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Volume 5, Number 6—December 1999
Dispatch

Effectiveness of Pneumococcal Polysaccharide Vaccine for Preschool-Age Children with Chronic Disease

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Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA

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Abstract

To estimate the effectiveness of pneumococcal polysaccharide vaccine, we serotyped isolates submitted to the Pneumococcal Sentinel Surveillance System from 1984 to 1996 from 48 vaccinated and 125 unvaccinated children 2 to 5 years of age. Effectiveness against invasive disease caused by serotypes included in the vaccine was 63%. Effectiveness against serotypes in the polysaccharide vaccine but not in a proposed seven-valent protein conjugate vaccine was 94%.

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, bacteremia, and death in young children. A polysaccharide vaccine has been recommended for use in chronically ill children and adults 2 to 64 years of age, as well as all adults >65 (1). While many studies have assessed the immunogenicity of the polysaccharide vaccine, scant data exist on its effectiveness in younger children.

More than 90 serotypes of S. pneumoniae have been described (2); however, most invasive infections in the United States are caused by <10 serotypes (3). Pneumococcal vaccines available since 1978 consist of a mixture of capsular polysaccharides from the most common serotypes causing invasive disease. This vaccine is recommended for children >2 years of age with underlying diseases or immunosuppressive medical treatments that are risk factors for invasive pneumococcal disease (1,3).

Clinical trials of pneumococcal polysaccharide vaccine effectiveness in children have shown conflicting results (4-7). Vaccine failure in immunized children has been reported (8), and one study comparing immunization with antibiotic prophylaxis in children with sickle cell disease concluded that the vaccine was inferior to penicillin prophylaxis (9). Uncertainty regarding the effectiveness of vaccination may contribute to low vaccination rates among persons at risk for pneumococcal disease (1).

In indirect cohort analysis (10), the distribution of pneumococcal serotypes causing invasive disease among vaccinated and unvaccinated groups is compared. If the vaccine is effective, vaccinated persons have fewer infections with serotypes represented in the vaccine than unvaccinated persons. This method has been used to calculate an overall effectiveness of 57% in persons >5 years of age, based on serotypes of invasive isolates obtained through a national, voluntary sentinel surveillance system (11). Using data from national surveillance, we examined vaccine effectiveness for children 2 through 5 years of age.

The Study

Since 1978, a national, hospital laboratory-based surveillance system has collected data on invasive pneumococcal disease (12). Participating institutions are requested to report all pneumococcal isolates obtained from normally sterile body sites, along with information on the patient's age, sex, symptoms, underlying diseases, and vaccination history. The specifics of how demographic and vaccination information is collected are the responsibility of participating institutions. Isolates are serotyped at the Centers for Disease Control and Prevention on the basis of capsular swelling with serotype-specific antisera (Quellung reaction).

Children included in the analysis were 24 to 59 months of age with one or more chronic illnesses, had vaccination status and date indicated on the surveillance form, received vaccine between January 1984 and April 1996, and had onset of invasive pneumococcal disease between January 1984 and April 1996. Only isolates from cerebrospinal fluid (CSF) or blood were considered in the analysis. Information on antibiotic prophylaxis was not collected. Chronic illness was defined as an underlying illness considered a risk factor for invasive pneumococcal disease and an indication for vaccination (3).

Vaccine effectiveness was defined as the percentage of reduction in the risk for infection from serotypes included in the vaccine (vaccine-type serotypes) among vaccinated persons compared with unvaccinated persons. Infections with vaccine-related serotypes (6A, 9A, 9L, 18B, 18F, 23A) not specifically included in the vaccine were categorized as infections with nonvaccine serotypes, except where noted. Effectiveness was expressed as 1 minus the odds ratio x 100%; the 95% confidence intervals (also x 100%) were calculated by the methods of Cornfield when cell sizes were all greater than five subjects and by exact methods otherwise. Calculations were performed with Epi-Info version 6.02 (CDC/World Health Organization, Atlanta, GA) with the EXACT supplemental program (David O. Martin).

