Pediatric Annals

PEDIATRIC IMMUNIZATION UPDATE 

An Update on the New Pneumococcal Conjugate Vaccine

Sharon Balter, MD; Chris Van Beneden, MD, MPH

Abstract

Streptococcus pneumoniae (pneumococcus) is the leading cause of bacterial pneumonia, bacteremia, sinusitis, and acute otitis media worldwide. Each year in the United States, S. pneumoniae causes approximately 17,000 cases of invasive disease among children younger than 5 years, including 700 cases of meningitis and 200 deaths.1 In February 2000, the Food and Drug Administration licensed a heptavalent pneumococcal conjugate vaccine for use among infants and toddlers.2 In October 2000, the Centers for Disease Control and Prevention published the recommendations of the Advisory Committee on Immunization Practices (ACIP) for routine use of the vaccine for all children younger than 24 months and for high-risk children 2 to 5 years old.3

BACKGROUND

In 1999, the estimated incidence of invasive pneumococcal disease in the United States was 163 cases per 100,000 population among children younger than 12 months and 205 cases per 100,000 population among those 12 to 23 months. The incidence among individuals of all ages was 24 per 100,000 population during the same time period.1 S. pneumoniae is also the most common cause of community-acquired pneumonia, acute otitis media, and sinusitis in young children.4-6

Children at the highest risk for invasive pneumococcal disease include those with sickle cell disease and other sickle hemoglobinopathies (eg, hemoglobin sickle cell disease or sickle cell thalassemia), those with functional or anatomic asplenia, and those with human immunodeficiency virus (HIV) infection.710 Rates of invasive pneumococcal disease are also higher among African Americans, Alaskan Natives, and specific American Indian populations.1,8,11-15 Children who attend group day care out of the home are at higher risk for all pneumococcal infections and infections due to antibiotic-resistant pneumococci.13

PNEUMOCOCCAL CONIUGATE VACCINE

Although the highest rates of invasive pneumococcal disease occur in young children, especially those younger than 2 years, no pneumococcal vaccine was available for this age group until recently. The previous vaccine contained unconjugated polysaccharide antigens, which fail to elicit a protective immune response in infants and young children because these individuals respond poorly to T-independent antigens.16 Conjugate vaccines are immunogenic even in younger children because they change the T-independent response to a Tdependent immune response. The first conjugate vaccine licensed in this country was the Haemophilus influenzae type b (Hib) vaccine. Hib vaccines have almost eliminated Hib disease in the United States.17

The new 7-valent pneumococcal conjugate vaccine (PCV7) is composed of 7 purified capsular polysaccharides of S. pneumoniae, each coupled (conjugated) with a nontoxic variant of diphtheria toxin (CRM197). The vaccine includes the saccharides from serotypes 4, 9 V, 14, 19F, 23F, 18C, and 6B. These serotypes account for 80% of invasive disease among children younger than 6 years in the United States.18 Antimicrobial resistance has increased substantially during the past decade and the 7 serotypes in the vaccine are also those responsible for most pneumococcal infections that are not susceptible to penicillin.19

A study of the effectiveness of this conjugate vaccine was conducted among 37,868 healthy children in a health maintenance organization in California. The vaccine had an efficacy of 97.4% (95% confidence interval [CI] = 82.7% to 99.9%) against invasive pneumococcal disease due to vaccine serotypes in fully vaccinated children.20

As a secondary outcome, the investigators examined the effectiveness in preventing pneumonia of any etiology. Children who received one or more doses of PCV7 had 11.4% (95% Cl = 1.3% to 20.5%) fewer episodes of clinical pneumonia and 73.1% (95% CI = 3.0% to 88.3%) fewer episodes of pneumonia confirmed by x-ray with consolidation of 2.5 cm or greater. The sample size for the latter category was small.21 Ongoing studies are evaluating the duration of protection.

