Abstract

BackgroundChanges in invasive pneumococcal disease (IPD) incidence were evaluated after 7 years of 7-valent pneumococcal conjugate vaccine (PCV7) use in US children

MethodsLaboratory-confirmed IPD cases were identified during 1998–2007 by 8 active population-based surveillance sites. We compared overall, age group-specific, syndrome-specific, and serotype group-specific IPD incidence in 2007 with that in 1998–1999 (before PCV7) and assessed potential serotype coverage of new conjugate vaccine formulations

ResultsOverall and PCV7-type IPD incidence declined by 45% (from 24.4 to 13.5 cases per 100,000 population) and 94% (from 15.5 to 1.0 cases per 100,000 population), respectively (P<.01 for all age groups). The incidence of IPD caused by serotype 19A and other non-PCV7 types increased from 0.8 to 2.7 cases per 100,000 population and from 6.1 to 7.9 cases per 100,000 population, respectively (P<.01 for all age groups). The rates of meningitis and invasive pneumonia caused by non-PCV7 types increased for all age groups (P<.05), whereas the rates of primary bacteremia caused by these serotypes did not change. In 2006–2007, PCV7 types caused 2% of IPD cases, and the 6 additional serotypes included in an investigational 13-valent conjugate vaccine caused 63% of IPD cases among children <5 years-old

ConclusionsDramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later. IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV7-type IPD

Streptococcus pneumoniae (pneumococcus) is a major bacterial cause of pneumonia, meningitis, and sepsis worldwide, resulting in almost 1 million childhood deaths annually [1]. Before 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in late 2000 for US children <5 years old, ∼65,000 cases of invasive pneumococcal disease (IPD) occurred annually. Children aged <5 years accounted for about 25% of IPD episodes, and 80% of disease in this age group was caused by the 7 serotypes included in the vaccine [2]

PCV7 uptake was rapid: estimated coverage of ⩾3 doses by 24 months of age for successive US birth cohorts increased from 9% for children born in 1999 to 93% for those born in 2006 [3, 4]. Shortly after PCV7 introduction, IPD incidence declined rapidly, not only among children targeted for vaccination but also among unvaccinated children and adults [5, 6], demonstrating strong direct and indirect vaccine effects. The potential for vaccination to contribute to the emergence of serotypes not included in the vaccine, so-called “replacement disease,” has been a concern. However, increases in the incidence of non-PCV7 serotypes in the general US population have been modest to date [7–11]. With the reduction in rates of PCV7-type IPD, non-PCV7 serotypes now account for a higher proportion of IPD. Whether these serotypes are associated with more severe infections than PCV7 types is unknown. We analyzed surveillance data collected through an active laboratory- and population-based system to evaluate changes in IPD 7 years after PCV7 introduction in the United States and to measure potential serotype coverage of new conjugate vaccine formulations

Methods

We identified IPD cases through Active Bacterial Core surveillance (ABCs), an active population- and laboratory-based system [5, 12]. For this analysis, we included cases identified between 1 January 1998 and 31 December 2007 in 8 continuously participating ABCs sites: selected counties in California, Georgia, Maryland, Minnesota, New York, Oregon, and Tennessee and the state of Connecticut. The total population under surveillance was 19,060,270, according to 2007 postcensus population estimates

We defined IPD cases as isolation of S. pneumoniae from normally sterile sites such as blood, cerebrospinal fluid, or pleural fluid. Regular audits of participating laboratories ensured completeness of reporting. Medical charts were reviewed to attain demographic and clinical information. Isolates were serotyped at the Streptococcus Laboratory of the Centers for Disease Control and Prevention (CDC) or the Minnesota Department of Health Laboratory using latex agglutination and confirmation by the Quellung reaction. We assigned serotypes to the following mutually exclusive categories: (1) PCV7 types (4, 6B, 9V, 14, 18C, 19F, and 23F), (2) PCV7-related types (serotypes in the same serogroups as the PCV7 types, excluding 19A), (3) serotype 19A (analyzed separately because of its distinct epidemiology [7, 13, 14]), and (4) non-PCV7 types. Serotypes 6A and 6C, included in the PCV7-related group, could not be distinguished using the Quellung reaction and were reported as type 6A/C [15]. We calculated the proportion of IPD cases caused by serotypes included in PCV7 and the 23-valent pneumococcal polysaccharide vaccine (PPV23) (PCV7 plus serotypes 1, 2, 3, 5, 7F, 8, 9N, 10A, 11A, 12F, 15B, 17F, 19A, 20, 22F, and 33F), as well as in 2 new conjugate vaccines, PCV10 (PCV7 plus serotypes 1, 5, and 7F) [16] and PCV13 (PCV10 plus types 3, 6A, and 19A) [17]