We performed a preliminary analysis of all pneumococcal isolates from children in the database to determine the proportion of vaccine-type organisms in unvaccinated persons by sex, underlying illness, or state of residence. Proportions of vaccine-type serogroups did not differ by underlying illness or by sex. Because the proportion of vaccine-type isolates from children from Alaska was 92.3%, compared with the 85.4% of isolates from children from other states (chi-square = 6.3; p <0.02), children from Alaska were excluded from the analysis.

Figure 1

Thumbnail of Invasive pneumococcal infections among 173 children ages 2 through 5 years (24-59 months), by serotype. Bottom bar represents proportion of total invasive infections in the cohort caused by each serotype. Top bar depicts cumulative proportion of invasive infections caused by serotypes represented by the bars to the left. Serotypes in the "other" category included 19 serotypes with three or fewer isolates. Two isolates could not be serotyped.

Figure 1. Invasive pneumococcal infections among 173 children ages 2 through 5 years (24-59 months), by serotype. Bottom bar represents proportion of total invasive infections in the cohort caused by each serotype. Top...

The analysis included 173 children, 52% male, median age 3 years; 48 children (28%) had received vaccine before acquiring invasive pneumococcal disease. Isolates were obtained from blood only from 156 children (90%), from CSF only from 10 children (6%), and from both sites from 7 children (4%). The median time between date of vaccination and date of specimen collection was 338.5 days (33 days to 1,341 days), and no child had been vaccinated within 30 days of invasive pneumococcal infection. Of serotypes from the 173 invasive infections, serotypes 4, 6A, 6B, 14, 23F, 19F, 9V, and 18C accounted for 81% of the isolates (Figure 1).

Figure 2

Thumbnail of Frequency of various underlying chronic illnesses among 173 children with invasive pneumococcal disease. The category "malignancy" excluded hematopoetic malignancies, which are included in the leukemia category. Organ transplant includes both solid organ and bone marrow transplants. CSF is cerebrospinal fluid.

Figure 2. Frequency of various underlying chronic illnesses among 173 children with invasive pneumococcal disease. The category "malignancy" excluded hematopoetic malignancies, which are included in the leukemia category. Organ transplant includes both solid...

Forty-six (27%) of children in the study had sickle cell disease (Figure 2). The "other" category included children with congenital anomalies such as congenital heart or lung defects, children with anatomic asplenia, and children on immunosuppressive medication regimens. Thirty-three (69%) of 48 vaccinated children had sickle cell disease.

The Table presents vaccine effectiveness estimates for the overall cohort and for children with and without sickle cell disease. For children with the disease, the lower bound of the 95% confidence interval included 0%. The estimate of vaccine effectiveness for children without sickle cell disease was higher than the estimate for children with the disease. Point estimates of effectiveness for children with nephrotic syndrome or HIV infection were 80%; however, the 95% confidence intervals included 0% (data not shown). Other chronic diseases reported in this cohort included leukemia, nonhematopoetic malignancy, and organ transplant; however, none of the children with these underlying diseases were vaccinated, and effectiveness could not be calculated.

Protein conjugate vaccines offer the advantage of being effective in the first 2 years of life, when response to polysaccharide vaccines is poor. However, the number of serotypes that can be represented in these vaccines is limited. To evaluate polysaccharide effectiveness for serotypes not represented in a protein conjugate vaccine under evaluation for license (13), we excluded children infected with serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. Polysaccharide vaccine was highly effective in preventing invasive disease due to serotypes included in the polysaccharide vaccine but not in the conjugate vaccine (Table). If the 14 children with serotypes 6A, 9A, 9L, 18B, 18F, and 23A are also excluded (because of potential protection conferred by the proposed conjugate vaccine for these vaccine-related serotypes), the vaccine effectiveness estimate is 92% (exact 95% confidence intervals 17% to 100%).

