Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction --- Eight States, 1998--2005

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Streptococcus pneumoniae (pneumococcus) is a major cause of meningitis, pneumonia, and bacteremia, especially among young children and older adults (1). Before the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States in 2000, the seven pneumococcal serotypes covered by the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F) caused 80% of invasive pneumococcal disease (IPD) cases among young children (1), and the incidence of IPD was relatively stable (2). In October 2000, the Advisory Committee on Immunization Practices recommended PCV7 for all children aged <2 years and for older children at increased risk for IPD (1). Introduction of PCV7 in the United States led to substantial reductions in the incidence of IPD among the target population of children aged <5 years. Use of the vaccine also reduced IPD among unvaccinated populations through reductions in nasopharyngeal colonization and transmission of vaccine-type pneumococci from vaccinated children (i.e., indirect, or herd, effects of PCV7) (2). To evaluate the effect of continued PCV7 use on IPD incidence among children aged <5 years in the United States, CDC analyzed population- and laboratory-based surveillance data. Results of that analysis indicated that in 2005, overall IPD rates among children aged <5 years were 77% lower, and an estimated 13,000 fewer cases of IPD occurred, compared with the years preceding vaccine introduction (1998--1999). Although IPD caused by PCV7 serotypes declined through 2005, overall IPD rates leveled off beginning in 2002, primarily because of increases in the incidence of IPD caused by non-PCV7 serotype 19A. Given these trends, use of expanded-valency conjugate vaccines might further reduce IPD incidence. Continued surveillance is needed to guide development of future formulations of conjugate vaccines and to monitor the effects of continued vaccine use.

Cases of IPD were defined as isolation of pneumococcus from normally sterile sites (e.g., blood, cerebrospinal fluid, or pleural fluid). Cases were identified through CDC's Active Bacterial Core surveillance (ABCs),* a population- and laboratory-based system ongoing since 1995. During 1998--2005, ABCs continuously monitored IPD in California (one county); the state of Connecticut; Georgia (20 counties); Maryland (six counties); Minnesota (seven counties); New York (seven counties); Oregon (three counties); and Tennessee (four counties). The total population aged <5 years under surveillance in 2005 was 1.26 million persons. Surveillance personnel at each site maintain routine contact with all clinical laboratories in the surveillance area and conduct laboratory audits every 6 months to ensure completeness of reporting. Pneumococcal isolates were serotyped at reference laboratories (CDC and Minnesota Department of Health) by use of the Quellung reaction and grouped as PCV7 types (the seven serotypes in the PCV7 formulation) and non-PCV7 types (all other serotypes).

Annual IPD incidence rates per 100,000 population were calculated using population estimates from the U.S. Census Bureau for prevaccine years (1998--1999), and race-bridged, postcensal population estimates from the National Center for Health Statistics for postvaccine years (2001--2005). Changes in incidence rates between 1998--1999 and 2005 were assessed by calculating relative risks (RRs) reported as percentage changes in rates of disease (percentage change in IPD = [1 -- RR] × 100). To assess statistical significance of a percentage change in the incidence of IPD, 95% confidence intervals were calculated. To estimate the annual number of IPD cases in the United States, race- and age-specific ABCs incidence rates were applied to the race and age distribution of the U.S. population. To estimate the number of IPD cases prevented in 2005, the estimated number of cases in 2005 was subtracted from the average estimated number of cases in 1998--1999. National estimates of IPD cases prevented through vaccination (direct effects of PCV7) in 2005 were calculated as the product of 1) the estimated mean number of PCV7-type cases among children aged <5 years during 1998--1999; 2) national estimates of PCV7 coverage (a range of >1 dose to >3 doses) for each birth cohort during 2001--2005 derived from the National Immunization Survey (3); and 3) 94% vaccine efficacy against PCV7-type IPD (1). Among children born in 2001, 68% and 89% received >1 dose and >3 doses, respectively. Among children born in 2005, 84% and 95% received >1 dose and >3 doses, respectively. To estimate the number of PCV7-type cases prevented through indirect effects of PCV7 among children aged <5 years, the estimated number of cases prevented directly was subtracted from the difference between estimated PCV7-type cases among children aged <5 years during 1998--1999 and 2005.

