Estimated public health impact of nationwide vaccination of infants with 7-valent pneumococcal conjugate vaccine (PCV7) in China

International Journal of Infectious Diseases 26 (2014) 116–122

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Estimated public health impact of nationwide vaccination of infants with 7-valent pneumococcal conjugate vaccine (PCV7) in China ShanLian Hu a,b, Qiang Shi c, Chieh-I Chen d, Ronald Caldwell e, Bruce Wang f, LiXia Du b, JiangJiang He b, Craig S. Roberts g,* a

School of Public Health, Fudan University, Shanghai, P.R. China Shanghai Health Development Research Center, Shanghai, P.R. China Health Economics and Outcomes Research, Pfizer Investment Co. Ltd, Shanghai, P.R. China d Health Economics and Outcomes Research, Pfizer Investment Co. Ltd, Beijing, P.R. China e Department of Economics, University of Michigan, Ann Arbor, Michigan, USA f Alliance Life Sciences, Somerset, New Jersey, USA g Health Economics and Outcomes Research, Pfizer Inc., 500 Arcola Road, Collegeville, PA 19424, USA b c

A R T I C L E I N F O

Article history: Received 21 March 2014 Accepted 12 April 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: 7-Valent pneumococcal conjugate vaccine (PCV7) Decision analytic model Herd effect

S U M M A R Y

Objectives: The goal of this study was to provide a comprehensive analysis of the potential health impact of universal vaccination of infants with the 7-valent pneumococcal conjugate vaccine (PCV7) in China. Methods: A decision-analytic model designed for pneumococcal disease and outcomes of pneumococcal infection was populated with local age-specific incidence and mortality data to estimate the expected health benefits of vaccinating birth cohorts of approximately 16 million infants per year over a 10-year time horizon in China. The model incorporates both the direct impact on vaccinated children and the indirect effect of herd protection on unvaccinated children and adults. Results: The model predicts that more than 16.2 million cases of pneumococcal disease and 709 411 deaths could be prevented in China over the initial 10-year period following the introduction of the PCV7 vaccine. The majority of these health benefits are due to the indirect effectiveness of the vaccine on the unvaccinated population, resulting in approximately 10.8 million cases prevented and 636 371 lives saved over 10 years. Conclusions: The results suggest that a policy of universal PCV7 vaccination among infants in China would have a substantial positive public health impact on the population of China. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).

1. Introduction Infectious diseases caused by Streptococcus pneumoniae are a leading cause of respiratory infection globally. One of the most important risk factors for pneumococcal disease is age, with young children below the age of 5 years and elderly adults being at highest risk. It is estimated that pneumococcal disease is the most common cause of vaccine-preventable death in children under 5 years of age globally,1 and is a primary cause of mortality and morbidity among children below the age of 5 years in China.2 The 7-valent pneumococcal conjugate vaccine (PCV7) containing the seven serotypes 4, 6B, 9 V, 14, 18C, 19F, and 23F, has been

* Corresponding author. Tel.: +1 484 865 4487; fax: +1 646 441 6334. E-mail address: Craig.roberts@pfizer.com (C.S. Roberts).

licensed for use in the USA since 2000. Out of the >91 known pneumococcal serotypes, a relatively small number account for the majority of pneumococcal disease globally.3,4 In China, it is estimated that the seven serotypes contained in the PCV7 vaccine would cover approximately 76% of the serotypes associated with pneumococcal disease among children less than 5 years of age.5 Thus far, in countries where PCV7 has been incorporated into the national immunization program, the full public health impact of PCV7 on pneumococcal disease has been very positive, due largely to the indirect effect of herd protection on unvaccinated children and adults.6,7 There have been a number of studies demonstrating the beneficial impact of introducing PCV7 into the national immunization programs of various countries in Asia,8–13 however there has not yet been a comprehensive analysis of the potential impact of universal vaccination of infants with PCV7 in China. The objective

http://dx.doi.org/10.1016/j.ijid.2014.04.012 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

