Pharmacology Update

Pneumococcal Conjugate Vaccine 7-Valent (Prevnar- Wyeth Laboratories)

By William T. Elliott, MD, FACP and James Chan, PharmD, PhD

The fda has approved a new pneumococcal vaccine for use in children. The 7-valent pneumococcal conjugate vaccine (diphtheria CRM197 protein) was given approval in February for the prevention of invasive pneumococcal disease in infants and young children. Streptococcus pneumoniae is a leading cause of serious illness in young children including bacteremia, meningitis, pneumonia, and upper respiratory tract infections such as otitis media. The 7-valent vaccine covers serotypes that account for approximately 80% of invasive pneumococcal disease in children younger than 6 years of age.1 The vaccine is marketed by Wyeth-Ayerst Laboratories under the name of Prevnar.

Indications

The vaccine is indicated for active immunization of infants and toddlers against invasive disease caused by S. pneumoniae due to capsular serotypes (4, 6B, 9V, 14, 18C, 19F, and 23 F).

Dosage

The routine immunization schedule is 2, 4, 6, and 12 -15 months of age. For previously unvaccinated infants 7-11 months of age, two doses should be administered at least four weeks apart and the third dose after the 1-year birthday, separated from the second dose by at least two months. For children 12-23 months of age, two doses should be administered at least two months apart. For children 24 months or older through 9 years of age, one dose should be administered. However, two doses, two months apart, should be administered to children 24-59 months in high-risk groups (e.g., sickle cell disease or anatomic or functional asplensia, HIV infected or immunocompromised, chronic illness such as nephrotic syndrome, diabetes, chronic pulmonary conditions, and symptomatic heart conditions). The dose is 0.5 mL administered intramuscularly.2

Potential Advantages

The conjugate vaccine is more immunogenic than the existing polysaccharide vaccine that is not effective in children younger than 2 years of age since it is T-cell independent and does not induce immunologic memory. Vaccination of infants at 2, 4, 6, and 12-15 months with Prevnar has been shown to be efficacious in preventing invasive pneumococcal disease caused by serotypes included in the vaccine.2,10 Efficacy based on an intent-to-treat analysis (including all children who received at least 1 dose) was 93.9% (95% CI: 79.6-98.5%) for serotypes included in the vaccine. Per protocol analysis (events occurring ³ 14 days after the third dose) showed efficacy of 97.4% (95% CI: 82.7-99.9%). The efficacy against all serotypes was 89% (95% CI: 73.7-95.4%).1,10 Data also suggest that the vaccine reduced acute otitis media (AOM) caused by S. pneumoniae and AOM-related outcomes such as visits, episodes, frequent and severe otitis, and ventilatory tube placement.9,10

Potential Disadvantages

Prevnar will not protect against S. pneumoniae disease caused by serotypes other than those included in the vaccine. It is contraindicated in patients with known hypersensitivity to diphtheria toxoid. Side effects include fever, irritability, restless sleep, vomiting, diarrhea, and injection site reactions.2 It is not certain how or if immunization against the seven serotypes would result in emergence of less common serotypes.

Comments

Prevnar is a pneumococcal vaccine prepared by the conjugation of seven serotypes of pneumococcal polysaccharide to protein carrier reactive molecule 197 (CRM 197). CRM 197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (ß197). The conjugated vaccine induces T cell-dependent immune response and is therefore immunogenic in children younger than 2 years of age.6,7 The efficacy trial involving 37,816 infants (18,906 Prevnar and 18,910 control) was conducted at Kaiser Permanente of Northern California. The control vaccine was an investigational meningococccal group C conjugate vaccine (CRM197).2,10 Efficacy was more than 93% for serotypes included in the vaccine and 89% for all pneumococcal serotypes. Black and associates also reported efficacy against visits, episodes, frequent and severe otitis, and ventilatory tube placement of 8.9%, 7.0%, 9.3%, and 20.1%, respectively, with P < 0.04 for all.1 In a study conducted in Finland, Eskola and associates reported a per protocol reduction of 57% (95% CI: 44-67%) in culture-confirmed serotype specific AOM, a 34% (95% CI:21-45%) reduction in cultured-confirm pneumococcal (any serotype) AOM, and a 6% (95% CI: -4-16%) reduction in AOM irrespective of etiology.9

Clinical Implications

The previously available polysaccharide pneumococcal vaccine is not effective in children younger than 2 years of age. The development of the pneumococcal 7-valent conjugate vaccine has the potential to prevent significant S. pneumonia-related morbidity and mortality in children. The seven serotypes, out of about 90 known serotypes, are responsible for approximately 80% of invasive pneumococcal disease and 60% of AOM in children. The seven serotypes account for 74% of penicillin-nonsusceptible (intermediate or high-level resistance) S. pneumoniae (PNSP) and 100% of pneumoccoci with a high level of penicillin resistance.1,4 S. pneumoniae is the most common cause of bacterial meningitis in children and is associated with 8% mortality as well as neurological sequelae and hearing loss.5 The vaccine has been reported effective in preventing invasive disease, reducing AOM due to vaccine serotypes, reduction in AOM of any serotype, and reduction in AOM visits, episodes, frequent otitis, and ventilatory tube placement.2,9,10 The preliminary recommendation of The Advisory Committee on Immunization Practices (ACIP) for Prevnar includes immunization of the birth cohort, catch-up immunization of infants up to 23 months of age, and children ages 24-59 months who are at risk for pneumococcal disease. These include children with sickle cell disease or anatomic or functional asplensia, HIV-infected or immunocompromised, chronic illness such as nephrotic syndrome, diabetes, chronic pulmonary conditions (excluding asthma), and symptomatic heart conditions. The vaccine may also be considered for children in certain ethnic groups such as American Indians, Alaskans, and African Americans.

Wyeth-Ayerst is required to submit monthly adverse event reports to the FDA for the first year. It is also committed to conduct Phase IV postmarketing studies in previously unvaccinated children receiving "catch-up" therapy for all age groups.8 The vaccine costs $58 per dose.

References

1. Butler JC, et al. J Infect Dis 1995;171:885-889.

2. Prevnar™ Product Information. February 2000. Wyeth Laboratories.

3. Eskola J, et al. Pediatr Infect Dis J 1999;18:543-551.

4. Butler JC, et al. J Infect Dis 1996;174:986-993.

5. Arditi M, et al. Pediatrics 1998;102:1087-1097.

6. Black S, et al. Pediatr Infect Dis J 1999;18:757-763.

7. Rennels MB, et al. Pediatrics 1998;101:604-611.

8. FDC Report. The Pink Sheet 2000;62(8):14-15.

9. Eskola J, et al. 39th ICAAC; San Francisco, Ca., Sept. 26-29, 1999;Abstract LB-13.

10. Black S, et al. Pediatr Infect Dis J 2000;19:187-195.