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. 2021 Jun;27(6):1627–1636. doi: 10.3201/eid2706.204238

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

Matt Wasserman 1,2,3,✉, Ruth Chapman 1,2,3, Rotem Lapidot 1,2,3, Kelly Sutton 1,2,3, Desmond Dillon-Murphy 1,2,3, Shreeya Patel 1,2,3, Erica Chilson 1,2,3, Vincenza Snow 1,2,3, Raymond Farkouh 1,2,3, Stephen Pelton 1,2,3
PMCID: PMC8153862  PMID: 34013855

Abstract

Pneumococcal conjugate vaccines (PCVs) have been used in the United States since 2000. To assess the cumulative 20-year effect of PCVs on invasive pneumococcal disease (IPD) incidence among children <5 years of age, we analyzed Active Bacterial Core Surveillance data, conducted a literature review, and modeled expected and observed disease. We found that PCVs have averted >282,000 cases of IPD, including ≈16,000 meningitis, ≈172,000 bacteremia, and ≈55,000 bacteremic pneumonia cases. In addition, vaccination has prevented 97 million healthcare visits for otitis media, 438,914–706,345 hospitalizations for pneumonia, and 2,780 total deaths. IPD cases declined 91%, from 15,707 in 1997 to 1,382 in 2019. Average annual visits for otitis media declined 41%, from 78 visits/100 children before PCV introduction to 46 visits/100 children after PCV13 introduction. Annual pneumonia hospitalizations declined 66%–79%, from 110,000–175,000 in 1997 to 37,000 in 2019. These findings confirm the substantial benefits of PCVs for preventing IPD in children.

Keywords: children, incidence, invasive pneumococcal disease, IPD, otitis media, pneumococcal disease, pneumococcal vaccination, PCV7, PCV13, pneumococcal pneumonia, literature review, United States, vaccination, vaccines, vaccine-preventable diseases, bacteria, bacterial infections, PCVs, pneumococcal conjugate vaccines, Streptococcus pneumoniae

Before 2000, children <2 years of age had the highest incidence of invasive pneumococcal diseases (IPDs) such as bacteremia, meningitis, or other infection of a normally sterile site (1). Researchers estimated that, in the United States, annual IPD incidence was 165 cases/100,000 children <12 months of age and 203 cases/100,000 children 12–23 months of age (1). Until the United States began a universal 7-valent pneumococcal conjugate vaccine (PCV7) immunization program for children in 2000, Streptococcus pneumoniae was the leading cause of bacterial meningitis (1). S. pneumoniae was also the most common bacterial cause of community-acquired pneumonia and otitis media (OM) in young children. Furthermore, in the 1990s, concerns emerged regarding the growing number of pneumococcal isolates with reduced susceptibility to first- and second-line antimicrobial drugs (1).

PCV7 was the first pneumococcal conjugate vaccine (PCV) approved for use in children <2 years of age in the United States. Pneumococcal polysaccharide vaccines, which preceded PCVs, are not immunogenic in children <2 years of age (1,2). PCV7 overcame the challenge of poor immunogenicity among infants and young children through conjugation technology; it was introduced into the US infant immunization schedule in 2000, providing direct protection against several serotypes of invasive and noninvasive pneumococcal disease (3,4). PCV7 protects against the S. pneumoniae serotypes responsible for >80% of IPD cases among children in North America (i.e., serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) (1,4). In 2010, PCV13, a vaccine providing protection against 6 additional serotypes (i.e., serotypes 1, 3, 5, 6A, 19A, and 7F), was approved in the United States, partially because of increasing incidence of serotypes not covered by PCV7 (1,4).

Clinical trial data suggested that PCV7 would be effective against IPD, OM, and according to a post-hoc analysis, pneumonia (5). The efficacy of PCV7 (and later PCV13) against all forms of pneumococcal disease was greater than expected, partly because of indirect protection gained through herd immunity (6–8). The United States was the first country to introduce a PCV program for infants and, during the transition to PCV13, recommended the largest catch-up program for children <5 years of age who had been vaccinated with PCV7 (9). After an initially slow uptake limited by constrained supply, the United States has achieved consistently high (>80%) 3-dose coverage since 2005 (10). It is one of a few countries continuing to use the licensed 4-dose schedule (10). A 2020 review demonstrated that PCVs were the only vaccines approved by the US Food and Drug Administration that had no postmarketing safety-related label modifications (11).

We quantified the decrease of IPD incidence associated with 20 years of PCV use in the United States. First, we conducted a literature review to inform a decision analytic model. The model estimated the 20-year cumulative effects associated with the PCV program on cases of IPD, OM, and hospitalizations for pneumonia among children <5 years of age in the United States.

