5) After purification by ammonium sulfate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered.
Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (6) 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 acellular pertussis vaccine antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (7) 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 copurified 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 separately onto aluminum phosphate.
Poliovirus Type 1, Type 2 and Type 3 are each grown in separate cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier method. (8) (9) The cells are grown in CMRL (Connaught Medical Research Laboratories) 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration, and purified by liquid chromatography steps. The monovalent viral suspensions are inactivated with formaldehyde. Monovalent concentrates of each inactivated poliovirus are combined to produce a trivalent poliovirus concentrate.
The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection, into an intermediate concentrate. The trivalent poliovirus concentrate is added and the DTaP-IPV component is diluted to its final concentration. The DTaP-IPV component does not contain a preservative.
Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL in the guinea pig potency test. The potency of the acellular pertussis antigens is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The immunogenicity of the inactivated polioviruses is evaluated by the antibody response in monkeys measured by virus neutralization.
PRP, a high molecular weight polymer, is prepared from the Haemophilus influenzae type b strain 1482 grown in a semi-synthetic medium. (10) The tetanus toxoid for conjugation to PRP is prepared by ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (11) The toxoid is filter sterilized prior to the conjugation process. The ActHIB vaccine component does not contain a preservative. Potency of the ActHIB vaccine component is specified on each lot by limits on the content of PRP polysaccharide and protein per dose and the proportion of polysaccharide and protein that is characterized as high molecular weight conjugate.
The vial stoppers for the DTaP-IPV and ActHIB vaccine components of Pentacel vaccine do not contain natural latex rubber.
12. CLINICAL PHARMACOLOGY
. 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. (12) Levels of 1.0 IU/mL have been associated with long-term protection. (13)
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. (12) (14) 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. (15)
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 studies (16) and an efficacy study with H influenzae type b polysaccharide vaccine in Finland, (17) 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 H influenzae type