These investigators also found that PCV7 prevented 6.4% of all…

Streptococcus pneumoniae (pneumococcus) is the leading cause of bacterial pneumonia, bacteremia, sinusitis, and acute otitis media worldwide. Each year in the United States, S. pneumoniae causes approximately 17,000 cases of invasive disease among children younger than 5 years, including 700 cases of meningitis and 200 deaths.1 In February 2000, the Food and Drug Administration licensed a heptavalent pneumococcal conjugate vaccine for use among infants and toddlers.2 In October 2000, the Centers for Disease Control and Prevention published the recommendations of the Advisory Committee on Immunization Practices (ACIP) for routine use of the vaccine for all children younger than 24 months and for high-risk children 2 to 5 years old.3

BACKGROUND

In 1999, the estimated incidence of invasive pneumococcal disease in the United States was 163 cases per 100,000 population among children younger than 12 months and 205 cases per 100,000 population among those 12 to 23 months. The incidence among individuals of all ages was 24 per 100,000 population during the same time period.1 S. pneumoniae is also the most common cause of community-acquired pneumonia, acute otitis media, and sinusitis in young children.4-6

Children at the highest risk for invasive pneumococcal disease include those with sickle cell disease and other sickle hemoglobinopathies (eg, hemoglobin sickle cell disease or sickle cell thalassemia), those with functional or anatomic asplenia, and those with human immunodeficiency virus (HIV) infection.710 Rates of invasive pneumococcal disease are also higher among African Americans, Alaskan Natives, and specific American Indian populations.1,8,11-15 Children who attend group day care out of the home are at higher risk for all pneumococcal infections and infections due to antibiotic-resistant pneumococci.13

PNEUMOCOCCAL CONIUGATE VACCINE

Although the highest rates of invasive pneumococcal disease occur in young children, especially those younger than 2 years, no pneumococcal vaccine was available for this age group until recently. The previous vaccine contained unconjugated polysaccharide antigens, which fail to elicit a protective immune response in infants and young children because these individuals respond poorly to T-independent antigens.16 Conjugate vaccines are immunogenic even in younger children because they change the T-independent response to a Tdependent immune response. The first conjugate vaccine licensed in this country was the Haemophilus influenzae type b (Hib) vaccine. Hib vaccines have almost eliminated Hib disease in the United States.17

The new 7-valent pneumococcal conjugate vaccine (PCV7) is composed of 7 purified capsular polysaccharides of S. pneumoniae, each coupled (conjugated) with a nontoxic variant of diphtheria toxin (CRM197). The vaccine includes the saccharides from serotypes 4, 9 V, 14, 19F, 23F, 18C, and 6B. These serotypes account for 80% of invasive disease among children younger than 6 years in the United States.18 Antimicrobial resistance has increased substantially during the past decade and the 7 serotypes in the vaccine are also those responsible for most pneumococcal infections that are not susceptible to penicillin.19

A study of the effectiveness of this conjugate vaccine was conducted among 37,868 healthy children in a health maintenance organization in California. The vaccine had an efficacy of 97.4% (95% confidence interval [CI] = 82.7% to 99.9%) against invasive pneumococcal disease due to vaccine serotypes in fully vaccinated children.20

As a secondary outcome, the investigators examined the effectiveness in preventing pneumonia of any etiology. Children who received one or more doses of PCV7 had 11.4% (95% Cl = 1.3% to 20.5%) fewer episodes of clinical pneumonia and 73.1% (95% CI = 3.0% to 88.3%) fewer episodes of pneumonia confirmed by x-ray with consolidation of 2.5 cm or greater. The sample size for the latter category was small.21 Ongoing studies are evaluating the duration of protection.

These investigators also found that PCV7 prevented 6.4% of all otitis media and 20.3% of otitis media requiring placement of tympanostomy tubes (P < .04).20 A similar study of 1,662 children in Finland found a 6% (95% CI = -4% to 16%) reduction against all acute otitis media irrespective of etiology and a 34% (95% CI - 21% to 45%) reduction of culture-confirmed pneumococcal acute otitis media irrespective of serotype.22 Both studies showed significant reductions of acute otitis media in children prone to otitis media.

