Impact of pneumococcal conjugate vaccine in children on the ...

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in children on the serotypic epidemiology of adult invasive pneumococcal diseases in. Taiwan. Hsiao-Chun Chi a. , Yu-Chia Hsieh a,b. , Ming-Han Tsai b,c.

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Journal of Microbiology, Immunology and Infection (2016) xx, 1e5

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ORIGINAL ARTICLE

Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan Hsiao-Chun Chi a, Yu-Chia Hsieh a,b, Ming-Han Tsai b,c, Chen-Hsiang Lee b,d, Kuang-Che Kuo b,e, Ching-Tai Huang b,f, Yhu-Chering Huang a,b,* a

Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan Chang Gung University College of Medicine, Taoyuan, Taiwan c Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan d Department of Internal Medicine, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan e Department of Pediatrics, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan f Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taiwan b

Received 30 April 2016; received in revised form 19 July 2016; accepted 8 August 2016

Available online - - -

KEYWORDS adult; invasive pneumococcal disease; serotype; Streptococcus pneumoniae; Taiwan

Abstract Background: Invasive pneumococcal disease (IPD) causes significant morbidity and mortality, especially in children and older adults. Pneumococcal 7-valent and 13-valent conjugate vaccines (PCV7 and PCV13) were introduced in Taiwan in 2005 and 2011, respectively, for children. This study was conducted to evaluate the impact of PCV administered in children on adult IPD. Methods: From the logbooks of microbiology laboratories, we retrospectively retrieved Streptococcus pneumoniae isolates, collected from normally sterile sites in adult patients. One hundred and fifty-seven consecutive, nonduplicated isolates were collected from one hospital during 2001 and 2003 (pre-PCV period) and 150 isolates from three hospitals from July 2011 to June 2015 (post-PCV period). Serotypes were determined by Quellung test. Results: Among the 307 isolates, 31 serotypes/serogroups were identified. PCV7 serotypes, particularly types 14 (31.2%), 23F (19.7%) and 6B (12.7%) dominated in the pre-PCV period (78.3%) but significantly decreased in the post-PCV period (36%) (p < 0.01). PCV13 specific serotypes (PCV13ePCV7) significantly increased from 7% of the isolates in the pre-PCV period to 28.7% of the isolates in the post-PCV period (p < 0.001), particularly type 19A (from 0.6% to 10%) and 6A (from 0 to 6.7%). Serotype 15B also increased significantly from 0.6% to 6.7%

* Corresponding author. Department of Pediatrics, Chang Gung Memorial Hospital, Number 5, Fu-Hsin Street, Kweishan 333, Taoyuan, Taiwan. E-mail address: [email protected] (Y.-C. Huang). http://dx.doi.org/10.1016/j.jmii.2016.08.009 1684-1182/Copyright ª 2017, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Chi H-C, et al., Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/ j.jmii.2016.08.009