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), 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 (Tables 1, 2; Figures 1, 2). However, we included these years in the analysis of the 20-year aggregate effect of PCV use.

Table 1. Invasive pneumococcal disease cases and deaths averted by pneumococcal conjugate vaccines, United States, 1997–2019*.

Year No. observed, by age, y
 No. expected, by age, y
 No. averted
<1 1 2–4 Overall <1 1 2–4 Overall Annual Cumulative
No. cases
1997 5,360 6,712 3,635 15,707 5,360 6,712 3,635 15,707 NA NA
1998 6,220 7,630 4,286 18,136 6,220 7,630 4,286 18,136 NA NA
1999 6,176 7,772 3,837 17,785 6,176 7,772 3,837 17,785 NA NA
2000 5,699 6,139 3,469 15,306 6,053 7,428 3,883 17,364 2,057 2,057
2001 2,099 2,645 3,143 7,887 6,299 7,539 3,852 17,689 9,802 11,860
2002 1,521 1,261 1,813 4,596 6,202 7,830 3,866 17,899 13,304 25,164
2003 1,642 1,405 1,530 4,577 6,241 7,696 3,936 17,874 13,296 38,460
2004 1,485 1,253 1,454 4,192 6,301 7,730 3,983 18,013 13,821 52,281
2005 1,450 1,419 1,467 4,336 6,286 7,796 4,019 18,101 13,765 66,046
2006 1,366 1,458 1,395 4,219 6,344 7,767 4,019 18,130 13,911 79,956
2007 1,680 1,296 1,560 4,537 6,511 7,826 4,036 18,372 13,835 93,792
2008 1,517 1,284 1,420 4,221 6,487 8,018 4,057 18,562 14,341 108,133
2009 1,485 1,309 1,654 4,449 6,284 7,975 4,099 18,358 13,910 122,043
2010 1,352 1,051 1,611 4,014 6,204 7,726 4,144 18,074 14,060 136,103
2011 832 670 1,012 2,515 6,221 7,755 4,109 18,085 15,571 151,674
2012 616 541 712 1,870 6,163 7,777 4,068 18,009 16,139 167,813
2013 578 595 814 1,988 6,171 7,709 4,036 17,916 15,928 183,741
2014 629 407 754 1,790 6,208 7,721 4,033 17,963 16,173 199,914
2015 733 513 610 1,856 6,253 7,769 4,031 18,053 16,198 216,112
2016 526 212 167 906 6,208 7,828 4,032 18,068 17,163 233,275
2017 452 314 625 1,391 6,112 7,770 4,052 17,934 16,544 249,818
2018 446 309 627 1,382 6,040 7,651 4,061 17,752 16,370 266,188
2019
 446
 309
 627
 1,382
6,040
 7,651
 4,061
 17,752
16,370
 282,558
No. deaths
1997 151 34 17 202 151 34 17 202 NA NA
1998 78 47 NA 126 78 47 NA 126 NA NA
1999 29 45 60 134 29 45 60 134 NA NA
2000 130 113 57 301 138 137 64 340 39 39
2001 22 46 57 125 103 66 36 204 79 118
2002 31 NA 32 62 101 68 36 205 143 261
2003 42 21 21 85 102 67 37 206 121 382
2004 39 48 20 107 103 67 37 207 101 483
2005 38 9 38 85 103 68 37 208 123 605
2006 29 9 47 85 104 68 37 209 124 729
2007 37 9 9 56 106 68 37 212 156 885
2008 37 NA 18 55 106 70 38 214 158 1,043
2009 36 9 9 54 103 70 38 210 156 1,199
2010 10 9 9 28 101 67 38 207 179 1,378
2011 38 19 28 85 102 68 38 207 123 1,501
2012 9 9 NA 19 101 68 38 206 187 1,688
2013 9 9 38 57 101 67 37 205 149 1,837
2014 19 NA 9 28 101 67 37 206 178 2,014
2015 10 9 19 38 102 68 37 207 170 2,184
2016 18 4 12 35 101 68 37 207 172 2,356
2017 28 19 38 85 100 68 38 205 120 2,476
2018 16 7 28 51 99 67 38 203 152 2,628
2019 16 7 28 51 99 67 38 203 152 2,780
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*Values are rounded to the nearest whole numbers. NA, not applicable.

Table 2. Cases of invasive pneumococcal disease averted by PCV13, United States, 1997–2019*.

