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Invasive Pneumococcal Disease in Young Children Before Licensure of 13-Valent Pneumococcal Conjugate Vaccine --- United States, 2007

Invasive pneumococcal disease (IPD), caused by Streptococcus pneumoniae (pneumococcus), remains a leading cause of serious illness in children and adults worldwide (1). After routine infant immunization with a 7-valent pneumococcal conjugate vaccine (PCV7) began in 2000, IPD among children aged <5 years in the United States decreased by 76%; however, IPD from non-PCV7 serotypes, particularly 19A, has increased (2). In February 2010, the Advisory Committee on Immunization Practices (ACIP) issued recommendations for use of a newly licensed 13-valent pneumococcal conjugate vaccine (PCV13) (3). PCV13 contains the seven serotypes in PCV7 (4, 6B, 9V, 14, 18C, 19F, and 23F) and six additional serotypes (1, 3, 5, 6A, 7F, and 19A). To characterize the potentially vaccine-preventable IPD burden among children aged <5 years in the United States, CDC and investigators analyzed 2007 data from Active Bacterial Core surveillance (ABCs). This report summarizes the results of that analysis, which found that among 427 IPD cases with known serotype in children aged <5 years, 274 (64%) were caused by serotypes contained in PCV13. In 2007, an estimated 4,600 cases of IPD occurred in children in this age group in the United States, including approximately 2,900 cases caused by serotypes covered in PCV13 (versus 70 cases caused by PCV7 serotypes). PCV13 use has the potential to further reduce IPD in the United States. Post-licensure monitoring will help characterize the effectiveness of PCV13 in different populations and track the potential changes in disease burden caused by non-PCV13 serotypes.

ABCs* of the Emerging Infections Program (EIP) Network is a collaboration between CDC and 10 selected sites. ABCs conducts population- and laboratory-based active surveillance. During 2006 and 2007, IPD surveillance was conducted in Connecticut, Minnesota, and New Mexico, and selected counties in California, Colorado, Georgia, Maryland, New York, Oregon, and Tennessee. In 2007, the total catchment population of children aged <5 years for these 10 sites was 2.1 million. A case of IPD was defined as isolation of S. pneumoniae from a normally sterile body site (primarily blood or cerebrospinal fluid) in a resident of an ABCs area. Pneumococcal isolates were serotyped at CDC and reference laboratories. Serotype information was analyzed by vaccine serotype group (Table 1). Age-, race- and vaccine serotype-specific rates of IPD were calculated using observed IPD cases in the 2007 ABCs data as the numerator and U.S. Census Bureau projections of the 2007 population of ABCs sites as the denominator. To estimate the incidence and total number of IPD cases in the United States in 2007, rates were standardized to the entire U.S. population, adjusting for small differences between age and race distributions of ABCs areas and the U.S. population.

Investigators reviewed medical records to identify children aged 24--59 months with underlying medical conditions who are recommended by ACIP to receive the 23-valent pneumococcal polysaccharide vaccine (PPSV23) (1). Characteristics of these high-risk children and healthy children were compared by chi-square test; data from 2006 and 2007 were summed because of the small number of IPD cases with underlying medical conditions among persons in this age group.

In 2007, a total of 493 children aged <5 years (<60 months) with IPD were identified in the ABCs population (Table 2), and information on the serotype of the pneumococcal isolate was available for 427 (87%) of those children. Among the 427, the group aged <12 months accounted for 36% of all cases, and the 12--23 months group accounted for 29%. Overall rates were highest in children aged <12 months and 12--23 months (40.5 and 31.2 cases per 100,000 population, respectively); among children aged 24--59 months, rates of all IPD decreased with each additional year of age. Information on race was available for 378 (89%) cases for which serotype information was available. Among children aged <5 years, rates of overall IPD in black children (35.8 cases per 100,000) and children of other races (30.7 cases per 100,000) were approximately twofold and 1.7-fold higher, respectively, than rates for white children (18.4 per 100,000).

