Diptheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus Vaccine

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice.

A total of 4,013 children were vaccinated with a single dose of KINRIX in 4 clinical trials. Of these, 381 children received a non-US formulation of KINRIX (containing ≤ 2.5 mg 2-phenoxyethanol per dose as preservative).

The primary study (Study 048), conducted in the United States, was a randomized, controlled clinical trial in which children 4 to 6 years of age were vaccinated with KINRIX (N = 3,156) or control vaccines (INFANRIX and IPOL® vaccine [IPV, Sanofi Pasteur SA]; N = 1,053) as a fifth DTaP vaccine dose following 4 doses of INFANRIX and as a fourth IPV dose following 3 doses of IPOL. Subjects also received the second dose of US-licensed measles, mumps, and rubella (MMR) vaccine (Merck & Co., Inc.) administered concomitantly, at separate sites.

Data on adverse events were collected by parents/guardians using standardized forms for 4 consecutive days following vaccination with KINRIX or control vaccines (i.e., day of vaccination and the next 3 days). The reported frequencies of solicited local reactions and general adverse events in Study 048 are presented in Table 1.

In 3 studies (Studies 046, 047, and 048), children were monitored for unsolicited adverse events, including serious adverse events, that occurred in the 31-day period following vaccination and in 2 studies (Studies 047 and 048), parents/guardians were actively queried about changes in the child's health status, including the occurrence of serious adverse events, through 6 months post-vaccination.

Table 1: Percentage of Children 4 to 6 Years of Age Reporting Solicited Local Reactions or General Adverse Events Within 4 Days of Vaccinationa With KINRIX or Separate Concomitant Administration of INFANRIX and IPV When Coadministered With MMR Vaccine (Study 048) (Total Vaccinated Cohort)

In Study 048, KINRIX was non-inferior to INFANRIX with regard to swelling that involved > 50% of the injected upper arm length and that was associated with a > 30 mm increase in mid-upper arm circumference within 4 days following vaccination (upper limit of two-sided 95% Confidence Interval for difference in percentage of KINRIX [0.6%, n = 20] minus INFANRIX [1.0%, n = 11] ≤ 2%).

Within the 31-day period following study vaccination in 3 studies (Studies 046, 047, and 048), in which all subjects received concomitant MMR vaccine (US-licensed MMR vaccine [Merck & Co., Inc.] in Studies 047 and 048; non-US-licensed MMR vaccine in Study 046), 3 subjects (0.1% [3/3,537]) who received KINRIX reported serious adverse events (dehydration and hypernatremia; cerebrovascular accident; dehydration and gastroenteritis) and 4 subjects (0.3% [4/1,434]) who received INFANRIX and inactivated poliovirus vaccine (Sanofi Pasteur SA) reported serious adverse events (cellulitis, constipation, foreign body trauma, fever without identified etiology).

Postmarketing Experience

In addition to reports in clinical trials, the following adverse events, for which a causal relationship to components of KINRIX is plausible, have been reported since market introduction. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

General Disorders and Administration Site Conditions: Injection site vesicles.

Nervous System Disorders: Syncope.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Additional adverse events reported following postmarketing use of INFANRIX, for which a causal relationship to vaccination is plausible, are: Allergic reactions, including anaphylactoid reactions, anaphylaxis, angioedema, and urticaria; apnea; collapse or shock-like state (hypotonic-hyporesponsive episode); convulsions (with or without fever); lymphadenopathy; and thrombocytopenia.

Mechanism of Action

Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection; a level of 0.1 IU/mL is regarded as protective.1

Tetanus is an acute toxin-mediated disease caused by a potent exotoxin released by C. tetani. Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.2,3 A level of ≥ 0.1 IU/mL is considered protective.4

Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood. There is no well established serological correlate of protection for pertussis. The efficacy of the pertussis component of KINRIX was determined in clinical trials of INFANRIX administered as a 3-dose series in infants (see INFANRIX prescribing information).