Year No. observed
 No. expected
 Cumulative cases averted
 Difference in non-PCV13 serotype cases†
All PCV13 serotypes Non-PCV13 serotypes All PCV13 serotypes Non-PCV13 serotypes All PCV13 serotypes
1997 15,543 14,439 1,104 15,543 14,439 1,104 NA NA NA
1998 18,136 16,848 1,288 18,136 16,848 1,288 NA NA NA
1999 17,785 16,839 945 17,785 16,839 945 NA NA NA
2000 15,306 13,808 1,498 17,364 16,178 1,186 2,057 2,369 −312
2001 7,887 6,561 1,325 17,689 16,481 1,208 11,860 12,289 −429
2002 4,596 3,109 1,487 17,899 16,677 1,223 25,164 25,857 −693
2003 4,577 2,743 1,834 17,874 16,653 1,221 38,460 39,767 −1,307
2004 4,192 2,374 1,818 18,013 16,783 1,230 52,281 54,175 −1,894
2005 4,336 2,589 1,747 18,101 16,864 1,236 66,046 68,450 −2,405
2006 4,219 2,592 1,627 18,130 16,891 1,238 79,956 82,750 −2,793
2007 4,537 3,019 1,518 18,372 17,118 1,255 93,792 96,848 −3,057
2008 4,221 2,635 1,585 18,562 17,294 1,268 108,133 111,507 −3,374
2009 4,449 3,037 1,412 18,358 17,104 1,254 122,043 125,575 −3,532
2010 4,014 2,626 1,388 18,074 16,839 1,235 136,103 139,788 −3,685
2011 2,515 805 1,710 18,085 16,850 1,235 151,674 155,833 −4,160
2012 1,870 400 1,470 18,009 16,779 1,230 167,813 172,213 −4,400
2013 1,988 397 1,591 17,916 16,692 1,224 183,741 188,508 −4,766
2014 1,790 397 1,392 17,963 16,736 1,227 199,914 204,846 −4,932
2015 1,856 398 1,457 18,053 16,820 1,233 216,112 221,268 −5,156
2016 906 398 507 18,068 16,834 1,234 233,275 237,703 −4,429
2017 1,391 398 993 17,934 16,709 1,225 249,818 254,015 −4,197
2018 1,382 396 986 17,752 16,539 1,213 266,188 270,158 −3,970
2019 1,382 396 986 17,752 16,539 1,213 282,558 286,302 −3,744
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*Values are rounded to the nearest whole numbers. NA, not applicable; PCV13, 13-valent pneumococcal conjugate vaccine. 
†Negative values indicate greater number observed than would be expected.

Figure 1.

Figure 1

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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.

Figure 2

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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.

Results

IPD

Among children <5 years of age, the annual number of IPD cases decreased from ≈16,000−18,000 during 1997−1999 to 1,382 in 2019 (Table 1; Figure 1, panel A). We estimated that PCVs averted a cumulative 282,558 cases of IPD during this timeframe. Of those averted cases, we estimated that 146,455 were prevented by PCV13 during 2010–2019. Among children <5 years of age, annual deaths caused by IPD decreased from 126−202 during 1997−1999 (Table 1) to 85 in 2019. We estimated that PCVs prevented a total of 2,780 deaths during this timeframe, including 1,402 deaths prevented by PCV13 during 2010–2019.

The overall IPD incidences in the input ABCs data were generally higher than in the sources used for validation. However, the ABCs and the Kaiser Permanente data (30) reflected similar overall trends for the pre-PCV and PCV7 eras; the ABCs and data from Yildrim et al. (31) reflected similar overall trends for the PCV7 and PCV13 eras. The differences were probably caused by variations in reporting and patient groups between data sources; the ABCs data are more nationally representative and therefore more generalizable than the population described by Black et al. (30).

We observed a decrease in IPD-related deaths after the introduction of PCV7; however, we could not identify whether this trend existed during the pre-PCV period because of limited data (Table 1). Pulido et al. (35) described a declining IPD mortality rate during 1990–2005, supporting the ABCs data and indicating that deaths were already decreasing before the introduction of PCVs. Reductions in smoking rates and implementation of laws regarding smoking in public places, shifts from inpatient to outpatient care settings, improved treatments, and varying case definitions might have also contributed to the declining trend.

We estimated that during 2000–2019, PCVs prevented 172,778 cases of bacteremia; 55,532 cases of bacteremic pneumonia and empyema; 16,660 cases of meningitis; and 37,017 cases of other forms of IPD (Figure 2). IPD cases caused by PCV13 serotypes decreased from 14,439 cases in 1997 to 396 in 2019 (Table 2; Figure 1, panel B). During 2000–2019, PCVs are estimated to have averted 286,302 IPD cases caused by vaccine serotypes. During this period, IPD cases caused by non-PCV13 serotypes increased slightly, consistent with modest serotype replacement.