S.L. Hu et al. / International Journal of Infectious Diseases 26 (2014) 116–122

of this study was to bridge this gap by applying Chinese specific demographic and epidemiologic data to a mathematical model designed to estimate the public health impact of PCV7 at the population level. 2. Materials and methods 2.1. Model structure A decision-analytic Markov state-transition model of pneumococcal disease and vaccination was adapted to China by populating the model with local Chinese specific incidence, mortality, and serotype coverage data. The model, previously published as applied to the US setting, estimates pneumococcal disease and outcomes of pneumococcal infection in annual cycles over a 10year time horizon.14 At the time of writing, the only pneumococcal vaccine available and approved for use in China was PCV7, so we focused on the introduction of the PCV7 vaccine into the Chinese population rather the 13-valent pneumococcal conjugate vaccine (PCV13) that was applied to the US market.14 The clinical starting point of the model is the vaccination strategy – comparing a case where no vaccinations are provided to a policy of universal vaccination of all newborn infants in China over a 10-year period. The population in the model is stratified into 10 age groups: <12 months, 12–23 months, 24–35 months, 36–47 months, 48–59 months, 5–17 years, 18–34 years, 35–49 years, 50– 64 years, and age 65+. Individuals within the model have a probability of developing invasive pneumococcal disease (IPD; bacteremia or meningitis), all-cause pneumonia, or all-cause otitis media with varying probabilities of entering into each disease state depending on the vaccination strategy and age of the individual. The model also incorporates the possibility of developing longterm complications resulting from meningitis (deafness or disability). In order to capture the full benefits of the PCV7 vaccine, health outcomes for the entire Chinese population were incorporated into the model. These benefits include both the direct benefits among the vaccinated and indirect benefits due to herd protection on the unvaccinated children and adults. Results are

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presented as raw estimates over ten years, as well as with future outcomes discounted at 3% per year. The rationale for applying a 10-year Markov model design, as opposed to a transmission dynamic model, is that several reports of the impact of the widespread use of PCV7 on disease have provided robust data to estimate population-level effectiveness that fit the structure of a cohort-based model.6,15 Whereas transmission dynamic models estimate the potential impact of the spread of disease and can be useful to make predictions where the total population effect may be highly uncertain, the 10-year Markov framework allows direct application of vaccine impact based on empirical evidence drawn from multiple ecological epidemiologic studies. Many of the published models applied to evaluate the public health and economic impact of PCVs in countries have similarly applied cohort-based Markov estimations, presumably due to the simplicity and transparency of the design, as well as the breadth of existing data that are amenable to informing such models.13,14 2.2. Population and coverage rates Estimates of the Chinese population by age for 2010 were based on data from the Ministry of Health PRC 2009 Chinese Health Statistical Annual Report.16 The sizes of incoming annual birth cohorts used in the model were based on projections from the international database of the US Census Bureau and were estimated to be approximately 16 million births per year.17 At the initial point of each model cycle, a new birth cohort enters the model and is vaccinated. All adults and children born prior to the initial starting point are considered unvaccinated during all stages in the model. 2.3. Disease incidence and case fatality rates Baseline disease incidence rates and case fatality rates for disease states included in the model are provided in Table 1. Allcause mortality rates for deaths unrelated to pneumococcal infection were included based on life tables for China in 2009.18 The incidence and case fatality rates for pneumococcal meningitis among children under 5 years of age were derived from

Table 1 Baseline disease incidence and case fatality rates Parameter

Age group (months) <12

Annual incidence rates/100 000 IPD Hospitalized pneumonia Percent of IPD that is meningitis Percent of meningitis that results in deafness Percent of meningitis that results in disability Case-fatality rates Meningitis Bacteremia Hospitalized pneumonia

11.56 4654 42% 13% 7%

8.3% 11.5% 4.8% Age group (years) 5–17

12–23 3.04 3823 26% 13% 7%

8.3% 3.9% 0.4%

18–34

24–35 1.85 3827 18% 13% 7%

8.3% 0.0% 0.4%

35–49

36–47 3.03 3830 11% 13% 7%

8.3% 3.6% 0.4%

50–64

Annual incidence rates/100 000 IPD Hospitalized pneumonia

63.39 664

10.71 113

11.30 215

12.62 443

Percent of IPD that is meningitis Percent of meningitis that results in deafness Percent of meningitis that results in disability

23% 6% 5%

23% 13% 7%

25% 13% 7%

27% 13% 7%

Case-fatality rates Meningitis Bacteremia Hospitalized pneumonia IPD, invasive pneumococcal disease.