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H.-C. Chi et al. (p < 0.01). Nonvaccine serotypes increased significantly in the post-PCV period (11.5% to 22.0%, p < 0.05), particularly type 15A (from 0 to 4.4%, p < 0.01). Conclusion: Serotype distribution of adult IPD in Taiwan has evolved after the introduction of PCV in children, indicating an indirect impact in adults. Continuous surveillance after the PCV13 vaccination program in children is needed. Copyright ª 2017, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction Pneumococcal disease is a major cause of morbidity and mortality in children and elderly people.1e3 In Taiwan, invasive Streptococcus pneumoniae infection has been a national notifiable disease since October 2007. The incidence of IPD is 3.2 per 100,000 population in adults. Case fatality rates for invasive pneumococcal disease (IPD) among all adults is 9.2% and as high as 19.0% in adults aged >75 years.4,5 Pneumococcal vaccination plays an important role in the prevention of IPD. Since 2005, four types of pneumococcal vaccines have been introduced in Taiwan: the 7-valent, 10valent, and 13-valent pneumococcal conjugate vaccines (PCV7, PCV10, and PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23).6 PCV7 (Prevnar 7) and PCV10 (SYNFLORIX) have been available for use in children, primarily in the private sector since 2005 and 2010, respectively.4 In 2011, PCV13 (Prevnar 13) was introduced and replaced PCV7 in children; also primarily in the private sector. In July 2009, PCV10 was freely provided by the government for children with conditions that placed them at high risk for IPD and children from low-income households. In March 2013, a one-dose PCV13 catch-up program was freely provided for children aged 2e5 years and a twodose PCV13 catch-up program for children aged 1 year was conducted in 2014. Since January 2015, PCV13 was included in the expanded program of immunization for children on a 2 þ 1 schedule. The first dose is given at the age of 2 months followed by a second dose after a 2-month interval, and then a booster dose at 12e15 months of age.6 PPV-23 (Pneumovax 23) was licensed in January 1998 and has been freely provided (1 dose) for elderly people at the age of 75 years since 2007 through a nonprofit foundation.7 According to the manufacturer’s estimates, in 2010, 45.5% of children aged 2 months to 5 years in Taiwan received at least one dose of PCV7.8 Between February 2013 and December 2013, the immunization rate for PCV13 in children aged 2e5 years increased from 31.9% to 64.2%.9 With the increased uptake rate of PCV in children in Taiwan, childhood IPD caused by PCV-specific serotypes has continuously decreased.9 In addition to the vaccine-targeted population (i.e., infants and young children), indirect protection from PCV7 serotypes has been observed in adult IPD and pneumonia cases in England as well as in the United States.10,11 Whether partial coverage of PCV in Taiwanese children (primarily through the private market), with transitions to higher valence conjugate vaccines, provides indirect

protection in adults merits further exploration. We present a hospital-based study to evaluate the impact of PCV on serotype distribution of adult IPD in Taiwan.

Materials and methods From the logbooks of microbiology laboratories, we retrospectively identified adult patients (>18 years old) with IPD, from whom S. pneumoniae was isolated from normally sterile sites including blood, cerebrospinal fluid (CSF), pleural fluid, peritoneal fluid, and synovial fluid in Chang Gung Memorial Hospital Network (CGMH), Taiwan.12 One hundred and fifty-seven consecutive, nonduplicated isolates (1 isolate from a single patient) were collected and retrieved from one CGMH center only (Linkou Medical Center) between 2001 and 2003 (pre-PCV period) and 150 consecutive, nonduplicated isolates from three CGMH centers (Linkou, Kaohsiung, and Keelung) between July 2011 and June 2015 (post-PCV period). All isolates were sent to Linkou Medical Center for serotype testing. We retrospectively reviewed the medical record of each patient to retrieve their demographic and clinical characteristics. S. pneumoniae was identified by standard methods.13 The serotype of each pneumococcal isolate was determined by the Quellung reaction using commercialized antisera (Statens Serum Institut, Copenhagen, Denmark). PCV7 serotypes included 4, 6B, 9V, 14, 18C, 19F, and 23F. PCV13-specific serotypes included 1, 3, 5, 6A, 7F, and 19A. PPV-23 specific serotypes included 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, and 33F. Serotypes not included in available pneumococcal vaccines were categorized as nonvaccine serotypes. Statistical analysis was performed with SPSS version 22 software (SPSS Inc., Chicago, IL, USA). The c2 test with Yates’ correction or Fisher exact test was used for analyzing categorical variables. Differences were considered statistically significant at p < 0.05.

Results During the study period, a total of 307 isolates of S. pneumoniae were identified and collected; 157 isolates from the pre-PCV period and 150 isolates from the post-PCV period. During the post-PCV period, 86 isolates were collected from Linkou Medical Center, 33 isolates from Kaohsiung Center, and 31 isolates from Keelung Branch Hospital. Of the 307 patients, 70% were male and the mean age was 59.6 years.

Please cite this article in press as: Chi H-C, et al., Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/ j.jmii.2016.08.009

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Impact of PCV on adult IPD in Taiwan

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Table 1 Demographic data of enrolled adult patients with invasive pneumococcal disease before and after PCV introduction in children in Taiwan Demographics

Pre-PCV period (n Z 153a) N (%)

Post-PCV period (n Z 150) N (%)

Male gender Mean age (y) 18e49 50e64 65

107 (69.9) 57.8 49 (32) 40 (26.1) 64 (41.8)

105 (70.0) 61.5 33 (22.0) 50 (33.3) 67 (44.7)

a Four patients had no demographic data. PCV Z pneumococcal conjugate vaccine.