We calculated annual IPD incidence rates (cases per 100,000 population) using US Census Bureau population estimates for prevaccine baseline years (1998–1999) and race-bridged postcensus population estimates [18] for postvaccine years (2000–2007) as denominators. Serotype-specific rates were calculated by imputing serotype for cases with missing isolates based on age group-specific distribution of cases with known serotypes. We assessed changes in incidence by calculating relative risks and 95% confidence intervals (CIs), expressed as percentage changes in rates of disease ([relative risk-1]×100%). We calculated case-fatality ratios (CFRs) as the proportion of case patients with known outcome who died during their hospitalization or illness episode. Outcome was unknown or missing for <1% of patients

Patients with any of the following chronic illnesses were classified as having a comorbid condition: human immunodeficiency virus (HIV) infection (with or without AIDS), Hodgkin disease, leukemia, myeloma, nephrotic syndrome, dialysis, immunoglobulin deficiency, asplenia, organ or bone marrow transplant, sickle cell disease, immunosuppressive therapy, cerebrospinal fluid leak, cirrhosis, diabetes, congestive heart failure, cardiomyopathy, atherosclerotic cardiovascular disease, chronic obstructive pulmonary disease, or alcohol abuse. Patients from Georgia were excluded from the analysis of comorbid conditions, because this information was not collected there before year 2000

To examine the independent contributions of comorbid conditions and serotype to severe IPD outcomes, we constructed 2 separate multivariable logistic regression models, one for children <5 years and one for adults ⩾18 years old, evaluating serotype group (PCV7 types vs all other types) and presence of comorbid conditions as predictors of death or hospitalization due to IPD. Death was not evaluated as an outcome in the first model, because very few deaths were identified among children. Similarly, because the majority of adult patients (94%–97% annually) were hospitalized, hospitalization was not evaluated as an outcome in the second model. We assessed 2-way interactions and colinearity of covariables in the models

Using methods described elsewhere [19], we estimated the annual number of IPD cases and deaths prevented, including PCV7-type IPD cases prevented among vaccinated children and unvaccinated children and adults through reduced transmission from vaccinated children [20]. We estimated coverage for ⩾1 or ⩾3 doses of PCV7 for each birth cohort during 1997–2006, as described elsewhere [3], and applied this range of coverage estimates to obtain the number of cases prevented annually among vaccinated children. We reported only the estimates applying PCV7 coverage for ⩾3 doses, because results obtained using the range of coverage estimates were similar (data not shown). We used SAS, version 9.1 (SAS Institute), and EpiInfo, version 3.3.2 (CDC), software for statistical analysis; χ2 or Fisher's exact tests were used to compare the proportions of patients with IPD who were hospitalized or had comorbid conditions and to compare CFRs in 2006–2007 with those in 1998–1999. Differences were considered statistically significant at P<.05 (2-sided P values)

ABCs case reporting and isolate collection were considered to be surveillance activities and were exempt from CDC institutional review. The surveillance protocol was also evaluated by each participating surveillance site, and either the protocol was deemed exempt from review or appropriate institutional review board approval was obtained. Informed consent was not required by the CDC or individual site institutional reviews

Results

From 1998 to 2007, 30,032 cases of IPD were identified, including 5410 among children aged <5 years. Eighty-nine percent of cases (range, 87%–90% by year) had isolates available for serotyping. The IPD incidence for all ages declined from 24.4/100,000 population (n=4048) in 1998–1999 to 13.5 cases per 100,000 population (n=2576) in 2007 (−45%; 95% CI, −47% to −42%) (Table 1). The incidence of PCV7-type IPD for all ages decreased significantly, and the incidence of IPD caused by non-PCV7 types and serotype 19A increased significantly in 2007 compared with baseline (Table 1)

Table 1

Changes in Incidence of Invasive Pneumococcal Disease, by Age Group and Serotype, 1998–1999 Average (Baseline) versus 2007

Table 1

Changes in Incidence of Invasive Pneumococcal Disease, by Age Group and Serotype, 1998–1999 Average (Baseline) versus 2007

Changes in overall and PCV7-type IPD by age group Overall IPD rates declined from baseline through 2002 and leveled off from 2004 through 2007 (Figure 1), whereas PCV7-type IPD rates continued to decline (Figure 2A and 2B). In 2007, children <5 years old, the PCV7 target age group, accounted for 12% of all IPD cases, compared with 28% at baseline. Among children <2 months old, too young to be immunized, the overall IPD incidence decreased from 49.5 at baseline to 25.0 cases per 100,000 population in 2007 (−50%; 95% CI, −1% to −74%), and the incidence of PCV7-type IPD in this age group decreased from 35.2 to 2.3 cases per 100,000 population (−94%; 95% CI, −52% to −99%). Among adults, the greatest absolute decreases in overall IPD rates were seen among those ⩾65 years old (rate difference, −22.2 cases per 100,000 population). The relative reductions in PCV7-type IPD were similar across adult age groups, ranging from 87% among 50–64-year-old persons to 92% among ⩾65-year-old persons (Table 1)

