Twenty-Year Public Health Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines in US Children

Matt Wasserman; Ruth Chapman; Rotem Lapidot; Kelly Sutton; Desmond Dillon-Murphy; Shreeya Patel; Erica Chilson; Vincenza Snow; Raymond Farkouh; Stephen Pelton

Disclosures

Emerging Infectious Diseases. 2021;27(6):1627-1636. 

In This Article

Methods

The US Centers for Disease Control and Prevention (CDC) began the Active Bacterial Core Surveillance (ABCs) program to monitor invasive S. pneumoniae infections in 1997.[12] Although this resource provides invaluable data for assessing IPD, it does not include data on noninvasive syndromes. We conducted a literature review to identify and synthesize published data on all pneumococcal diseases during the past 20 years. We used data from these publications to model the effects of PCVs on childhood pneumococcal disease.[13]

Literature Review

To estimate the amount of pneumococcal disease averted in the United States, we conducted a systematic literature review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.[14] After defining the research questions, data sources, search strategies, and selection criteria (Appendix Tables 1–5, https://wwwnc.cdc.gov/EID/article/27/6/20-4238-App1.pdf), we conducted electronic searches of the PubMed and Embase (https://www.embase.com) databases and manual searches of the gray literature, CDC website (https://www.cdc.gov), and reference lists of 7 published literature reviews[15–21] (Appendix Figure 1). This study describes only references used for input data or to validate our findings.

Calculations and Outputs

We developed a model using Excel (Microsoft, https://www.microsoft.com) to calculate the national numbers of cases, healthcare visits, hospitalizations, and deaths caused by pneumococcal infection among children <5 years of age during the 20 years after PCV introduction. We used published incidences of each syndrome (i.e., meningitis, bacteremia, bacteremic pneumonia/empyema, sepsis, and other) and relevant population data to calculate the number of cases averted by vaccination. We conducted these calculations for the pre-PCV (i.e., 1997–1999), PCV7 (i.e., 2000–2009), and PCV13 (i.e., 2010–2019) eras (Appendix Figure 2). Although we attributed decreasing illness and deaths to the direct effects of PCVs, policy changes or other interventions also might have contributed to the reduction of disease.

We calculated average incidences for each of the 3 described time periods. Because variance measures were unavailable, we performed all calculations as point estimates. We assumed that without PCVs, disease incidence would have remained constant. We calculated the estimated effect of PCV7 by comparing the difference in reported incidence between the pre-PCV and PCV7 eras; likewise, we considered the effect of PCV13 to be the difference in incidence between the pre-PCV and PCV13 eras. We estimated the incremental effect of including the additional serotypes in PCV13 by comparing incidence between the PCV7 and PCV13 eras. Because factors such as program rollout and uptake delayed the achievement of population-level equilibrium, we excluded the transition years 2000–2001 from the calculation of the effect of PCV7. Similarly, we excluded 2010 from the calculation of the effect of PCV13 (Table 1, Table 2; Figures 1, 2). However, we included these years in the analysis of the 20-year aggregate effect of PCV use.

Figure 1.

Effects of PCVs on invasive pneumococcal disease (IPD) and otitis media among children <5 years of age, United States, 1997–2019 (8,12). A) Cases of IPD. B) Cases of IPD caused by 13-valent PCV serotypes. C) Healthcare visits for otitis media. The United States approved 7-valent PCV in 2000 and 13-valent PCV in 2010. Asterisk (*) indicates that for data on healthcare visits for otitis media, age range is 0–2 years. PCV, pneumococcal conjugate vaccine.

Figure 2.

Effects of PCVs on different syndromes of IPD in children <5 years of age, United States, 1997–2019. The United States approved 7-valent PCV in 2000 and 13-valent PCV in 2010. IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine.

We calculated the number of expected IPD cases without PCV7 as the average incidence during 1997–1999 × population size in each year. We calculated the expected IPD cases if PCV7 vaccination had continued but PCV13 had not been introduced as the average incidence during 2002–2009 × population size in each year. We stratified each calculation by age.

In addition, we calculated total IPD cases averted by PCVs as the difference between the cases expected without vaccination and the cases observed during 2002–2019 (Table 1; Appendix Figure 2). We also calculated the incremental effect of PCV13 versus PCV7 as the difference between cases expected if PCV7 use had continued after 2010 and cases observed during 2011–2019.

To calculate the number of expected IPD deaths without PCVs, we multiplied the observed case-fatality ratio from 1997–2000 (cumulative deaths divided by the cumulative cases in that period) by the expected number of cases from 2000–2019.[12] We considered deaths averted by PCVs to be the difference between expected deaths if PCVs had never been introduced and the observed deaths in this period.