More than 40% of the patients were  65 years of age. Detailed demographic data are shown in Table 1. Two hundred and eighty-five isolates (92.8%) were identified from the bloodstream. Other sources were less common and included CSF (n Z 10), pleural fluid (n Z 8), synovial fluid (n Z 1), and peritoneal fluid (n Z 3). The detailed source distribution of isolates identified in each year is listed in Table 2. Of the 307 isolates, a total of 31 serogroups/serotypes were identified. The major serotypes of S. pneumoniae during the pre-PCV period were types 14 (31.2%), 23F (19.7%), 6B (12.7%), 9V (7.0%), 19F (6.4%), and 3 (6.4%) (Table 3). During the post-PCV period, the major serotypes were types 14 (14.7%), 3 (10.7%), 19A (10%), 23A (8%), and 6A, 6B, and 15B (each 6.7%). Comparing both periods, we found that Serotypes 9V, 14, and 23F significantly decreased, while Serotypes 6A, 15A, 15B, 19A, and 23A significantly increased. PCV7 serotypes dominated during the pre-PCV period and accounted for 123 (78.3%) isolates but significantly decreased during the post-PCV period, accounting for 54 (36%) isolates only. PCV13 serotypes accounted for 134 (85.3%) isolates during the pre-PCV period and 97 (64.7%) isolates during the post-PCV period. PPV-23 isolates accounted for 139 (88.4%) isolates during the pre-PCV period and 107 (71.3%) isolates during the post-PCV period. Nonvaccine serotypes increased significantly from 18 (11.5%) isolates in the pre-PCV period to 33 (22.0%) isolates in the post-PCV period (p < 0.05) (Table 3).

The absolute number of cases caused by PCV7, PCV13, and PPV23 serotypes decreased during the post-PCV period. However, the additional serotypes in PCV13 (PCV13ePCV7) significantly increased from 7% of the isolates during the pre-PCV period to 28.7% of the isolates during the post-PCV period (p < 0.001). In particular, serotype 19A increased from one (5.3%) isolate in 2011 to five (11.9%) isolates in 2012 (Supplementary Table 1). This trend may be slowing after the introduction of PCV13 in children; Serotype 19A decreased from four (11.4%) isolates in 2013 to two (9.1%) isolates in 2015. However, the data must be interpreted with caution due to the small sample size included in the study. The additional serotypes in PPV23 (PPV23ePCV13) also increased significantly from five (3.2%) isolates in the prePCV period to 20 (13.3%) isolates in the post-PCV period (p < 0.05). Serotype 15B increased significantly from 0.6% of isolates during the pre-PCV period to 6.7% of the isolates during the post-PCV period (p Z 0.005), particularly in 2015 when it accounted for 22.7% of all isolates. Among nonvaccine serotypes, 23A increased from 3.2% of all isolates during the pre-PCV period to 8% of all isolates in the post-PCV period, particularly in 2012 when it accounted for 14.3% of all isolates. Serotype 15A significantly increased from zero isolates in the pre-PCV period to seven (4.7%) isolates in the post-PCV period (p < 0.05).

Discussion Results from the present study show that in Taiwan, PCV7 serotypes, particularly 14, 23F, and 6B, accounted for nearly 80% of isolates during the pre-PCV period. In the post-PCV period, the distribution of serotypes was more diverse. Only three serotypes each, including 14, 3, and 19A, accounted for at least 10% of isolates. PCV7-containing serotypes significantly decreased, accounting for only 36% of the isolates. These findings indicate that there may be herd immunity induced by PCV vaccination in children, even in a country that has transitioned from lower valence to higher valence vaccines, and from partial coverage in the private sector to national coverage through the routine immunization program. After the introduction of PCV, the incidence of vaccinetype IPD in children significantly decreased in western countries,9,10,14,15 as well as in Taiwan.8 In addition to the

Table 2 Source distribution of enrolled Streptococcus pneumoniae isolates from adult invasive pneumococcal disease before and after PCV introduction in children in Taiwan Source