8.8% 2.4% 0.8%

43.3% 12.0% 3.9%

51.1% 13.9% 5.1%

63.6% 17.7% 5.7%

48–59 11.12 3834 3% 13% 7%

8.3% 2.6% 0.4%

65+ 42.86 3700 16% 13% 7%

76.8% 28.8% 10.0%

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a published meta-analysis.19 In this meta-analysis, all-cause meningitis was estimated to be 14 cases per 100 000 person-years, of which 9.8% were estimated to be pneumococcal. To improve the estimation of disease impact by age, an adjustment was applied using data from a meta-analysis of international incidence rates and estimates of the proportion of IPD cases by age group for children under 5 years of age taken from the Center for Disease Control in Taiwan.1,20 Incidence and case fatality rates for individuals 5 years of age and older were derived using estimates of incidence from a cost-effectiveness analysis of lower-middle income countries.13 Long-term sequelae resulting from meningitis infection were assumed to occur to a proportion of meningitis survivors.21,22 The incidence of hospitalized pneumonia in children less than 5 years of age was derived using data from an analysis of child mortality in China.2 To derive the incidence rates used in the model, these mortality data were divided by case fatality rates of 4.8% for infants under 1 year of age23 and 0.37% for children 1–4 years of age, for a total case fatality rate of 1.4% for all children under 5 years of age.19 Estimates of incidence and case fatality rates for ages 5–64 years were applied from those presented in an international costeffectiveness analysis.13 Data for persons 65 years of age and older were taken from a previously published local analysis.23 2.4. Serotype distribution Data from four studies identified in a systematic literature review were used to estimate the serotype distribution for pneumococcal meningitis and pneumonia in the model. The most common serotypes were identified as 19F (52.7%), 23F (10.6%), 19A (9.3%), 6B (6.7%), and 14 (5.9%). Based on this serotype distribution, the coverage of PCV7 for China was estimated as 79.7% (95% confidence interval 47.9–94.3%).19 2.5. Vaccine effectiveness 2.5.1. Vaccine direct effectiveness The direct effectiveness of the PCV7 vaccine on immunized children in China in terms of percentage of reduction in disease incidence relative to the pre-vaccine incidence rates for both IPD and hospitalized pneumonia are presented in the top panel of Table 2. In all cases, the estimated effectiveness in vaccinated children during the year of birth was reduced by one third in order to incorporate the fact that children less than 4 months of age may not have received their initial dose and were, therefore, considered to be unvaccinated during the initial period. The model also assumes, consistent with the previous literature,21,24 that the direct benefits of vaccination begin to wane 2 years after the initial

Table 2 Estimated direct and indirect effectiveness of PCV7 vaccination Direct effectiveness (% reduction in disease) Age group IPD <12 months 51.4% 12–23 months 77.0% Indirect effectiveness (% reduction in disease) Age group IPD <12 months 44.5% 12–23 months 44.5% 24–35 months 39.8% 36–47 months 39.8% 48–59 months 39.8% 5–17 years 25.0% 18–34 years 64.1% 35–49 years 47.4% 50–64 years 25.9% 65+ years 47.5% IPD, invasive pneumococcal disease.

Hospitalized pneumonia 16.2% 24.3% Hospitalized pneumonia 28.2% 28.2% 8.4% 8.4% 8.4% 12.9% 16.9% 15.1% 13.8% 11.0%