Case numbers and incidences were not available for OM and noninvasive pneumonia because they are nonnotifiable diseases. As a result, we calculated the expected ambulatory healthcare visit rates for OM and hospitalization rates for pneumonia without PCVs using the same method as for IPD cases averted.

Model Inputs

We conducted our calculations using population data from the US Census Bureau[22] (Appendix Table 6). We considered data on total IPD incidence, distribution of vaccine serotypes, syndrome distribution, healthcare visits for OM, and pneumonia incidence.

We obtained national estimates for IPD cases, rates, and syndromes among children <1, 1–<2, and 2–4 years of age from ABCs reports[12] (Appendix Table 7). Because data for 2018 and 2019 were not available, we assumed these years to have the same rates as 2017. We used these data to calculate the average incidence for each of the 2 pre-PCV13 eras (Appendix Table 8).

We also obtained national estimates for overall annual incidence of IPD caused by PCV13 serotypes among children <5 years of age during 1998–2016[12] (Appendix Table 9). We assumed rates during 2017–2019 to be the same as 2016; we weighted these rates by population distribution during those years. We calculated pre-PCV era distribution of PCV13 and non-PCV13 serotypes as the average of 1997–1999 distributions (Appendix Table 10). To ensure serotype incidences were consistent with the observed trends of all IPDs, we imputed PCV13 serotype incidence in 1997 using weighted proportions (i.e., by population size in each age group) and percent change (Appendix Table 9) during 1997–1998. We calculated expected cases caused by PCV13 and non-PCV13 serotypes by multiplying the average pre-PCV era serotype distributions to the total expected number of annual IPD cases. Although the measurement of all averted cases of IPD includes the effects of vaccination and serotype replacement, the measurement of cases averted by PCV13 indicates only the reduction in vaccine type IPDs.

We obtained the proportions of meningitis, bacteremia, bacteremic pneumonia/empyema, sepsis, and other infections among children <2 and 2–4 years of age with IPD from additional unpublished data provided by CDC (;[12] R. Gierke, CDC, pers. comm., 2017 Nov 7) (Appendix Table 11). We assumed the distributions in 1997–1999 to be the same as 2000.

We used the mean rate of ambulatory care visits for OM in children <2, 2–<5, and <5 years of age overall provided by Zhou et al. (;[23] Appendix Table 12, Figure 3). Zhou et al.[23] described PCV eras using similar definitions: the pre-PCV period during 1997–1998, the PCV7 period during 2002–2009, and the PCV13 period during 2011–2013 (Appendix Table 13). We assumed the rates in 2014–2019 to be the same as 2013 (Appendix Table 12).

The data sources used various classifications and definitions of pneumonia. The types of data reported also varied widely, including measurements such as ambulatory visits, hospitalizations, index cases in inpatients, and estimates of cases of community-acquired pneumonia. No single data source covered the combined PCV7 and PCV13 periods, nor estimated the incidence of only noninvasive pneumococcal pneumonia. Because hospitalization data represent more severe cases with the largest use of healthcare costs and resources and because no consistent data for ambulatory/outpatient visits for pneumonia during the entire study period were available, we considered only hospitalized cases of pneumonia in this analysis. We used data on hospitalization for pneumonia from multiple sources. We obtained data for the pre-PCV relative to PCV7 eras from Simonsen et al.,[24] Foote et al.,[25] and Grijalva et al.,[26] and for the PCV7 relative to PCV13 period from a 2005–2014 study[27] and Tong et al..[28] In addition, we used estimates of the difference in hospitalization incidences during the PCV7 period from Grijalva et al..[23] We estimated the total number of hospitalizations averted by PCVs using the expected hospitalization data from all sources for 1997–2019 (Appendix Table 14).

Validation

During the literature review, we identified appropriate references against which to validate the consistency of our findings. We did not identify other sources of national multistate data for IPD comparable to the ABCs dataset. Black et al.[30] reported Kaiser Permanente data from northern California about the effect of PCV7 on disease epidemiology in children and adults, whereas Yildirim et al.[31] reported serotype-specific invasive capacity among children in Massachusetts after PCV introduction (Appendix Figure 4).

We used a large national claims database,[32] a commercial claims and encounters database,[33] and Ray et al.[34] to validate our OM estimates. We wanted to validate our pneumonia estimates with respect to different types of cases and definitions used by various data sources; however, because of constraints on data availability, we limited our validation to hospitalized cases of all-cause pneumonia. Because of the variation in reporting of pneumonia data, we did not identify any alternate sources for an appropriate validation of our analysis.

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