OM Healthcare Visits

The average rate of OM visits among children <5 years of age declined from 78/100 to 46/100 children per year from the pre-PCV (1997–1998) to the PCV13 era (2011–2013). In other words, these visits declined by 39%, from 15,000,483 in 1997 to 9,112,727 in 2019 (Figure 1, panel C). We estimated that PCVs averted a cumulative 97,326,688 OM-related healthcare visits (Table 3).

Table 3. Estimated average incidence of otitis media cases and visits averted by PCVs, United States, 1997–2019*.

Measure 1997–1999 2000–2009 2010–2019 Cumulative
Average incidence of visits per 100 children 78 59 46 NA
Expected visits† NA 154,269,900 155,511,917 309,781,817
Estimated visits NA 119,429,938 93,025,190 212,455,128
Visits averted‡ NA 34,839,962 62,486,726 97,326,688
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*Values are rounded to the nearest whole numbers. PCV7 was approved for use in the United States in 2000; PCV13 was approved for use in the United States in 2010. NA, not applicable; PCV, pneumococcal conjugate vaccine; PCV7, 7-valent PCV; PCV13, 13-valent PCV.
†Visits expected if PCVs had not been introduced.
‡Calculated by subtracting estimated visits from expected visits.

The overall visit numbers in the input data (23) were generally lower than in the sources used for validation (32–34), but the overall trends for the pre-PCV and PCV7 eras were comparable. The differences might have been caused by varying database populations, because Zhou et al. (23) used national data whereas Marom et al. (32) and Tong et al. (33) mainly considered privately insured patients who might have been more likely to seek care. Therefore, the estimates from Zhou et al. (23) are probably more representative on a national level.

Pneumonia Hospitalizations

Annual pneumonia hospitalizations in children <5 years of age declined from 113,116–175,420 in 1997 to 37,882 in 2019. We estimated that PCVs averted a cumulative 438,914–706,345 pneumonia hospitalizations, including 216,303 cases caused by PCV13 serotypes, during the 20 years after PCV introduction in the United States (Table 4).

Table 4. Estimated total hospitalized cases of pneumonia averted by PCVs, United States, 1997–2019*.

Time period Estimated hospitalizations
 Total hospitalizations averted
Observed, with vaccination
Expected without vaccination
Minimum Maximum Minimum Maximum Minimum Maximum
Pre-PCV era: 1997–1999 NA NA 339,474 525,675 NA NA
PCV7 era: 2000–2009† 959,543 1,336,673 597,479 1,822,591 222,611 490,043‡
PCV13 era: 2010–2019§ 382,182
 598,484
 216,303
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*PCV7 was approved for use in the United States in 2000; PCV13 was approved for use in the United States in 2010. NA, not applicable; PCV, pneumococcal conjugate vaccine; PCV7, 7-valent PCV; PCV13, 13-valent PCV.
†Averted hospitalizations during PCV7 era are shown as the difference within the same study with minimum based on Simonson et. al. (24) and maximum based on Grijalva et al (29) (Appendix Table 14).
‡Grijalva et al (29) reported a change in hospitalization rate; as a result, no observed and expected values were generated.
§Values based on calculations using a single data point.

Discussion

Vaccines, especially PCVs, are lifesaving and cost-effective public health interventions. At the time PCV7 was introduced in the United States, pneumococcal disease caused high rates of death and disease among infants. Despite conservative findings from the clinical trials (8), public health officials and healthcare professionals were optimistic about the potential of PCVs to prevent pneumococcal disease. We conducted a literature review and modeling analysis to quantify the effects of PCVs on pneumococcal disease incidence among children <5 years of age, a population at higher risk for IPD and therefore the focus of IPD prevention efforts (36). Our analysis demonstrated that PCVs have averted >282,000 cases of IPD and 2,780 associated deaths, with reductions across various IPD syndromes. Since their introduction in 2000, PCVs have averted >430,000 pneumonia hospitalizations and >97,000,000 OM-related healthcare visits.

We could not find data on all OM cases; our analysis instead measured ambulatory care visits using input data from Zhou et al. (23). However, because not all children with OM receive treatment through ambulatory care visits, our findings probably underestimate the true effects of PCVs on OM incidence. The annual number of OM visits declined from 78 visits/100 to 46 visits/100 children from the pre-PCV era (1997–1999) to PCV13 era (2010–2019); this 41% decline exceeds the original predictions based on early clinical trial data (8). Vaccination is probably the main direct contributor to this reduction; however, vaccination also might have had indirect effects such as changes in the disease definition or clinical coding of OM, as well as changes in prescribing patterns of antimicrobial drugs, which might affect healthcare use. Although not all cases of OM prompt healthcare visits, even mild illnesses might require family members to take time from work to care for their children, further reducing productivity and quality of life in ways not reflected by this metric (37).