dose to a level 91% of their initial effectiveness and that there is no protection beyond the fifth year after vaccination. 2.6. Direct effect on the reduction of IPD The direct effectiveness of the PCV7 vaccine on the reduction of IPD caused by covered serotypes was estimated from the immune response in Chinese children as observed in a clinical trial and applied to an accepted correlate of protection. On a population basis, the effectiveness of PCV7 in preventing IPD from vaccine-type serotypes correlates with a response 0.35 mg of antibody/ml, as measured 4 weeks after the primary immunization series.25,26 This correlate of protection has been recommended by a World Health Organization Working Group as applicable on a global population basis for assessing the likely efficacy of future PCVs against IPD in vaccinated infants and children less than 2 years of age.27 In order to estimate the local effectiveness of PCV7 on invasive disease, efficacy data were used from an immunogenicity study of PCV7 that was conducted on healthy infants from Guangxi, China.28 This randomized, controlled immunogenicity study compared the level of antibody to pneumococcal antigens of children who received PCV7 with DTaP (diphtheria–tetanus– acellular pertussis) to a control group who received DTaP only. The proportion of subjects who achieved >0.35 mg of pneumococcal antibody/ml 30–50 days after the primary series by serotype were 4 (99%), 6B (83%), 9 V (98%), 14 (99%), 18C (99%), 19F (99%), and 23F (94%).28 These data were multiplied by the respective serotype prevalence locally to estimate an effectiveness of 96.9% reduction in IPD versus covered serotypes in China. 2.6.1. Direct effect on hospitalized pneumonia The direct effectiveness of PCV7 on hospitalized pneumonia was derived from the observed effectiveness of PCV7 on the reduction of X-ray-confirmed pneumonia in US clinical trials.29 These data were adjusted to account for Chinese serotype coverage derived from a recent meta-analysis19 relative to US PCV7 serotype coverage at the time of the studies, using the following conversion formula: EPCV7_local = EPCV7_US  (CoveragePCV7_local/CoveragePCV7_US). 2.7. Vaccine indirect effectiveness 2.7.1. Indirect effectiveness on IPD The estimated indirect effectiveness of PCV7 on IPD incidence was derived from US invasive disease surveillance data by applying the observed reductions in overall disease incidence from PCV7 serotypes to relative serotype coverage of PCV7 in China. Data from US surveillance 7 years following the introduction of PCV7 were used as the basis of estimation.15 For children under 5 years of age, the estimated impact of direct effects were subtracted from the overall disease reduction so that the indirect effect estimate only comprised the additional reduction expected due to herd effects. For children and adults over 5 years of age the net reduction in IPD from the pre-PCV7 period to 7 years following the initial introduction of PCV7 in the USA were applied. 2.7.2. Indirect effectiveness on hospitalized pneumonia The estimated indirect effectiveness of PCV7 on hospitalized pneumonia in children was derived by combining direct effectiveness and ecologic data. Since it is unclear how much of the observed decreases in hospitalized pneumonia are directly attributable to PCV7, the midpoint of the direct effectiveness from the PCV7 trial29–31 and reductions in disease from observational studies were assumed to represent the total effectiveness, both direct and indirect, of PCV7 on hospitalized pneumonia.32–35 The overall indirect effectiveness for PCV7 in China was obtained by multiplying the effectiveness of PCV7 by the

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ratio of the proportion of IPD cases caused by serotypes covered by PCV7 in China to the proportion of pneumonia cases caused by serotypes covered by PCV7 in the USA at the time of its introduction. Serotype coverage for pneumonia was assumed to be the same as for IPD. Indirect effectiveness was derived from the total effectiveness by assuming that all changes in incidence not attributable to the direct impact of the vaccine were a result of indirect effectiveness. The indirect effectiveness of PCV7 against pneumonia in adults was similarly derived from data regarding reductions in pneumonia admissions following the introduction of PCV7 in the USA, again adjusted to reflect serotype prevalence in China.36 In order to account for the uncertainty regarding how much of the observed reduction in pneumonia can be attributed to the introduction of the PCV7 vaccine, it was assumed that the indirect effectiveness was equal to 50% of the estimated effect reported by Grijalva et al.36 2.8. Utility weights Utility values for various disease states were incorporated into the model as a one-time reduction in the quality-adjusted

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life-years (QALY) for each disease occurrence in the year in the annual cycle in which it occurs. The values of the reductions were 0.0232 for meningitis, 0.0079 for bacteremia, and 0.006 for hospitalized pneumonia.37 Utility weights for deafness and disability resulting from meningococcal complications were taken from published sources and valued at 0.73 for deafness and 0.68 for disability for each year over the remainder of the individual’s life.38,39 3. Results A summary of the key results is provided in Tables 3 and 4. Given the available evidence suggesting the importance of the indirect effect related to the PCV7 vaccine, we present the combined direct and indirect results as the primary base case and present the direct only effect purely as an additional sensitivity analysis. The model estimates that, with no pneumococcal vaccination, approximately 3.1 million cases of IPD and 103 million cases of hospitalized pneumonia would occur in China over a 10-year period, leading to 5.5 million deaths. Of these totals, approximately 31 million cases of disease and more than 435 000 deaths would occur in children under the age of 5 years.