Figure 1

Changes in overall invasive pneumococcal disease (IPD) incidence rates by age group, 1998–2007. *Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States for routine use among young children and infants in the second half of 2000

Figure 1

Changes in overall invasive pneumococcal disease (IPD) incidence rates by age group, 1998–2007. *Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States for routine use among young children and infants in the second half of 2000

Figure 2

Changes in invasive pneumococcal disease (IPD) incidence by serotype group among children aged <5 years (A) and adults aged ⩾65 years (B) 1998–2007. *Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States for routine use among young children and infants in the second half of 2000

Figure 2

Changes in invasive pneumococcal disease (IPD) incidence by serotype group among children aged <5 years (A) and adults aged ⩾65 years (B) 1998–2007. *Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the United States for routine use among young children and infants in the second half of 2000

In 2006–2007, PCV7 serotypes accounted for only 2% of all IPD among children aged <5 years, compared with 83% at baseline. The proportions of IPD cases caused by PCV7-type strains decreased from 56% to 10% and from 56% to 9% among 18–64-year-old and ⩾65-year-old adults, respectively (Table 2)

Table 2

Distribution of Pneumococcal Serotypes by Age Group before and after Introduction of 7-Valent Pneumococcal Conjugate Vaccine (PCV7)

Table 2

Distribution of Pneumococcal Serotypes by Age Group before and after Introduction of 7-Valent Pneumococcal Conjugate Vaccine (PCV7)

Changes in IPD caused by serotypes other than PCV7 typesWe evaluated trends in IPD caused by PCV7-related serotypes (excluding 19A) to determine whether PCV7 may have had population-level effects on potentially cross-reactive serotypes. IPD caused by PCV7-related serotypes declined significantly among children aged <5 years, remained stable among older children and young adults, and increased significantly among ⩾50-year-old adults (Table 1). Reductions in PCV7-related serotypes among children <5 years were due mostly to declines in rates of serotype 6A/C IPD, for which we observed an 82% decline (from 5.1 to 0.9 cases per 100,000 population; 95% CI, −67% to −90%). No changes in rates of serotype 6A/C IPD were observed among 18–64-year-old adults, but among adults aged ⩾65 years, IPD rates caused by this serotypes increased 70% (from 2.2 to 3.8 cases per 100,000 population; 95% CI, +25% to +131%). The rate of IPD caused by serotype 23A increased from 0.2 to 0.5 cases per 100,000 population (+147%; 95% CI, +13% to +450%) and from 0.4 to 2.2 cases per 100,000 population (+514%; 95% CI, +227% to +980%) among 50–64-year-old and >65-year-old adults, respectively. No changes in other PCV7-related serotypes were observed among children or adults of any age group

The incidence of IPD caused by serotype 19A increased significantly among all age groups (Table 1). Although percentage changes were large (range, +144% to +344%), absolute rate increases in each age group were relatively small (range, 0.4–8.5 cases per 100,000 population) compared with observed reductions in PCV7-type IPD (Figure 2A and 2B). Similarly, non-PCV7-type IPD rates increased significantly among children <5 years and all adults, and absolute rate differences ranged from 0.6 to 4.2 cases per 100,000 population (Table 1). The incidence of IPD caused by the 16 serotypes included in PPV23 but not in PCV7 increased 26% (from 16.7 to 21.1 cases per 100,000 population; 95% CI, +12% to +42%) among ⩾65-year-old adults and 48% (from 4.9 to 7.4 cases per 100,000 population; 95% CI, 27% to 72%) among 18–64-year-old adults. In 2006–2007, 47% of IPD episodes among children <5 years old were due to serotype 19A, with an additional 46% caused by other non-PCV7 types; the most common non-PCV7 serotypes were 7F (9%), 22F (5%), 33F (5%), and 3 (5%). In 2006–2007, the proportions of IPD cases among children <5 years old covered by serotypes contained in PCV7, PCV10, and PCV13 were 2%, 12%, and 68%, respectively. In 2006–2007, the proportions of IPD cases among ⩾65-year-old adults covered by serotypes contained in PCV7, PCV10, PCV13, and PPV23 were 9%, 16%, 50%, and 65%, respectively (Table 2)

Changes by syndrome and disease severityOverall rates of bacteremia without focus, invasive pneumonia, and meningitis decreased significantly among all age groups, with the exception of meningitis among adults, for which reductions in PCV7-type disease were offset by increases in non-PCV7-type disease (Table 3). Rates of hospitalization (per 100,000 population) decreased significantly among all age groups. However, the proportion of pediatric and older adult patients resulting in hospitalization in 2006–2007 was higher than in 1998–1999 (56% vs 32% among children aged <5 years [P<.001]; 97% vs 94% among adults aged ⩾65 years [P=.003]). These observations raised the hypotheses that non-PCV7 serotypes might be more virulent than PCV7 serotypes or that the populations may have become more susceptible to circulating pneumococcal strains and more likely to experience adverse outcomes