2001

2002

2003

Pre-PCV total

2011a

2012

2013

2014

2015a

Post-PCV total

Blood Pleural effusion Cerebrospinal fluid Peritoneal fluid Synovial fluid Total

58 2 1 0 0 61

44 3 2 0 0 49

45 1 1 0 0 47

147 6 4 0 0 157

18 1 0 0 0 19

40 1 1 0 0 42

32 0 2 1 0 35

32 0 0 0 0 32

16 0 3 2 1 22

138 2 6 3 1 150

a

The period of data collection in 2011 and 2015 is only 6 months (from July 2011 to June 2015). PCV Z pneumococcal conjugate vaccine.

Please cite this article in press as: Chi H-C, et al., Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/ j.jmii.2016.08.009

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H.-C. Chi et al. Table 3 Serotype distribution of Streptococcus pneumoniae isolates from adult patients with invasive pneumococcal disease before and after PCV introduction in Taiwan Serotype

Pre-PCV total (n Z 157) N (%)

PCV7 serotypes 4 1 (0.6) 6B 20 (12.7) 9V 11 (7.0) 14 49 (31.2) 18 1 (0.6) 19F 10 (6.4) 23F 31 (19.7) Total 123 (78.3) PCV13 serotypes 1 0 3 10 (6.4) 6A 0 7F 0 19A 1 (0.6) PCV13ePCV7 11 (7.0) Total PCV13 134 (85.3%) PPV23 serotypes 8 2 (1.3) 11A 1 (0.6) 15B 1 (0.6) 20 0 22F 1 (0.6) PPV23ePCV13 5 (3.2) Total PPV23 139 (88.4) Nonvaccine serotypes 6F 1 (0.6) 7 2 (1.3) 9A or 9V 0 10 (F or C) 11 0 15A 0 15C 0 19B 0 23A 5 (3.2) G 0 33C 1 (0.6) Nontypeable 7 (4.5) Total nonvaccine 18 (11.5)

Post-PCV total (n Z 150) N (%)

p

7 (4.7) 10 (6.7) 0 22 (14.7) 0 7 (4.7) 8 (5.3) 54 (36.0)

0.033 0.085 0.01 0.001 1 0.621 18

150

36.0

64.7

68.7

PCV Z pneumococcal conjugate vaccine. Please cite this article in press as: Chi H-C, et al., Impact of pneumococcal conjugate vaccine in children on the serotypic epidemiology of adult invasive pneumococcal diseases in Taiwan, Journal of Microbiology, Immunology and Infection (2016), http://dx.doi.org/10.1016/ j.jmii.2016.08.009

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Impact of PCV on adult IPD in Taiwan increased. An indirect impact of childhood vaccination was observed in adults in Taiwan, even in the context of incremental expansion of the childhood vaccination program, and transitions to higher-valence pneumococcal vaccines. Continuous surveillance after the PCV13 vaccination program in children is needed.

Conflicts of interest No conflicts of interest.

Acknowledgments This study was supported by a grant from Chang Gung Memorial Hospital (BMRP236) and Merck & Co (XMRPG3D05912). The authors would like to acknowledge JSS Medical Research and Choice Pharma for their assistance with data collection.

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5 10. Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis 2011;11:760e8. 11. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med 2013;369:155e63. 12. Randle E, Ninis N, Inwald D. Invasive pneumococcal disease. Arch Dis Child Educ Pract Ed 2011;96:183e90. 13. Spellerberg B, Brandt C. Streptococcus. In: Versalovic J, editor. Manual of clinical microbiology. Washington, DC: ASM Press; 2011. p. 331e49. 14. Broome CV, Facklam RR, Fraser DW. Pneumococcal disease after pneumococcal vaccination: an alternative method to estimate the efficacy of pneumococcal vaccine. N Engl J Med 1980;303:549e52. 15. Ben-Shimol S, Greenberg D, Givon-Lavi N, Schlesinger Y, Somekh E, Aviner S, et al. Early impact of sequential introduction of 7-valent and 13-valent pneumococcal conjugate vaccine on IPD in Israeli children

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