Table 3 Estimated number of events over a 10-year time horizon 0% Discount

Vaccine (Direct effect only)

Vaccine (Direct and indirect effects)

47 414 30 972 159

22 862 25 538 787

16 481 22 379 637

5+ years of age IPD Hospitalized pneumonia

3 102 072 72 142 665

3 102 148 72 143 464

2 266 070 65 310 056

All ages IPD Hospitalized pneumonia

3 149 486 103 114 824

3 125 010 97 682 251

2 282 551 87 689 693

Deaths due to disease <5 years of age IPD Hospitalized pneumonia

2776 433 120

1325 361 523

919 293 230

5+ years of age IPD Hospitalized pneumonia

451 745 4 614 345

451 748 4 614 352

301 450 4 196 977

All ages IPD Hospitalized pneumonia

454 521 5 047 465

453 073 4 975 875

302 369 4 490 207

Disease cases <5 years of age IPD Hospitalized pneumonia

3% Discount Disease cases <5 years of age IPD Hospitalized pneumonia

No vaccine

No Vaccine

41 627 27 189 357

Vaccine (Direct effect only)

Vaccine (Direct and indirect effects)

20 574 22 525 362

15 057 19 830 032

5+ years of age IPD Hospitalized pneumonia

2 731 610 63 256 535

2 731 670 63 257 173

2 019 375 57 446 892

All ages IPD Hospitalized pneumonia

2 773 237 90 445 892

2 752 244 85 782 535

2 034 432 77 276 924

Deaths due to disease <5 years of age IPD Hospitalized pneumonia

2440 380 834

1179 318 271

831 260 007

5+ years of age IPD Hospitalized pneumonia

395 899 4 034 959

395 902 4 034 964

268 181 3 680 772

All ages IPD Hospitalized pneumonia

398 339 4 415 793

397 081 4 353 235

269 012 3 940 779

IPD, invasive pneumococcal disease.

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Table 4 Clinical impact of routine infant vaccination: PCV7 vs. no vaccination All ages 0% Discounting Cases avoided IPD Hospitalized pneumonia Total Deaths avoided IPD Hospitalized pneumonia Total QALYs gained Life-years saved

<5 years of age

Direct only

Indirect only

Total

Direct only

Indirect only

24 477 5 432 573 5 457 050

842 458 9 992 558 10 835 017

866 935 15 425 131 16 292 067

24 553 5 433 372 5 457 925

6381 3 159 150 3 165 531

30 934 8 592 522 8 623 456

(76) (799) (875)

836 077 6 833 409 7 669 486

836 001 6 832 610 7 668 611

1448 71 592 73 040 4 845 621 5 438 442

150 704 485 667 636 371 15 032 321 17 674 717

152 152 557 259 709 411 19 877 941 23 113 159

1451 71 598 73 049 4 848 624 5 441 833

406 68 293 68 699 4 549 357 5 128 223

1857 139 891 141 748 9 397 980 10 570 057

(3) (6) (9) (3003) (3391)

150 298 417 374 567 672 10 482 964 12 546 494

150 295 417 368 567 663 10 479 961 12 543 102

All ages 3% Discounting Cases avoided IPD Hospitalized pneumonia Total Deaths avoided IPD Hospitalized pneumonia Total QALYs gained Life-years saved

5+ years of age Total

Direct only

<5 years of age

Indirect only

Total

5+ years of age

Direct only

Indirect only

Total

Direct only

Indirect only

Total

Direct only

20 992 4 663 357 4 684 350

717 812 8 505 612 9 223 423

738 804 13 168 969 13 907 773

21 053 4 663 995 4 685 048

5517 2 695 330 2 700 847

26 570 7 359 325 7 385 895

1258 62 558 63 816 2 027 283 2 169 329

128 068 412 456 540 524 8 458 042 9 845 522

129 326 475 014 604 340 10 485 324 12 014 851

1260 62 563 63 823 2 028 598 2 170 757

348 58 264 58 612 1 890 720 2 039 881

1608 120 827 122 435 3 919 318 4 210 638

Indirect only

Total

(61) (638) (699)

712 295 5 810 281 6 522 576

712 234 5 809 643 6 521 877

(2) (5) (7) (1315) (1428)

127 720 354 192 481 912 6 567 322 7 805 641

127 718 354 187 481 905 6 566 006 7 804 214

IPD, invasive pneumococcal disease; QALY, quality-adjusted life-year.