Table 3

Changes in Disease Rates, by Serotype Group, Clinical Syndrome, and Disease Severity, among Patients with Invasive Pneumococcal Disease, 1998–1999 and 2006–2007

Table 3

Changes in Disease Rates, by Serotype Group, Clinical Syndrome, and Disease Severity, among Patients with Invasive Pneumococcal Disease, 1998–1999 and 2006–2007

To test these hypotheses, we evaluated trends in the prevalence of comorbid conditions among persons with IPD. From baseline to 2006–2007, the proportion of patients with IPD who had ⩾1 comorbid condition increased from 3% to 7% among children aged <5 years (P=.003), from 52% to 59% among adults 18–64 years old (P<.001), and from 69% to 81% among those ⩾65 years old (P<.001). In multivariable analysis controlling for serotype group (PCV7 types vs all other types) and presence of comorbid conditions, case patients <5 years old with comorbid conditions were more likely than those without them to be hospitalized (adjusted odds ratio [aOR], 9.9; 95% CI, 3.0–33.0); hospitalization was equally common among PCV7 types and all other types (aOR, 1.3; 95% CI, 0.3–5.3)

Among children aged <5 years old, the CFR increased from 0.7% at baseline to 1.4% in 2006–2007 (P=.08), whereas the overall IPD mortality rate remained stable (Table 3). There were no changes in the CFR among adults 18–64 years old (11% vs 10%; P=.197) or ⩾65 years old (19% vs 18%; P=.657), but mortality rates due to overall and PCV7-type IPD declined significantly among all adult age groups. In a multivariable model controlling for age, presence of comorbid conditions, and serotype group (PCV7 types vs all others), infections in ⩾18-year-old adult patients with comorbid conditions were more likely to be fatal than those occurring in adults without comorbid conditions (aOR, 1.5; 95% CI, 1.2–1.9), whereas serotype group did not affect the likelihood of fatal outcome (aOR, 1.1; 95% CI, 0.8–1.5)

Estimating changes in IPD burden in the United StatesCompared with the expected number of PCV7-type IPD cases in the absence of vaccination, an estimated 5200–43,100 fewer cases occurred annually during 2000–2007. Among vaccinated children aged <5 years, based on PCV7 coverage data for ⩾3 doses, an estimated 2700–14,000 fewer PCV7-type cases occurred annually. Among unvaccinated children and adults, 2500–29,000 fewer PCV7-type cases occurred annually. After accounting for an annual increase of 2900–10,500 cases caused by serotypes other than PCV7 types, an estimated 211,000 fewer IPD cases occurred during 2000–2007. An estimated 13,000 fewer IPD-related deaths occurred in the United States since the introduction of PCV7

Discussion

Introduction of PCV7 in the United States has been associated with dramatic reductions in the burden of IPD, and marked public health benefits remain evident 7 years later. In our surveillance areas, the overall IPD incidence in 2007 was 45% lower for all age groups and 76% lower for children aged <5 years compared with prevaccine baseline incidence. Overall disease rates in 2007 among children aged <5 years (23.6 cases per 100,000 population) and adults ⩾65 years old (37.9 cases per 100,000 population) remain below the US Department of Health and Human Services Healthy People 2010 objectives (children aged <5 years, 46 cases per 100,000 population; adults aged ⩾65 years, 42 cases per 100,000 population). Our data complement the findings of recent studies documenting reductions in meningitis [21], noninvasive pneumonia [22], otitis media [23, 24], and pneumococcal infections resistant to antibiotics [25] after PCV7 introduction. Although noninvasive pneumococcal disease is more common than invasive disease, surveillance for invasive disease avoids the difficulty of distinguishing between upper respiratory tract colonization and true infection and allows detection of serotype-specific changes in disease incidence

Following a dramatic decline after PCV7 introduction, overall IPD incidence rates during 2002–2007 have been steady. However, sustained year-to-year reductions in the incidence of PCV7-type IPD in the vaccine target population as well as unvaccinated populations strongly suggest continued benefits of the vaccine. The incidence of IPD caused by vaccine serotypes has declined to <1 cases per 100,000 population among children aged <5 years. Beneficial indirect effects of PCV7 among unvaccinated populations documented in earlier studies [5, 6, 26] were still evident in 2007 for ages. Among infants <2 months old, we found that reductions in overall and vaccine-type IPD reported previously [20] have continued and remain substantial, a finding relevant to developing countries, where pneumococcal infections are acquired earlier in life [27]. Our data also show evidence of herd immunity among children aged 5–17 years, many of whom are too old to have received PCV7. Despite large reductions in overall and PCV7-type IPD rates among adults of all ages, rates in 2007 remain high compared with disease rates in children, especially among older adults