Among the 427 IPD cases with known serotype in children aged <5 years, 274 (64%) were caused by serotypes contained in PCV13. Of these 274 cases, 260 (95%) were caused by three of the six additional serotypes (3, 7F, and 19A) that are not included in PCV7; overall, 180 (42%) of the 427 were caused by serotype 19A. Within each 1-year age group, the proportions of all IPD cases caused by serotypes covered by PCV13 were relatively similar, ranging from 59% to 71%. The proportions of all IPD cases caused by the 13 serotypes were comparable in black children (61%), children of other races (62%), and white children (67%).

Information on hospitalization and clinical outcome was available for 99% of serotyped IPD cases. Among 272 children with IPD caused by serotypes covered by PCV13 for whom hospitalization status, clinical presentation, and outcome were known, 168 (62%) were hospitalized, and four (2%) died; 101 (37%) had bacteremia without confirmed source, 24 (9%) had meningitis, and 115 (42%) had pneumonia with bacteremia.

Based on the 2007 rate of IPD in children aged <5 years (22 cases per 100,000), an estimated 4,600 cases of IPD occurred in this age group in the United States. Included among those cases were an estimated 70 cases caused by serotypes covered in PCV7 and 2,900 cases caused by serotypes covered in PCV13.

During 2006--2007, a total of 301 IPD cases with a known serotype occurred among children aged 24--59 months; 31 cases (10%) occurred in a child at high risk recommended for vaccination with PPSV23 (1). Of these 31 cases, the 11 serotypes included in PPSV23 but not in PCV13 (Table 1) accounted for four cases (13%), serotypes covered in PCV13 accounted for 13 cases (42%), and the remaining 14 cases (45%) were caused by serotypes not covered in either vaccine. PCV13 serotypes accounted for a smaller proportion of cases among children with underlying medical conditions than among healthy children aged 24--59 months (42% [13 of 31] versus 65% [175 of 270]; p = 0.01).

Reported by

MM Farley, MD, Georgia Emerging Infections Program. S Petit, MPH, Connecticut Dept of Public Health, Emerging Infections Program. LH Harrison, MD, RA Hollick, MS, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. SM Zansky, PhD, New York State Dept of Health, Emerging Infections Program. K Gershman, MD, Colorado Dept of Public Health and Environment, W Schaffner, MD, B Barnes, T McMinn, Vanderbilt Univ School of Medicine, Nashville, Tennessee. A Thomas, Oregon Public Health Div. PD Kirley, MT, MPH, California Emerging Infections Program. J Baumbach, MD, New Mexico Dept of Health. C Lexau, PhD, Minnesota Dept of Health. J Henry, MSPH, B Beall, PhD, CG Whitney, MD, M Moore, MD, JP Nuorti, MD, Respiratory Diseases Br, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases; JB Rosen, MD, EIS Officer, CDC.

Editorial Note

Routine infant immunization with PCV7 since 2000 has decreased rates of IPD in young children markedly, but IPD from non-PCV7 serotypes, predominantly serotype 19A, has increased and partially offset these reductions (2,4). Overall, rates of IPD have remained stable at 22--25 cases per 100,000 since 2002 (2,4). Based on the findings in this report, the use of PCV13 in the routine immunization schedule has the potential to further reduce IPD caused by the six additional serotypes (1, 3, 5, 6A, 7F, or 19A) among children aged <5 years.

PPSV23 has been available for use in adults aged ≥65 years and persons aged ≥2 years with certain underlying medical conditions since 1983 (1). In this analysis, approximately 42% of IPD cases among children aged 24--59 months with underlying medical conditions were caused by serotypes covered in PCV13; an additional 13% of cases were caused by serotypes not covered in PCV13 but included in PPSV23. The role for PPSV23 in high-risk children might become clearer when more data are available on disease burden and serotype distribution after routine use of PCV13.