ADVERSE EVENTS FOLLOWING VACCINATION

Before licensure, the safety of PCV7 was studied in two groups: (1) more than 18,000 infants and children who were vaccinated with both PCV7 and routine childhood vaccines at 2, 4, 6, and 12 to 15 months old; and (2) more than 500 older children who were initially vaccinated at 7 months to 9 years old.

Among infants, PCV7 resulted in fewer local reactions than did whole cell pertussis vaccine, but slightly more than those for acellular pertussis vaccine and other control vaccines. Among those who received the acellular pertussis vaccine, approximately 10% to 14% of the infants had some erythema and 10% to 12% of the infants had some induration within 2 days of one dose of PCV7. Significant (> 2.4 cm) erythema or induration was less common (0.6% to 5.5%). Fifteen percent to 24% of the children had a fever of 100.40F or greater following a dose of PVC7, whereas 0.9% to 2.5% had a fever of 102.20F or greater. No deaths were attributed to the vaccine.

In studies of older children, the frequency of local reactions was higher than it was for children younger than 1 year. Approximately 7% to 37% of the children had a fever of 100.40F or greater after one dose of PCV7. Fussiness was the most common systemic reaction among these older children.2

ACIP RECOMMENDATIONS

According to the ACIP, PCV7 is indicated for the immunization of children 23 months or younger and of children 24 to 59 months old who are at high risk for disease due to sickle cell disease or asplenia, chronic illness, HlV infection, or other immunocompromising conditions (Table 1).

Schedule

The vaccine should be administered at 2, 4, and 6 months. The minimum interval between these three doses is 4 weeks. A fourth dose should be administered at least 8 weeks later, between 12 and 15 months of age. Children who receive their first dose at or after 7 months of age should receive it according to the schedule in Table 2. For children for whom there is a lapse in immunization, it is not necessary to begin the series again. Although the vaccine is not recommended for children older than 5 years, it is not contraindicated for those younger than 9 years who are at high risk for pneumococcal disease.

Should Children Who Received PPV23 Be Vaccinated With PCV7?

Children 2 years or older who have already received the pneumococcal polysaccharide vaccine (PPV23) because they have sickle cell disease, functional or anatomic asplenia, chronic diseases, HIV infection, or other immunocompromising conditions should also receive PCV7. Two doses should be given 2 months apart, with the first dose a minimum of 2 months following the last PPV23 dose. The addition of PPV23 following PCV7 is optional for children of Native Alaskan or American Indian descent. Although data on the safety of PPV23 given after PCV7 are limited, some children may benefit from receiving PPV23 after receiving PCV7. The need to provide optimal immune responses and cover a broader range of serotypes in these children at high risk for infection justifies the sequential use of vaccines. Thus, immunocompromised children or those with sickle cell disease or functional or anatomic asplenia who receive PCV7 before 2 years old should be vaccinated and revaccinated with PPV23, as recommended in the ACIP 1997 pneumococcal prevention guidelines.23

Table

TABLE 1Recommendations for the Use of the 7-Valent Pneumococcal Conjugate Vaccine (PCV7)

TABLE 1

Recommendations for the Use of the 7-Valent Pneumococcal Conjugate Vaccine (PCV7)

Contraindications

PCV7 is contraindicated for children who are allergic to any components of the vaccine. Minor illnesses are not contraindications to vaccination, although health care providers should delay vaccination of children with moderate or severe illnesses. Concurrent administration of PCV7 and PPV23 is not recommended.3

Table

TABLE 2Recommended Schedule for the Use of the 7-Valent Pneumococcal Conjugate Vaccine in Previously Unvaccinated Infants and Children, Including Primary Series and Catch-up Immunizations

TABLE 2

Recommended Schedule for the Use of the 7-Valent Pneumococcal Conjugate Vaccine in Previously Unvaccinated Infants and Children, Including Primary Series and Catch-up Immunizations

REFERENCES

1. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network (EIP), Streptococcus pneumoniae. Atlanta, GA: Centers for Disease Control and Prevention; 1998. Available at: www.cdc.gov/ncidod/dbmd/abcs.