Although PCV7-type IPD incidence continued to decline through 2007, further reductions in overall IPD during 2002–2007 were offset by increases in IPD serotypes not included in PCV7, predominantly serotype 19A. Rates of IPD caused by serotype 19A have increased for all ages, making this serotype now the most common among all age groups. Importantly, absolute increases in rates of non-PCV7-type IPD remain modest in comparison with the reductions in PCV7-type IPD observed since 2000. However, recent studies reported more prominent increases in non-PCV7 serotypes in some populations, and these increases have partially eroded disease reductions observed after PCV7 introduction [28–31]. The reasons for the varying magnitude of increases in non-PCV7 serotypes among different populations are unknown, but differences in the frequency of comorbid conditions or immunosuppression [28, 32], antibiotic use [33], serotype distributions, or environmental conditions [31] could be important. Although the effect of increases in nonvaccine serotypes on overall IPD rates was less apparent in other studies [5, 26], increases in non-PCV7 types have been observed in recent studies of carriage and acute otitis media [27, 34, 35]

We observed significant increases in the incidence of meningitis and invasive pneumonia caused by nonvaccine serotypes but not in the incidence of primary bacteremia caused by these serotypes. This observation may relate to changes in the circulating serotypes and their ability to cause different clinical syndromes [8–10, 36–38]. Although the incidence of hospitalization or death associated with IPD decreased, we observed increases in the proportions of patients with IPD who were hospitalized among all age groups and increases in CFRs among children compared with pre-PCV7 years. Increases in nonvaccine serotypes were more prominent among hospitalized patients than among outpatients. These findings raised the question of whether, in the setting of widespread immunization with PCV7, nonvaccine serotype cases are more likely than PCV7-type cases to be associated with death or hospitalization. As in another recent study [39], we found that the presence of comorbid conditions, and not infection with nonvaccine serotypes, had greater influence on IPD severity. Reductions in IPD after PCV7 introduction may have been greater among healthy individuals than among those with underlying comorbid conditions. The latter group is at increased risk of severe outcomes of IPD because of their comorbid conditions, irrespective of the serotype to which they are exposed

We considered whether increased use of PPV23 could explain the observed reductions in IPD among adults. This seems unlikely, given that increases in PPV23 coverage have been modest [40], declines in IPD were limited to PCV7-type cases, and rates of IPD caused by serotypes that were only in PPV23 increased. The finding that the rate of IPD caused by the serotypes unique to PPV23 has increased in the elderly (subjects ⩾65 years old) also merits comment. A likely explanation is increased carriage of these strains by children vaccinated with PCV7 and subsequent increased exposure of elderly adults who were still susceptible to these strains. The possibility that PPV23 is at least somewhat protective against these serotypes should be considered. However, these ecologic data cannot prove the relative contribution of PPV23 to the observed trends

Factors other than PCV7 introduction may have played a role in some of the observed increases in the incidence of non-PCV7-type IPD. The distribution of pneumococcal serotypes, including serotype 19A, can change over time in the absence of vaccine [41, 42]. In addition, characteristics of circulating pneumococcal strains that place them at selective advantage, such as the ability to cause invasive disease [36, 43], prevalence in nasopharyngeal carriage [36], resistance to commonly prescribed antibiotics [7, 43], and age-based susceptibility to different serotypes [41], could contribute to changes in serotype distribution

This study has certain limitations. Our surveillance areas may not be representative of the United States as a whole. We adjusted for differences in age and racial distributions between our study population and the United States, but there may be residual confounding. We could not directly explore the relationship between PCV7 coverage and IPD incidence, because vaccination status was not available for individual IPD cases. Influenza activity [44] and reductions in smoking prevalence among adults [45] may also have independently contributed to changes in disease incidence. However, these factors were unlikely to have influenced rates of IPD caused by PCV7 serotypes more than other types, and the relative magnitude of the declines, sustained over several years, support the hypothesis that the observed IPD trends are associated with PCV7 introduction. Changes in clinical practices after PCV7 introduction, such as decreases in blood culturing among children presenting with an acute febrile illness, may have influenced the findings of increases in nonvaccine serotypes among hospitalized patients and not among outpatients, as well as increases in these serotypes among patients with meningitis or invasive pneumonia and not among those with primary bacteremia. We did not distinguish between serotypes 6A and 6C for all years of our study, and we were therefore unable to evaluate the contribution of these serotypes to the observed differences in IPD trends among adults versus children [46]

After consistently robust reductions in IPD rates during the first 3 years of PCV7 use in the United States, the overall trends during 2002–2007 reached an equilibrium between reductions in PCV7-type IPD and increases in non-PCV7 serotypes. This equilibrium and the emergence of non-PCV7 serotypes, especially among persons with underlying illnesses, highlight the need for several important prevention measures [28, 32]. First, improving coverage with existing vaccines [47, 48] is important, because disparities in coverage with the pediatric vaccine [4] and low coverage with PPV23 continue, despite the long-standing availability of PPV23 [49]. Second, new higher-valency conjugate vaccines are in development. Assuming their effectiveness is similar to that of PCV7, they may be able to prevent pneumococcal disease caused by a greater variety of serotypes. Use of conjugate vaccines among adults, especially those with underlying illnesses, may also play an important role, as was recently suggested by a study of PCV7 among HIV-infected adults [50]. Third, common protein vaccines now under development may provide broad protection against pneumococcal diseases, regardless of the serotype involved, therefore eliminating the issue of changes in the prevailing serotypes. Finally, introduction of pneumococcal conjugate vaccines into more countries should be a high priority [51], given the large burden of disease globally and sustained reductions in disease observed in the United States