Conclusions

Case-control studies have demonstrated that pneumococcal capsular polysaccharide vaccines are effective (14-16) and cost-effective (17,18) in the prevention of invasive pneumococcal disease among elderly and chronically ill adults. We used data from a national sentinel surveillance system for invasive pneumococcal disease to determine whether children ages 2 to 5 years were also protected. An overall vaccine effectiveness of 63% was demonstrated by indirect cohort analysis (15). The indirect cohort analysis presented here strengthens the case for the use of pneumococcal polysaccharide vaccine for children with underlying conditions. For children with sickle cell disease, penicillin prophylaxis remains the most effective preventive measure for reducing pneumococcal disease.

Accuracy of vaccine history is critical to this analysis and may vary between surveillance sites. To minimize inaccuracies, patients with no indication of vaccine history were excluded. For those with a reported vaccine history, misclassification due to inaccurate history should be as likely among patients with vaccine-type as among nonvaccine-type infections because the serotype of patient isolates was not known when vaccine status was determined (serotyping was done at CDC). Bias due to this nondifferential misclassification will be towards the null hypothesis (no effect of vaccination) (19).

Newly developed pneumococcal protein conjugate vaccines are safe and immunogenic for infants and young children (13,20,21). Preliminary results from a large, Phase-III trial of a heptavalent conjugate vaccine among healthy children indicate substantial efficacy in preventing invasive disease (13). However, the expense and technical difficulty of creating conjugates for each serotype will likely limit the number of serotypes represented in a polyvalent conjugate vaccine to fewer than 12. Available data suggest that polysaccharide vaccine, when administered after primary immunization with a conjugate vaccine, elicits a significant booster effect in healthy infants (22) equivalent to the booster response engendered by a second conjugate vaccine series (23). These results and the level of effectiveness seen with pneumococcal polysaccharide vaccine in our study suggest that the polysaccharide vaccine will still be a useful adjunct to conjugate vaccine, by providing additional protection to children >2 years of age for whom polysaccharide vaccine is currently indicated.

Dr. Fiore is a medical epidemiologist in the Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases.

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Acknowledgment

The authors thank A.R. Franklin, D. Jackson, L. LaClaire, and N. Pigott for serotyping of pneumococcal isolates and the members of the Pneumococcal Sentinel Surveillance Working Group: Carol Camp, Patricia Charache, Mel Jackson, W. Keith Hadley, Joan Hoppe-Bauer, Michael R. Jacobs, Phyllis Tyler, Janet Monahan, Harold Moore, Jane D. Siegel, David Sherer, and David Welch.