Table 4 presents the impact of introducing PCV7 on the number of cases and deaths related to pneumococcal disease over the 10year period. The model predicts that routine PCV7 vaccination among infants in China would result in a reduction of 866 935 cases of IPD, 15.4 million cases of all-cause hospitalized pneumonia, and 709 411 deaths over the 10-year period. Among these, approximately 8.6 million cases of pneumococcal disease and 141 748 deaths would be avoided among children below the age of 5 years. In older children and adults, the model predicts that approximately 7.6 million cases of disease could be prevented and 567 663 lives could be saved, all attributable to the indirect effectiveness of the vaccination. Overall, the direct effectiveness of the vaccination is estimated to result in a reduction of disease cases by approximately 5.4 million and 73 040 lives saved, while the herd protection that is expected to develop following the inclusion of the PCV7 vaccine into the routine infant vaccination schedule is expected to reduce the number of pneumococcal disease cases by 10.8 million over the 10-year period and save more than 630 000 lives. The estimated direct health impact of vaccination is apparent soon after the initial introduction of the vaccine, with significant reductions in IPD and pneumonia in children below the age of

2 years observable within the first 2 years following the inclusion of PCV7 into the infant immunization schedule. These patterns are shown in Figures 1 and 2. The overall estimated health benefits continue to grow through the first 7 years after starting a vaccination program as each incoming cohort continues to benefit from the direct protection as they progress through the model and, more importantly, the indirect effectiveness of the vaccine continues to expand into the older population. 4. Discussion The model predicts that including PCV7 into the national immunization program for infants in China would reduce the incidence of IPD by 866 935, reduce all-cause hospitalized pneumonia by approximately 15.4 million, and save approximately 709 411 lives over the initial 10-year period following the introduction of the vaccine. A significant portion of these benefits is attributable to indirect protection in the unvaccinated, which accounts for over 66% of the cases prevented and 89.7% of the deaths averted. The net impact of indirect effectiveness is a critical component of the value of vaccination and there is substantial evidence to support the

0

0

-500

-100,000 -200,000

-1000

-300,000 -1500

-400,000 -2000

-2500 Year 0

-500,000

Year 1

Year 2

Year 3

Year 4

Year 5

Year 6

Year 7

Year 8

Year 9 Year 10

-600,000 Year 0

Year 1

Year 2

Year 3

Year 4

Year 5

Year 6

Year 7

Year 8

< 2 yrs, no herd

2-4 yrs, no herd

< 2 yrs, no herd

2-4 yrs, no herd

< 2 yrs, herd

2-4 yrs, herd

< 2 yrs, herd

2-4 yrs, herd

Figure 1. Estimated reduction in invasive pneumococcal disease cases with PCV7 over 10 years in children <5 years of age, with and without indirect (herd) effects.

Year 9 Year 10

Figure 2. Estimated reduction in hospitalized pneumonia cases with PCV7 over 10 years in children <5 years of age, with and without indirect (herd) effects.

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estimated reduction of IPD and pneumonia in non-vaccinated populations following widespread use of PCV7.36,40 The study, as implemented, is subject to a number of limitations regarding data availability. The analysis required extrapolation of several parameters from local and international epidemiologic data to derive necessary age-specific incidence rates, further complicated by the limited availability of local disease estimates and the high variability in the estimates that were available. The model used an incidence of pneumococcal meningitis of 1.33 per 100 000, derived from a thorough literature review and meta-analysis, which reported an incidence rate of 14/100 000 for all-cause meningitis, 9.8% of which was pneumococcal.19 Two international studies, however, estimate pneumococcal meningitis rates of 10.5 to 14.3 per 100 000, far above the rates we estimated from the local literature.1,13 It is likely, therefore, that incidence rates used are an underestimate of the true incidence rate of pneumococcal meningitis and the estimated benefits from PCV7 on pneumococcal meningitis derived by this model will be conservative. Reductions in hospitalized pneumonia are the greatest contributor of morbidity and mortality benefits estimated by the model, with an estimated 15.4 million cases and more than 500 000 deaths avoided. A recent analysis, however, suggests that pneumonia deaths in China vary greatly across provinces and over time, rendering estimates from historical, individual studies unreliable.2 Additionally, estimates in the literature of the incidence among children less than 5 years of age in China of all-cause pneumonia are also highly variable, ranging from 4776 to 22 700 per 100 000 population19 to 6000 to 66 000 per 100 000.23 The estimates used in the model were derived from a more contemporary analysis of mortality reports from across China for 2008,2 and estimated outputs are more conservative than reported in previous published estimates.19,23 Further, for children over 5 years of age and adults, we sought to derive incidence and mortality rates of all-cause hospitalized pneumonia consistent with the broad pneumonia definition applied to effectiveness studies similar to that from which our herd effect assumption is based,33,34,36,40 but such measures were not available. Among these values, the most influential in the model was the assumption of pneumonia incidence in adults older than 65 years of age. Our estimate of 3700 per 100 000 in adults over 65 years of age was a direct estimate from a local study,23 but is higher than incidence rates reported in Hong Kong (1600/ 100 000),11 Taiwan (2165/100 000),10 Malaysia (2041/100 000),9 and Singapore (1939/100 000, age 60 years).12 More research on the incidence, etiology, and mortality of hospitalized pneumonia in adults is necessary to understand the potential impact of pneumococcal vaccination on disease in China. In conclusion, applying Chinese specific demographic and epidemiologic data to a mathematical model designed to estimate the public health impact, both direct and indirect, of PCV7 at the population level, resulted in significant estimated reductions in morbidity and mortality from pneumococcal-related diseases for all age groups in China. The model estimated that more than 16.2 million cases of pneumococcal-related disease and 709 411 deaths could be prevented in China over the initial 10-year period following the introduction of the PCV7 vaccine. The majority of the health benefits were due to the indirect effectiveness of the vaccine on the unvaccinated population, resulting in approximately 10.8 million cases prevented and 636 371 lives saved, primarily among adults and children over the age of 5 years. It is likely that a policy of universal PCV7 vaccination among infants in China would be a cost-effective health care intervention and have a substantial positive public health impact on the population of China. Funding source: This study was funded by Pfizer Inc. Authors employed by Pfizer Inc. were involved in the design, analysis, and writing of the manuscript.