ABCs/Emerging Infections Program Network

California Emerging Infections ProgramGretchen Rothrock, Pam Daily, Susan Brooks, Joelle Nadle, and Mirasol Apostol

Connecticut Emerging Infections ProgramSusan Petit, M. Zachariah Fraser, and Nancy Barrett

Georgia Emerging Infections ProgramPaul Malpiedi, Wendy Baughman, and Kathryn E. Arnold

Maryland Emerging Infections ProgramKim D. Holmes and Elisabeth A. Vaeth

Minnesota Emerging Infections ProgramRuth Lynfield, Lori Triden, Brenda Jewell, Jean Rainbow, and Craig Morin, Clinical Microbiology Section, Minnesota Public Health Laboratory

New York Emerging Infections ProgramBridget Anderson, Shelley Zansky, Glenda Smith, and Christine Long

Oregon Emerging Infections ProgramMark Schmidt and Karen Stefonek

Tennessee Emerging Infections ProgramBrenda Barnes and Terry McMinn

CDCChris Van Beneden, Tami H. Skoff, Carolyn Wright, Elizabeth Zell, Saundra Mathis, Richard Facklam, Alma R. Franklin, Patricia L. Shewmaker, and Delois Jackson

Acknowledgments

We are grateful for the contributions of members of the ABCs/Emerging Infections Program Network

References

1
World Health Organization
Challenges in global immunization and the Global Immunization Vision and Strategy 2006–2015
Wkly Epidemiol Rec
 , 
2006
, vol. 
19
 (pg. 
190
-
5
Available at http://www.who.int/wer/2006/wer8119.pdf
2
Robinson
K
Baughman
W
Rothrock
G
, et al.  . 
Epidemiology of Streptococcus pneumoniae infections in the U.S., 1995–1998: opportunities for prevention in the conjugate vaccine era
JAMA
 , 
2001
, vol. 
285
 (pg. 
1729
-
35
)
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
, vol. 
120
 (pg. 
1165
-
73
)
4
US Department of Health and Human Services
National Center for Health Statistics
 
The National Immunization Survey, 2001–2006. Available at http://www.cdc.gov/nis/. Accessed 16 September 2008
5
Whitney
C
Farley
M
Hadler
J
, et al.  . 
Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine
N Engl J Med
 , 
2003
, vol. 
348
 (pg. 
1737
-
46
)
6
Lexau
C
Lynfield
R
Danila
R
, et al.  . 
Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine
JAMA
 , 
2005
, vol. 
294
 (pg. 
2043
-
51
)
7
Moore
MR
Gertz
RE
Woodbury
RL
, et al.  . 
Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005
J Infect Dis
 , 
2008
, vol. 
197
 (pg. 
1016
-
27
)
8
Byington
CL
Samore
MH
Stoddard
GJ
, et al.  . 
Temporal trends of invasive disease due to Streptococcus pneumoniae among children in the Intermountain West: emergence of nonvaccine serogroups
Clin Infect Dis
 , 
2005
, vol. 
41
 (pg. 
21
-
9
)
9
Long
SS
Capsules, clones, and curious events: pneumococcus under fire from polysaccharide conjugate vaccine
Clin Infect Dis
 , 
2005
, vol. 
41
 (pg. 
30
-
4
)
10
Calbo
E
Garau
J
Invasive pneumococcal disease in children: changing serotypes and clinical expression of disease
Clin Infect Dis
 , 
2005
, vol. 
41
 (pg. 
1821
-
3
)
11
Hicks
L
Harrison
L
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
, vol. 
196
 (pg. 
1346
-
54
)
12
Schuchat
A
Hilger
T
Zell
E
, et al.  . 
Active Bacterial Core surveillance of the Emerging Infections Program Network
Emerg Infect Dis
 , 
2001
, vol. 
7
 (pg. 
92
-
9
)
13
Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children
JAMA
 , 
2007
, vol. 
298
 (pg. 
1772
-
8
)
14
Centers for Disease Control and Prevention
Emergence of antimicrobial-resistant serotype 19A Streptococcus pneumoniae: Massachusetts, 2001–2006
MMWR Morb Mortal Wkly Rep
 , 
2007
, vol. 
56
 (pg. 
1077
-
80
)
15
Park
IH
Pritchard
DG
Cartee
R
Brandao
A
Brandileone
MCC
Discovery of a new capsular serotype (6C) within serogroup 6 of Streptococcus pneumoniae
J Clin Microbiol
 , 
2007
, vol. 
45
 (pg. 
1225
-
33
)
16
GlaxoSmithKline
 