Based on available safety, immunogenicity and disease burden data, ACIP also recommends that a single supplemental PCV13 dose be given to healthy children aged 14--59 months and to children with underlying medical conditions up to age 71 months who already have completed a schedule of PCV7 (3). In one study, a single dose of PCV13 in children aged ≥12 months who had received 3 previous doses of PCV7 induced an antibody response comparable to the 3-dose infant PCV13 series, and the safety profile of this supplemental dose was comparable to that after a fourth dose of PCV13 (5). Although rates of IPD are relatively low in these older children, ACIP also considered the emergence of multidrug-resistant serotype 19A strains causing meningitis and other severe invasive infections (6,7) and the substantial burden of noninvasive pneumococcal disease as additional factors in making the recommendation. Cost-effectiveness evaluations suggest that supplemental PCV13 vaccination appears comparable in cost effectiveness to other accepted interventions (CDC, unpublished data, 2009).

After PCV7 was introduced, rates of IPD caused by the seven serotypes covered in the vaccine also decreased substantially among unvaccinated children and adults. This indirect (or herd) effect resulted from reduced nasopharyngeal carriage of pneumococcus in vaccinated children and reduced transmission from children to unvaccinated children and adults (8). Immunization of children with PCV13 also is anticipated to have herd effects among adults. For example, as of 2007, serotype 19A had emerged as the most common cause of IPD in all age groups after PCV7 introduction (CDC, unpublished data, 2009). Colonization and disease caused by serotype 19A have a similar epidemiological pattern to those caused by PCV7 serotypes, and some degree of herd effects in the population might be expected. In contrast, some of the other new serotypes in PCV13 might have different epidemiologic characteristics (9). In particular, serotypes 1 and 5 are rarely found in the nasopharynx, so the potential herd effects of PCV13 vaccination on disease caused by these serotypes is uncertain. In the United States, however, serotypes 1 and 5 are relatively uncommon causes of IPD.

Although rates of pneumonia hospitalizations decreased after PCV7 introduction among children aged <2 years (10), the potential effects of PCV13 on noninvasive disease, such as nonbacteremic pneumonia and otitis media, are difficult to evaluate because of lack of standard case definitions, sensitive and specific diagnostic methods, and routine surveillance for these conditions. Information on these noninvasive pneumococcal diseases is not available in the ABCs dataset. Because PCV13 was licensed on the basis of immunogenicity studies rather than clinical efficacy trials, post-licensure monitoring is important to characterize the effectiveness of PCV13 in different populations and to track the potential changes in disease burden caused by non-PCV13 serotypes.

Acknowledgments

The findings in this report are based, in part, on contributions by W Baughman, MSPH, P Malpiedi, MPH, KE Arnold, MD, Georgia Emerging Infections Program; M Cartter, MD, Z Fraser, Connecticut Dept of Public Health, Emerging Infections Program; G Smith, N Spina, MPH, J Karr, MPH, S Solghan, MPH, G Nattanmai, New York State Dept of Health, Emerging Infections Program; MM Lewis, MPH, ER Zell, MStat, C Van Beneden, MD, KA Toews, MPH, E Weston, MPH, and C Wright, ABCs Team, Respiratory Diseases Br, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Atlanta, Georgia.

References

  1. CDC. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(No. RR-9).
  2. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010;201:32--41.
  3. CDC. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children---Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59:258--61.
  4. CDC. Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction---eight states, 1998--2005. MMWR 2008;57:144--8.
  5. Kieninger DM, Kueper K, Steul K, et al. Safety and immunologic non-inferiority of 13-valent pneumococcal conjugate vaccine compared to 7-valent pneumococcal conjugate vaccine given as a 4-dose series with routine vaccines in healthy infants and toddlers. In: Proceedings of the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; October 25--28, 2008; Washington, DC. Arlington, VA: Infectious Diseases Society of America; 2008.
  6. Pelton SI, Huot H, Finkelstein JA, et al. Emergence of 19A as virulent and multidrug resistant pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine. Pediatr Infect Dis J 2007;26:468--72.
  7. Kaplan SL, Barson WJ, Lin PL, et al. Serotype 19A is the most common serotype causing invasive pneumococcal infections in children. Pediatrics 2010;125:429--36.
  8. CDC. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease---United States, 1998--2003. MMWR 2005;54:893--7.
  9. Hausdorff WP, Feikin DR, Klugman KP. Epidemiological differences among pneumococcal serotypes. Lancet Infect Dis 2005;2:83--93
  10. CDC. Pneumonia hospitalizations among young children before and after introduction of pneumococcal conjugate vaccine---United States, 1997--2006. MMWR 2009;58:1--4.