The overall incidence of IPD among children aged <5 years declined from 98.7 cases per 100,000 during 1998--1999 to 23.4 cases per 100,000 in 2005 (Table). Overall IPD rates were significantly lower in 2005 compared with 1998--1999 for each age group of children aged <5 years (Figure 1). The largest percentage decline (82%) and the largest absolute rate reduction in overall IPD (175.8 cases per 100,000) were observed among children aged 1 year, the age group with the highest baseline rate (Table). The incidence of PCV7-type IPD decreased significantly among all children aged <5 years from 1998--1999 to 2005. The largest absolute rate reduction in PCV7-type disease was observed among children aged 1 year (175.7 cases per 100,000). Non-PCV7--type IPD increased significantly among children aged <1 year and 4 years (Table). The largest absolute rate increase in non-PCV7--type disease was observed among children aged <1 year (10.8 cases per 100,000). Among children aged <5 years, the incidence of serotype 19A IPD increased from 2.6 cases in 1998--1999 to 9.3 cases per 100,000 in 2005, the largest increase for any one serotype. In 2005, 40% of IPD among children aged <5 years was caused by serotype 19A. Although PCV7-type incidence rates continued to decline through 2005 for all children aged <5 years, overall IPD rates plateaued during 2002--2005.

An estimated 14,200 fewer PCV7-type IPD cases occurred in the United States among children aged <5 years in 2005 compared with 1998--1999 (Figure 2). Of these, 11,000 (using >3-dose PCV7 coverage estimates) to 13,000 (using >1-dose estimates) PCV7-type cases were prevented directly by vaccination. The remaining PCV7-type cases (1,200--3,200) were prevented through the indirect effects of PCV7. After accounting for an estimated 1,200 additional non-PCV7--type cases that occurred in 2005 compared with 1998--1999 (Figure 2), a total of 13,000 IPD cases (14,200 PCV7-type cases prevented minus 1,200 additional non-PCV7--type cases) were prevented in 2005 among children aged <5 years. During 2001--2005, an estimated 62,000 cases of IPD were prevented among children aged <5 years, with 59% of these cases prevented through direct effects of PCV7 and the remainder prevented among unvaccinated children (i.e., herd effects).

Reported by: A Reingold, MD, California Emerging Infections Program, Oakland, California. J Hadler, MD, Emerging Infections Program, Connecticut Dept of Public Health. MM Farley, MD, Georgia Emerging Infections Program, Veterans Affairs Medical Center and Emory Univ School of Medicine, Atlanta, Georgia. L Harrison, MD, Maryland Emerging Infections Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. R Lynfield, MD, C Lexau, PhD, Minnesota Dept of Health. N Bennett, MD, Monroe County Dept of Public Health, Rochester, New York. A Thomas, MD, Oregon Public Health Div, Dept of Human Svcs. AS Craig, MD, Tennessee Dept of Health. PJ Smith, Immunization Services Div; B Beall, PhD, CG Whitney, MD, M Moore, MD, T Pilishvili, MPH, Respiratory Diseases Br, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases.

Editorial Note:

The introduction of PCV7 in the United States led to substantial reductions in IPD among the target population (children aged <5 years), and the benefits of vaccination with PCV7 remain evident 5 years later. Overall IPD rates in 2005 were 77% lower for children aged <5 years compared with average rates in 1998--1999. Results of this report indicate that overall IPD rates in 2005 among children aged <5 years (23.2 per 100,000) remain below the Healthy People 2010 objective (14-5a) of 46 per 100,000.^† Findings in this report are supported by a growing body of evidence of the beneficial effects of PCV7 introduction on noninvasive pneumococcal disease; recent studies report dramatic declines in all-cause pneumonia and pneumococcal pneumonia in the PCV7 target population (4) and reductions in frequent otitis media (5).

Results of this analysis also demonstrate that, after reductions in IPD rates among children targeted for vaccination during the first 3 years after PCV7 introduction, further reductions were offset by increases in non-PCV7 serotypes. PCV7-type IPD rates continued to decline, but overall IPD rates leveled off during 2002--2005. Since the introduction of PCV7, a shift in the distribution of serotypes causing IPD in this age group has occurred; only 7% of cases were caused by PCV7 serotypes in 2005, compared with approximately 80% during 1998--1999. Serotype 19A was the most common serotype causing IPD among children in 2005, and changes in non-PCV7--type IPD were largely driven by increases in IPD caused by this serotype. Even though absolute increases in rates of non-PCV7--type IPD remain modest relative to reductions in PCV7-type IPD, an estimated 1,200 additional cases of IPD not preventable by PCV7 occurred among children aged <5 years in 2005, compared with prevaccine baseline. Increases in non-PCV7--type disease among vaccinated and unvaccinated populations have been reported since PCV7 introduction (2,6). The results of this analysis indicate that, in the general U.S. population, these increases have been small relative to declines in PCV7-type disease.

The findings in this report are subject to at least one limitation. The relationships between PCV7 coverage or numbers of PCV7 doses received and PCV7 effects could not be explored directly. Vaccination status was not available for persons with IPD, and PCV7 coverage estimates from a different data source were used to estimate PCV7 direct effects. Therefore, the level of PCV7 coverage needed to induce indirect (i.e., herd) effects is unknown. In this analysis, a range of PCV7 coverage estimates (>3 or >1 doses) for each birth cohort was used to obtain a range of estimates for the direct and indirect effects of PCV7.