Because we could not find data on noninvasive pneumonia, we combined multiple data sources to compare pneumonia hospitalizations during the study period. These data are probably underestimates of the true effect of PCVs because most pneumonia cases among children <5 years of age do not require hospitalization.

The overall findings are impressive but nevertheless conservative. We did not consider the direct benefits of reduced sequelae among children >5 years of age nor adults; we also did not consider indirect benefits such as herd immunity, reduced use of antimicrobial drugs and other healthcare resources, increased educational attainment, or improved parental productivity. In addition, we did not analyze data on common but less resource-intensive manifestations of S. pneumoniae such as conjunctivitis (38,39). Finally, this analysis does not reflect PCVs’ effects on antimicrobial resistance (17), although preventing infection through vaccination reduces the need for antimicrobial treatment (40).

In agreement with other studies (40,41), we found that IPD cases caused by PCV13 serotypes declined while the number of cases caused by non-PCV13 serotypes slightly increased, reflecting modest serotype replacement. PCVs have been used in the United States longer than in any other country. Because of the large quantity of available data, we conducted a literature review to independently identify appropriate references for model inputs and validation. However, although the available data were extensive, it was not comprehensive. As a result, this research was limited by the lack of a single data source for pneumonia and OM incidences during the entire study period, prompting us to impute values for years when no data were available. In addition, because IPD is a notifiable disease but OM and pneumonia are not, we can only estimate PCVs’ true effects on OM and pneumonia incidence using alternative metrics such as ambulatory care visits and hospitalizations. Furthermore, healthcare providers do not usually distinguish the causative bacteria of pneumonia and OM cases, which poses difficulties in analyzing serotype distributions. Finally, we could not find alternative national-level IPD data for the validation analysis, prompting us to compare our results with trends from smaller regions.

CDC and the Advisory Committee on Immunization Practices have recommended the use of PCVs in a national infant immunization program since 2000 (1). Our model used available data to quantify the effects of PCV7 and PCV13 on pneumococcal disease burden among children in the United States. Our results demonstrate the effectiveness of PCVs in preventing illness and death among children <5 years of age.

Appendix

Further information on effects of 7- and 13-valent pneumococcal conjugate vaccines on disease in children, United States, 1997–2019.

20-4238-Techapp-s1.pdf (778.9KB, pdf)

Acknowledgments

This work was supported by Pfizer Inc. Pfizer participated in study design; data identification, synthesis, and analysis; manuscript writing; and the decision to submit the article for publication.

E.C., V.S., R.F., and M.W. are employees and stockholders of Pfizer Inc. R.C., K.S., D.D.M., and S.P. are employees of Evidera Market Access Ltd, a healthcare research firm that provides consulting and other research services to pharmaceutical and related organizations. In these salaried positions, they work with a variety of companies and are explicitly precluded from accepting any payment or honoraria directly from them for services rendered. Evidera received payment from Pfizer Inc. for collaboration on this project and article.

S.P. and R.L. received consulting fees from Pfizer, Inc. for their participation in study design and data analysis for this project. S.P. and R.L. are also recipients of investigator-initiated research awards (i.e., Surveillance of Pneumococcal Colonization and Invasive pneumococcal Disease reveals Shift in Prevalent Carriage Serotypes in Massachusetts’ Children to Relatively Low Invasiveness [31], Evaluation of Serotype 3 Strains collected from Massachusetts’ Children 2002–2019) from Pfizer (through Boston Medical Center) relevant to pneumococcal vaccine studies. S.P. has also received honoraria from Merck, Pfizer, and Sanofi for participation in pneumococcal advisory boards and Data and Safety Monitoring Board.

Biography

Mr. Wasserman is Director of Health Economics and Outcomes Research at Pfizer Inc. His research interests include cost-effectiveness and transmission dynamic modeling of vaccine-preventable diseases.

Footnotes

Suggested citation for this article: Wasserman M, Chapman R, Lapidot R, Sutton K, Dillon-Murphy D, Patel S, et al. Twenty-year public health impact of 7- and 13-valent pneumococcal conjugate vaccines in US children. Emerg Infect Dis. 2021 June [date cited]. https://doi.org/10.3201/eid2706.204238

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix

Further information on effects of 7- and 13-valent pneumococcal conjugate vaccines on disease in children, United States, 1997–2019.

20-4238-Techapp-s1.pdf (778.9KB, pdf)

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