What is already known on this topic?

In February 2010, a new 13-valent pneumococcal conjugate vaccine (PCV13) was licensed by the Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices (ACIP) for prevention of invasive pneumococcal disease in children; PCV13 succeeds the 7-valent vaccine (PCV7) used in the routine childhood immunization schedule since 2000.

What is added by this report?

In 2007, 64% of 427 invasive pneumococcal disease (IPD) cases observed in the Active Bacterial Core surveillance (ABCs) were caused by the serotypes covered by PCV13; 42% of cases were caused by serotype 19A alone.

What are the implications for public health practice?

Achieving and maintaining a high coverage of PCV13 can further reduce IPD among children aged <5 years; postlicensure monitoring will help characterize the effectiveness of PCV13 and track the potential change in disease burden caused by non-PCV13 serotypes.


TABLE 1. Serotypes included in the three pneumococcal vaccine formulations* available in the United States, 2010

Pneumococcal serotype

Vaccine

PCV7

PCV13

PPSV23

4

X

X

X

6B

X

X

X

9V

X

X

X

14

X

X

X

18C

X

X

X

19F

X

X

X

23F

X

X

X

1

X

X

3

X

X

5

X

X

6A

X

7F

X

X

19A

X

X

2

X

8

X

9N

X

10A

X

11A

X

12F

X

15B

X

17F

X

20

X

22F

X

33F

X

* The 13-valent pneumococcal conjugate vaccine (PCV13) includes the seven serotypes in the 7-valent vaccine (PCV7) and six additional serotypes. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) includes 12 of the serotypes included in PCV13 (it does not include serotype 6A) and 11 additional serotypes.


TABLE 2. Number of cases and incidence of invasive pneumococcal disease (IPD), by age and serotype group, among children aged <5 years --- Active Bacterial Core surveillance (ABCs), 10 U.S. sites, 2007*

Age (mos)

All IPD

PCV13 serotypes§

Non-PCV13 serotypes

Serotype 19A

No.

(%)

Incidence

No.

(%)

Incidence

No.

(%)

Incidence

No.

(%)

Incidence

<12

155

(36)

40.5

104

(38)

27.2

51

(33)

13.3

60

(33)

16.2

12--23

124

(29)

31.2

73

(27)

18.4

51

(33)

12.8

57

(32)

14.7

24--35

71

(17)

17.4

43

(16)

10.5

28

(18)

6.9

32

(18)

8.3

36--47

48

(11)

12.4

34

(12)

8.8

14

(9)

3.6

20

(11)

5.2

48--59

29

(7)

7.8

20

(7)

5.4

9

(6)

2.4

11

(6)

3.1

All <60

427

(100)

22

274

(100)

14.1

153

(100)

7.9

180

(100)

9.4

* Cases per 100,000 population. A case of IPD was defined as isolation of Streptococcus pneumoniae from a normally sterile body site (primarily blood or cerebrospinal fluid) in a resident of an ABCs surveillance area. Sites include Connecticut, Minnesota, and New Mexico, and selected counties in California, Colorado, Georgia, Maryland, New York, Oregon, and Tennessee.

Excludes cases missing serotypes (13%); a total of 493 IPD cases were identified among children aged <5 years.

§ The 13-valent pneumococcal conjugate vaccine (PCV13) includes serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.



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