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Conflict of interest: Dr Roberts, Mr Shi, and Mrs Chen are employed by Pfizer and own stock in Pfizer. Dr Hu, Dr Caldwell, Dr Wang, Mrs Du, and Mr He have received an honorarium from Pfizer to plan, conduct, prepare, and present the current analyses and have acted as consultants for Pfizer.

References 1. O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009;374:893–902. 2. Rudan I, Chan KY, Zhang JS, Theodoratou E, Feng XL, Salomon JA, et al. Causes of deaths in children younger than 5 years in China in 2008. Lancet 2010;375: 1083–9. 3. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 2000;30:100–21. 4. Shouval DS, Greenberg D, Givon-Lavi N, Porat N, Dagan R. Site-specific disease potential of individual Streptococcus pneumoniae serotypes in pediatric invasive disease, acute otitis media and acute conjunctivitis. Pediatr Infect Dis J 2006;25:602–7. 5. Yao KH, Wang LB, Zhao GM, Zheng YJ, Deng L, Huang JF, et al. Pneumococcal serotype distribution and antimicrobial resistance in Chinese children hospitalized for pneumonia. Vaccine 2011;29:2296–301. 6. Fitzwater SP, Chandran A, Santosham M, Johnson HL. The worldwide impact of the seven-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2012;31:501–8. 7. Centers for Disease Control and, Prevention, Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease—United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005;54:893–7. 8. Miller MA, McCann L. Policy analysis of the use of hepatitis B, Haemophilus influenzae type b, Streptococcus pneumoniae-conjugate and rotavirus vaccines in national immunization schedules. Health Econ 2000;9:19–35. 9. Aljunid S, Abuduxike G, Ahmed Z, Sulong S, Nur AM, Goh A. Impact of routine PCV7 (Prevenar) vaccination of infants on the clinical and economic burden of pneumococcal disease in Malaysia. BMC Infect Dis 2011;11:248. 10. Wu DB, Chang CJ, Huang YC, Wen YW, Wu CL, Fann CS. Cost-effectiveness analysis of pneumococcal conjugate vaccine in Taiwan: a transmission dynamic modeling approach. Value Health 2012;15(1 Suppl):S15–9. 11. Lee KK, Rinaldi F, Chan MK, Chan STH, So TMT, Hon EKL, et al. Economic evaluation of universal infant vaccination with 7vPCV in Hong Kong. Value Health 2009;12(3 Suppl):S42–8. 12. Tyo KR, Rosen MM, Zeng W, Yap M, Pwee KH, Ang LW, et al. Cost-effectiveness of conjugate pneumococcal vaccination in Singapore: comparing estimates for 7-valent, 10-valent, and 13-valent vaccines. Vaccine 2011;29:6686–94. 13. Nakamura MM, Tasslimi A, Lieu TA, Levine OS, Knoll MD, Russell LB, et al. Cost effectiveness of child pneumococcal conjugate vaccination in middle-income countries. Int Health 2011;3:270–81. 14. Rubin JL, McGarry LJ, Strutton DR, Klugman KP, Pelton SI, Gilmore KE, et al. Public health and economic impact of the 13-valent pneumococcal conjugate vaccine (PCV13) in the United States. Vaccine 2010;28:7634–43. 15. Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010;201:32–41. 16. Chinese Health Statistical Annual. In: Report.. China: Ministry of Health PRC; 2009. 17. U.S. Census Bureau International Database. Available at: http://www.census.gov/population/international/data (accessed July 31, 2013). 18. World Health Organization. Life expectancy: Life expectancy by country. China 2009 data. Global Health Observatory Data Repository. Geneva: WHO; Available at: http://apps.who.int/gho/data/node.main (accessed July 31, 2013). 19. Chen Y, Deng W, Wang SM, Mo QM, Jia H, Wang Q, et al. Burden of pneumonia and meningitis caused by Streptococcus pneumoniae in China among children under 5 years of age: a systematic literature review. PLoS One 2011;6:e27333. 20. Chuang SY, Yen CC, Wu JS, Huang CC, Chiang CS, Cheng XW, Chen YY. The Surveillance and Epidemiological Analysis of Streptococcus Pneumoniae Infection. Category Four Communicable Disease in Taiwan Taiwan Epidemiology Bulletin 2009;25(1):1–20. 21. Lieu TA, Ray GT, Black SB, Butler JC, Klein JO, Breiman RF, et al. Projected costeffectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA 2000;283:1460–8. 22. Shepard CW, Ortega-Sanchez IR, Scott RD, Rosenstein NE. Pediatrics 2005;115: 1220–32. 23. Guan X, Silk BJ, Li W, Fleischauer AT, Xing X, Jiang X, et al. Pneumonia incidence and mortality in Mainland China: systematic review of Chinese and English literature, 1985-2008. PLoS One 2010;5:e11721. 24. Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB. Cost-effectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects. Pediatr Infect Dis J 2006;25:494–501. 25. Jodar L, Butler J, Carlone G, Dagan R, Goldblatt D, Kayhty H, et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine 2003;21:3265–72.