GlaxoSmithKline files pneumococcal paediatric vaccine in the EU: breakthrough vaccine design targeting two bacterial pathogens. Press release. 31 January 2008. Available at http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_0056.htm. Accessed 16 November 2009
17
Scott
DA
Komjathy
SF
Hu
BT
, et al.  . 
Phase 1 trial of a 13-valent pneumococcal conjugate vaccine in healthy adults
Vaccine
 , 
2007
, vol. 
25
 (pg. 
6164
-
6
)
18
United States Census Bureau
 
Population estimates. Available at http://www.census.gov/popest/datasets.html. Accessed 1 December 2008
19
Centers for Disease Control and Prevention
Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction: eight states, 1998–2005
MMWR Morb Mortal Wkly Rep
 , 
2008
, vol. 
57
 (pg. 
144
-
8
)
20
Poehling
KA
Talbot
TR
Griffin
MR
, et al.  . 
Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine
JAMA
 , 
2006
, vol. 
295
 (pg. 
1668
-
74
)
21
Hsu
HE
Shutt
KA
Moore
MR
, et al.  . 
Effect of pneumococcal conjugate vaccine on pneumococcal meningitis
N Engl J Med
 , 
2009
, vol. 
360
 (pg. 
244
-
56
)
22
Grijalva
CG
Nuorti
JP
Arbogast
PG
Martin
SW
Edwards
KM
Decline in pneumonia admissions after routine childhood immunization with pneumococcal conjugate vaccine in the USA: a time-series analysis
Lancet
 , 
2007
, vol. 
369
 (pg. 
1179
-
86
)
23
Poehling
KA
Szilagyi
PG
Grijalva
CG
, et al.  . 
Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine
Pediatrics
 , 
2007
, vol. 
119
 (pg. 
707
-
15
)
24
Grijalva
CG
Poehling
KA
Nuorti
JP
, et al.  . 
National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States
Pediatrics
 , 
2006
, vol. 
118
 (pg. 
865
-
73
)
25
Kyaw
MH
Lynfield
R
Schaffner
W
, et al.  . 
Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
1455
-
63
)
26
Black
S
Shinefield
H
Baxter
R
, et al.  . 
Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente
Pediatr Infect Dis J
 , 
2004
, vol. 
23
 (pg. 
485
-
9
)
27
Mbelle
N
Huebner
RE
Wasas
AD
Kimura
A
Chang
I
Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine
J Infect Dis
 , 
1999
, vol. 
180
 (pg. 
1171
-
6
)
28
Flannery
B
Heffernan
RT
Harrison
LH
, et al.  . 
Changes in invasive pneumococcal disease among HIV-infected adults living in the era of childhood pneumococcal immunization
Ann Intern Med
 , 
2006
, vol. 
144
 (pg. 
1
-
9
)
29
Hennessy
TW
Singleton
RJ
Bulkow
LR
, et al.  . 
Impact of heptavalent pneumococcal conjugate vaccine on invasive disease, antimicrobial resistance and colonization in Alaska Natives: progress towards elimination of a health disparity
Vaccine
 , 
2005
, vol. 
23
 (pg. 
5464
-
73
)
30
Hennessy
TW
Singleton
RJ
Bulkow
LR
, et al.  . 
Increase in invasive pneumococcal disease in Alaska Native children due to serotypes not in the heptavalent pneumococcal conjugate vaccine, 2001–2005 [abstract 59]
International Conference on Emerging Infectious Diseases
 , 
2006
Washington, DC
American Society for Microbiology; and Atlanta: Centers for Disease Control and Prevention and Association for Public Health Laboratories; and World Health Organization
31
Singleton
RJ
Hennessy
TW
Bulkow
LR
, et al.  . 
Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska Native children with high levels of 7-valent pneumococcal conjugate vaccine coverage
JAMA
 , 
2007
, vol. 
297
 (pg. 
1784
-
92
)
32
Kyaw
M
Rose
CJ
Fry
A
, et al.  . 
The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults
J Infect Dis
 , 
2005
, vol. 
192
 (pg. 
377
-
86
)
33
Dagan
R
Givon-Lavi
N
Leibovitz
E
Greenberg
D
Porat
N
Introduction and proliferation of multidrug-resistant Streptococcus pneumoniae serotype 19A clones that cause acute otitis media in an unvaccinated population
J Infect Dis
 , 
2009
, vol. 
199
 (pg. 
776
-
85
)
34
Obaro
SK
Confronting the pneumococcus: a target shift or bullet change
Vaccine
 , 
2000
, vol. 
19
 (pg. 
1211
-
7
)
35
Kilpi
T
Ahman
H
Jokinen
J
, et al.  . 
Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children
Clin Infect Dis
 , 
2003
, vol. 
37
 (pg. 
1155
-
64
)
36
Brueggemann
AB
Griffiths
DT
Meats
E
Peto
T
Crook
DW
Clonal relationships between invasive and carriage Streptococcus pneumoniae and serotype- and clone-specific differences in invasive disease potential
J Infect Dis
 , 
2003
, vol. 
187
 (pg. 
1424
-
32
)
37
Sandgren
A
Sjostrom
K
Olsson-Liljequist
B
, et al.  . 
Effect of clonal and serotype-specific properties on the invasive capacity of Streptococcus pneumoniae
J Infect Dis
 , 
2004
, vol. 
189
 (pg. 
785
-
96
)
38
Byington
CL
Korgenski
K
Daly
J
Ampofo
K
Pavia
A
Impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema
Pediatr Infect Dis J
 , 
2006
, vol. 
25
 (pg. 
250
-
4
)
39
Alanee
SRJ
McGee
L
Jackson
D
, et al.  . 
Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study
Clin Infect Dis
 , 
2007
, vol. 
45
 (pg. 
46
-
51
)
40
Centers for Disease Control and Prevention
Influenza and pneumococcal vaccination coverage among persons aged >65 years: United States, 2004–2005
MMWR Morb Mortal Wkly Rep
 , 
2006
, vol. 
55
 (pg. 
1065
-
8
)
41
Feikin
DR
Klugman
KP
Historical changes in pneumococcal serogroup distribution: Implications for the era of pneumococcal conjugate vaccines
Clin Infect Dis
 , 
2002
, vol. 
35
 (pg. 
547
-
55
)
42
Choi
E
Kim
S
Eun
B
Kim
S
Kim
N
Streptococcus pneumoniae serotype 19A in children, South Korea
Emerg Infect Dis
 , 
2008
, vol. 
14
 (pg. 
275
-
81
)
43
Pai
R
Moore
M
Pilishvili
T
, et al.  . 
Post vaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States
J Infect Dis
 , 
2005
, vol. 
192
 (pg. 
1988
-
95
)
44
Talbot
TR
Poehling
KA
Hartert
TV
, et al.  . 
Seasonality of invasive pneumococcal disease: temporal relation to documented influenza and respiratory syncytial viral circulation
Am J Med
 , 
2005
, vol. 
118
 (pg. 
285
-
91
)
45
Dobson
R
US cigarette consumption falls to lowest point since 1951
BMJ
 , 
2006
, vol. 
332
 pg. 
687
 