Initial substantial declines in IPD after PCV7 introduction are strikingly similar to reductions in invasive disease caused by Haemophilus influenzae type b (Hib) after Hib conjugate vaccine introduction in the United States (7). Increases in disease caused by H. influenzae serotypes other than type b were a concern; however, the experience with Hib conjugate vaccine indicates that non--type b H. influenzae were not as successful as Hib in causing invasive disease (8). In contrast with the six serotypes of H. influenzae, approximately 90 pneumococcal serotypes have been described. Fortunately, different pneumococcal serotypes also vary in their ability to cause invasive disease (9). The findings in this report suggest that expanded-valency conjugate vaccines for children that also provide protection against serotype 19A would be useful to improve prevention of IPD. A 13-valent conjugate vaccine containing type 19A polysaccharide and a 10-valent conjugate vaccine, which might provide cross protection against type 19A (10), are currently in clinical trials. Continued surveillance for IPD is crucial to provide information on emerging pneumococcal serotypes and the optimal composition of future conjugate vaccines.

Acknowledgments

This report is based, in part, on contributions by P Daily, MPH, G Rothrock, MPH, California Emerging Infections Program, Oakland, California; S Petit, MPH, Emerging Infections Program, Connecticut Dept of Public Health; W Baughman, MSPH, P Malpiedi, MPH, Georgia Emerging Infections Program, Veterans Affairs Medical Center and Emory Univ School of Medicine; KE Arnold, MD, Div of Public Health, Georgia Dept of Human Resources, Atlanta, Georgia. R Hollick, Maryland Emerging Infections Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; J Besser, PhD, R Danila, PhD, B Juni, MS, G Kupferschmidt, Minnesota Dept of Health; C Long, Univ of Rochester, Rochester, New York; D Hoefer, New York State Dept of Health; Karen Stefonek, MPH, Oregon Dept of Human Svcs; B Barnes, W Schaffner, Vanderbilt Univ Medical Center, Nashville, Tennessee; TH Skoff, MS, E Weston, MPH, ER Zell, MStat, C Wright, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC.

References

1. Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(No. RR-9).
2. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737--46.
3. Smith PJ, Nuorti JP, Singleton JA, Zhao Z, Wolter KM. Effect of vaccine shortages on timeliness of pneumococcal conjugate vaccination: results from the 2001--2005 National Immunization Survey. Pediatrics 2007;120:1165--73.
4. Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time series analysis. Lancet 2007;369:1179--86.
5. Poehling KA, Szilagyi PG, Grijalva CG, et al. Reduction of frequent otitis media and pressure-equalizing tube insertion in children after introduction of pneumococcal conjugate vaccine. Pediatrics 2007;119:707--15.
6. Hicks LA, Harrison LH, Flannery B, et al. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998--2004. J Infect Dis 2007;196:1346--54.
7. Bisgard KM, Kao A, Leake J, Strebel PM, Perkins BA, Wharton M. Haemophilus influenzae disease in the United States, 1994--1995: near disappearance of a vaccine-preventable childhood disease. Emerg Infect Dis 1998;4:229--37.
8. CDC. Active Bacterial Core surveillance reports, Emerging Infections Program Network, Haemophilus influenzae, 1998--2006. Available at http://www.cdc.gov/ncidod/dbmd/abcs/survreports.htm.
9. Brueggemann AB, Griffiths DT, Meats E, Peto T, Crook DW, Spratt BG. Clonal relationships between invasive and carriage Streptococcus pneumoniae and serotype- and clone-specific differences in invasive disease potential. J Infect Dis 2003;187:1424--32.
10. Nurkka A, Lehtonen H, Vuorela A, Ekström N, Käyhty H. Functionality of antibodies against serotypes 6A and 19A induced by three different pneumococcal conjugate vaccines (PCV) in infants [Poster]. Presented at the 5th International Symposium on Pneumococci and Pneumococcal Diseases, Alice Springs, Australia, April 2--6, 2006.

* ABCs of CDC's Emerging Infections Programs Network is a collaborative surveillance system for invasive bacterial pathogens of public health importance conducted by CDC, state health departments, and universities. For each case of invasive disease in the surveillance population, a case report with basic demographic information is completed and bacterial isolates are sent to CDC and other reference laboratories for additional laboratory evaluation. Additional information is available at http://www.cdc.gov/ncidod/dbmd/abcs/index.htm.

^† US Department of Health and Human Services. Healthy people 2010 (conference ed, in 2 vols). Washington, DC: US Department of Health and Human Services; 2000. Available at http://www.healthypeople.gov.

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Date last reviewed: 2/14/2008