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S.L. Hu et al. / International Journal of Infectious Diseases 26 (2014) 116–122

26. Siber GR, Chang I, Baker S, Fernsten P, O’Brien KL, Santosham M, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine 2007;25:3816–26. 27. World Health Organization. Recommendations to assure the quality, safety and efficacy of pneumococcal conjugate vaccines. Expert Committee on Biological Standardization. Geneva, 19 to 23 October 2009. 28. Li RC, Li FX, Li YP, Guo SY, Nong Y, Ye Q, et al. Safety and immunogenicity of a 7-valent pneumococcal conjugate vaccine (Prevenar): primary dosing series in healthy Chinese infants. Vaccine 2008;26:2260–9. 29. Hansen J, Black S, Shinefield H, Cherian T, Benson J, Fireman B, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs. Pediatr Infect Dis J 2006;25:779–81. 30. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19:187–95. 31. Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21:810–5. 32. Zhou F, Kyaw MH, Shefer A, Winston CA, Nuorti JP. Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States. Arch Pediatr Adolesc Med 2007;161:1162–8.

33. Grijalva CG, Poehling KA, Nuorti JP, Zhu Y, Martin SW, Edwards KM, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics 2006;118:865–73. 34. Jardine A, Menzies RI, Deeks SL, Patel MS, McIntyre PB. The impact of pneumococcal conjugate vaccine on rates of myringotomy with ventilation tube insertion in Australia. Pediatr Infect Dis J 2009;28:761–5. 35. Zhou F, Shefer A, Kong Y, Nuorti JP. Trends in acute otitis media-related health care utilization by privately insured young children in the United States, 19972004. Pediatrics 2008;121:253–60. 36. 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. 37. Melegaro A, Edmunds WJ. Cost-effectiveness analysis of pneumococcal conjugate vaccination in England and Wales. Vaccine 2004;22:4203–14. 38. Oostenbrook R, Moll H, Essink-Bot ML. The EQ-5D and the Health Utilities Index for permanent sequelae after meningitis: a head-to-head comparison. J Clin Epidemiol 2002;55:791–9. 39. Erickson LJ, De Wals P, McMahon J, Heim S. Complications of meningococcal disease in college students. Clin Infect Dis 2001;33:737–9. 40. Grijalva CG, Moore MR, Griffin MR. Assessing the effect of pneumococcal conjugate vaccines: what is the value of routinely collected surveillance data? Lancet Infect Dis 2011;11:724–6.