46
Carvalho
MG
Pimenta
FC
Gertz
RE
Jr
, et al.  . 
PCR-based quantitation and clonal diversity of the current prevalent invasive serogroup 6 pneumococcal serotype 6C, in the United States in 1999 and 2006 to 2007
J Clin Microbiol
 , 
2009
, vol. 
47
 (pg. 
554
-
9
)
47
Thomas
CM
Loewen
A
Coffin
C
Campbell
NRC
Improving rates of pneumococcal vaccination on discharge from a tertiary center medical teaching unit: a prospective intervention
BMC Public Health
 , 
2005
, vol. 
5
 pg. 
110
 
48
Centers for Disease Control and Prevention
Facilitating influenza and pneumococcal vaccination through standing orders programs
JAMA
 , 
2003
, vol. 
289
 pg. 
1238
 
49
Centers for Disease Control and Prevention; National Center for Health Statistics
 
Early release of selected estimates based on data from the January–September 2007 National Health Interview Survey. Available at http://www.cdc.gov/nchs/data/nhis/earlyrelease/earlyrelease200803.pdf. Accessed 16 April 2008
50
French
N
Gordon
S
Mwalukomo
T
, et al.  . 
Pneumococcal conjugate vaccine efficacy in HIV-infected Malawian adults: a randomised double-blind placebo-controlled clinical efficacy trial [abstract S11-KS3]
International Symposium on Pneumococci and Pneumococcal Disease (Reykjavik, Iceland)
 , 
2008
51
World Health Organization
Pneumococcal conjugate vaccine for childhood immunization: WHO position paper
Wkly Epidemiol Rec
 , 
2007
, vol. 
12
 (pg. 
93
-
104
Available at http://www.who.int/wer/2007/wer8212.pdf
Potential conflicts of interest: L.H.H. received lecture honoraria from Wyeth and consulting fees from Merck. W.S. received a consulting fee from Wyeth and is a member of Safety Evaluation Committee for experimental vaccine trials for Merck. N.M.B. has served on adult vaccine advisory boards for Wyeth and Merck. All other authors report no potential conflicts
Presented in part: 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America, Washington, DC, 25–28 October 2008
Financial support: Emerging Infections Programs, Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention's Emerging Infections Programs provided funding but made no other contributions to the design and conduct of this study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of this manuscript

Author notes

a
Section members are listed at the end of the text