Poliovirus is an enterovirus that belongs to the picornavirus family. Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Neutralizing antibodies against the 3 poliovirus serotypes are recognized as conferring protection against poliomyelitis disease.5

Clinical Studies

In a US multicenter study (Study 048), 4,209 children were randomized in a 3:1 ratio to receive either KINRIX or INFANRIX and IPV (Sanofi Pasteur SA) administered concomitantly at separate sites. Subjects also received MMR vaccine (Merck & Co., Inc.) administered concomitantly at a separate site. Subjects were children 4 through 6 years of age who previously received 4 doses of INFANRIX, 3 doses of IPV, and 1 dose of MMR vaccine. Among subjects in both vaccine groups combined, 49.6% were female; 45.6% of subjects were white, 18.8% Hispanic, 13.6% Asian, 7.0% black, and 15.0% were of other racial/ethnic groups.

Levels of antibodies to the diphtheria, tetanus, pertussis (PT, FHA, and pertactin), and poliovirus antigens were measured in sera obtained immediately prior to vaccination and 1 month (range: 31 to 48 days) after vaccination (Table 2). The co-primary immunogenicity endpoints were anti-diphtheria toxoid, anti-tetanus toxoid, anti-PT, anti-FHA, and anti-pertactin booster responses, and anti-poliovirus Type 1, Type 2, and Type 3 geometric mean antibody titers (GMTs) 1 month after vaccination. KINRIX was shown to be non-inferior to INFANRIX and IPV administered separately, in terms of booster responses to DTaP antigens and post-vaccination GMTs for anti-poliovirus antibodies (Table 2).

Table 2: Pre-Vaccination Antibody Levels and Post-Vaccinationa Antibody Responses Following KINRIX Compared With Separate Concomitant Administration of INFANRIX and IPV in Children 4 to 6 Years of AgeWhen Coadministered With MMR Vaccine (Study 048) (ATP Cohort for Immunogenicity)

In a US study (Study 055) that enrolled children 4 to 6 years of age, KINRIX was administered concomitantly at separate sites with MMR vaccine (Merck & Co., Inc.) [N = 237] or with MMR vaccine and varicella vaccine (Merck & Co., Inc.) [N = 239]. Immune responses to the antigens contained in KINRIX were measured approximately one month (28 to 48 days) after vaccination. Booster responses to diphtheria, tetanus, and pertussis antigens and GMTs for poliovirus (Type 1, 2, and 3) after the receipt of KINRIX administered concomitantly with MMR vaccine and varicella vaccine were non-inferior to immune responses following concomitant administration of KINRIX administered with MMR vaccine.

REFERENCES

1. Vitek CR and Wharton M. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:139-156.

2. Wassilak SGF, Roper MH, Kretsinger K, and Orenstein WA. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, and Offit PA, eds. Vaccines. 5th ed. Saunders; 2008:805-839.

3. Department of Health and Human Services, Food and Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review; Proposed rule. Federal Register December 13, 1985;50(240):51002-51117.

4. Centers for Disease Control and Prevention. General Recommendations on Immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR-15):1-48.

5. Sutter RW, Pallansch MA, Sawyer LA, et al. Defining surrogate serologic tests with respect to predicting protective vaccine efficacy: Poliovirus vaccination. In: Williams JC, Goldenthal KL, Burns DL, Lewis Jr BP, eds. Combined vaccines and simultaneous administration. Current issues and perspectives. New York, NY: The New York Academy of Sciences; 1995:289-299.

Parents or guardians should be:

• informed of the potential benefits and risks of immunization with KINRIX.
• informed about the potential for adverse reactions that have been temporally associated with administration of KINRIX or other vaccines containing similar components.
• given the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization. These materials are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Contact your doctor if you will miss a booster dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure your child receives all recommended doses in the DTaP and IPV series. If your child does not receive the full series of vaccines, he or she may not be fully protected against the disease.

Follow your doctor's instructions about any restrictions on food, beverages, or activity after receiving the vaccine.

Your doctor or pharmacist may have information about this vaccine written for health professionals that you may read. You may also find additional information from your local health department or the Centers for Disease Control and Prevention.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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