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References

  1. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1997;46(RR-8).
  2. Henrichsen  J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol. 1995;33:275962.PubMedGoogle Scholar
  3. American Academy of Pediatrics. Pneumococcal infections. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village (IL): American Academy of Pediatrics; 1997. p. 410-9.
  4. Riley  ID, Everingham  FA, Smith  DE, Douglas  RM. Immunisation with a polyvalent pneumococcal vaccine: Effect on respiratory mortality in children living in the New Guinea highlands. Arch Dis Child. 1981;56:3547. DOIPubMedGoogle Scholar
  5. Rosén  C, Christensen  P, Hovelius  B, Prellner  K. Effect of pneumococcal vaccination on upper respiratory tract infections in children: Design of a follow-up study. Scand J Infect Dis. 1983;Suppl 39:3944.
  6. Douglas  RM, Miles  HB. Vaccination against Streptococcus pneumoniae in childhood: lack of demonstrable benefit in young Australian children. J Infect Dis. 1984;149:8619.PubMedGoogle Scholar
  7. Ammann  AJ, Addiego  J, Wara  DW, Lubin  B, Smith  WB, Mentzer  WC. Polyvalent pneumococcal-polysaccharide immunization of patients with sickle-cell anemia and patients with splenectomy. N Engl J Med. 1977;297:897900.PubMedGoogle Scholar
  8. Ahonkhai  VI, Landesman  SH, Fikrig  SM, Smalzer  EA, Brown  AK, Cherubin  CE, Failure of pneumococcal vaccine in children with sickle-cell disease. N Engl J Med. 1979;301:267.PubMedGoogle Scholar
  9. John  AB, Ramlal  A, Jackson  H, Maude  GH, Waight-Sharma  A, Serjeant  GR. Prevention of pneumococcal infection in children with homozygous sickle cell disease. BMJ. 1984;288:156770. DOIPubMedGoogle Scholar
  10. Broome  CV, Facklam  RR, Fraser  DW. Pneumococcal disease after pneumococcal vaccination: an alternative method to estimate the efficacy of pneumococcal vaccine. N Engl J Med. 1980;:54952.PubMedGoogle Scholar
  11. Butler  JC, Breiman  RF, Campbell  JF, Lipman  HB, Broome  CV, Facklam  RR. Pneumococcal vaccine efficacy: an evaluation of current recommendations. JAMA. 1993;270:182631. DOIPubMedGoogle Scholar
  12. Broome  CV. Efficacy of pneumococcal polysaccharide vaccines. Rev Infect Dis. 1981;Suppl 3:S828.PubMedGoogle Scholar
  13. Black  SB, Shinefield  H, Ray  P, Lewis  E, Fireman  P, Efficacy of heptavalent conjugate pneumococcal vaccine (Wyeth Lederle) in 37,000 infants and children: results of the Northern California Kaiser Permanente Efficacy Trial. In: Programs and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998; San Diego, California. Washington: American Society for Microbiology, 1998.
  14. Shapiro  ED, Berg  AT, Austrian  R, Schroeder  D, Parcells  V, Margolis  A, The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med. 1991;325:145360.PubMedGoogle Scholar
  15. Sims  RV, Steinmann  WC, McConville  JH, King  LR, Zwick  WC, Schwartz  JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med. 1988;108:6537.PubMedGoogle Scholar
  16. Farr  BM, Johnston  BL, Cobb  JK, Fisch  MJ, Germanson  TP, Adal  KA, Preventing pneumococcal bacteremia in patients at risk: Results of a matched case-control study. Arch Intern Med. 1995;155:233640. DOIPubMedGoogle Scholar
  17. Gable  CB, Holzer  SS, Engelhart  L, Friedman  RB, Smeltz  F, Schroeder  D, Pneumococcal vaccine: efficacy and associated cost savings. JAMA. 1990;264:29105. DOIPubMedGoogle Scholar
  18. Sisk  JE, Moskowitz  AJ, Whang  W, Lin  JD, Fedson  DS, McBean  AM, Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA. 1997;278:13339. DOIPubMedGoogle Scholar
  19. Copeland  KT, Checkoway  H, Holbrook  RH, McMichael  AJ. Bias due to misclassification in the estimate of relative risk. Am J Epidemiol. 1977;105:48895.PubMedGoogle Scholar
  20. Käyhty  H, Åhman  H, Rönnberg  P-R, Tillikainen  R, Eskola  J. Pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. J Infect Dis. 1995;172:12738.PubMedGoogle Scholar
  21. Rennels  MB, Edwards  KM, Keyserling  HL, Reisinger  KS, Hogerman  DA, Madore  DV, Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Paediatrics. 1998;101:60411. DOIGoogle Scholar
  22. Åhman  H, Käyhty  H, Lehtonen  H, Leroy  O, Froeschle  J, Eskola  J. Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to produce immunologic memory. Pediatr Infect Dis J. 1998;17:2116. DOIPubMedGoogle Scholar
  23. Obaro  SK, Huo  Z, Banya  WAS, Henderson  DC, Monteil  MA, Leach  A, A glycoprotein conjugate vaccine primes for antibody responses to a pneumococcal polysaccharide vaccine in Gambian children. Pediatr Infect Dis J. 1997;16:113540. DOIPubMedGoogle Scholar

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DOI: 10.3201/eid0506.990616

Table of Contents – Volume 5, Number 6—December 1999

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Anthony E. Fiore, National Center for Infectious Diseases, Centers for Disease Control and Prevention; 1600 Clifton Road, Mail Stop G37, Atlanta, GA 30333, USA; fax: 404-639-1538

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Page created: December 16, 2010
Page updated: December 16, 2010
Page reviewed: December 16, 2010
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
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