2. Food and Drug Administration. Product Approval Information: Biological License Application Approvals. Washington, DC: US. Department of Health and Human Services, Center for Biologies Evaluation and Research; 2000.

3. Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2000;49(RR09):1-38. Available at: www.cdc.gov/mmwr/mmvvr_rr.html.

4. Heiskanen-Kosma T, Korppi M, Jokinen C, et al. Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis ]. 1998;17:986-991.

5. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med. 1999340:260-264.

6. WaId ER, Mümoe GJ, Bowen A, Ledesma-Medina J, Salamon N, Bluestone CD. Acute maxillary sinusitis in children. N Engl f Med. 1981304:749-754.

7. Zangwill KM, Vadheim CM, Vannier AM, Hemenway LS, Greenberg DP, Ward JI. Epidemiology of invasive pneumococcal disease in southern California: implications for the design and conduct of a pneumococcal conjugate vaccine efficacy trial. J Inject Dis. 1996;174:752-759.

8. Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease in Dallas County, Texas: results from population-based surveillance in 1995. Clin Infect Dis. 1998;26:590-595.

9. Overturf G. Infections and immunizations of children with sickle cell disease. In: Adi'ances in Pediatric Infectious Diseases. St. Louis, MO: Mosby; 1999:191-218.

10. Moore D, Nelson M, Henderson D. Pneumococcal vaccination and HTV infection. Int ] STD AIDS. 1998;9:1-7.

11. Hofmann J, Cetron MS, Farley MM, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med. 1995333:481-486.

12. Davidson M, Parkinson AJ, Bulkow LR Fitzgerald MA, Peters HV, Parks DJ. The epidemiology of invasive pneumococcal disease in Alaska, 1986-1990: ethnic differences and opportunities for prevention. J infect Dis. 1994;170:368-376.

13. Levine OS, Farley M, Harrison LH, Lefkowitz L, McGeer A, Schwartz B. Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America. Pediatrics. 1999;103:e28. Available at: www.pediatrics.org/cgi/content/full/103/3/e28.

14. Cortese MM, Wolff M, Almedio-Hill J, Reid R, Ketcham J, Santosham M. High incidence rates of invasive pneumococcal disease in the White Mountain Apache population. Arch Mem Med. 1992;152:2277-2282.

15. OBrien KL, Croll J, Parkinson AJ, Reid R Santosham M. Active laboratory-based surveillance for invasive Streptococcus pneumoniae (pneumococcus) among Navajo people in the American Southwest, 1989-19%. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, CA. Abstract 678.

16. Douglas RM, Paton JC, Duncan SJ, Hansman DJ. Antibody response to pneumococcal vaccination in children younger than five years of age. / Infect Dis. 1983;148:131-137.

17. Adams WG, Deaver KA, Cochi SL, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA. 1993;269:221-226.

18. Butler JC, Breiman RF, Lipman FTB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. J Infect Dis. 1995;171:885-889.

19. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000;343:1917-1924.

20. Black S1 Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187-195.

21. Black S, Shinefield H, Ray P, et al. Efficacy of heptavalent conjugate pneumococcal vaccine (Wyeth Lederle) in 37,000 infants and children: impact on pneumonia, otitis media and an update on invasive disease. Results of the Northern California Kaiser Permanente Efficacy Trial. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, CA. Abstract.

22. Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001344:403-409.

23. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1997;46(RR08):1-24.

TABLE 1

Recommendations for the Use of the 7-Valent Pneumococcal Conjugate Vaccine (PCV7)

TABLE 2

Recommended Schedule for the Use of the 7-Valent Pneumococcal Conjugate Vaccine in Previously Unvaccinated Infants and Children, Including Primary Series and Catch-up Immunizations

10.3928/0090-4481-20010601-10

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