Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland

Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland Hanna Rinta-Kokkoa, Arto A. Palmub, Kari Auranenc, J. Pekka Nuortid,e, Maija Toropainend, Lotta Siirad, Mikko J. Virtanend, Hanna Nohynekd, Jukka Jokinena Affiliations a Department of Public Health Solutions, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland b Department of Public Health Solutions, National Institute for Health and Welfare, Biokatu 10, FI33520 Tampere, Finland c Department of Mathematics and Statistics, University of Turku, 20014 Turun yliopisto, Turku, Finland d Department of Health Security, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland e Department of Epidemiology, School of Health Sciences, University of Tampere, Kalevantie 4, FI33014, Tampere, Finland Corresponding author Hanna Rinta-Kokko, MSc National Institute for Health and Welfare Mannerheimintie 166, P.O. Box 30 00271 Helsinki, Finland [email protected] tel. +358 295248141 This is the post print version of the article, which has been published in Vaccine 2018, 36(15), 1934-1940. The final publication is available via https://doi.org/10.1016/j.vaccine.2018.03.001 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Abstract Background The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high, possibly due to cross-protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types) in addition to protection against PCV10 serotypes. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross-protection. Methods We used data on IPD from the national, population-based surveillance. A target cohort of vaccineeligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. To assess the indirect effect, another cohort of older, PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of seasonand age-matched reference cohorts before NVP introduction. Results Among vaccine-eligible children, the incidence of all IPD decreased by 79% (95%CI 74 to 83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant. In the unvaccinated older children, the incidence of all IPD decreased by 33% (95%CI 8 to 52%) compared to the reference cohort. There was no impact on serotype 6A or 19A IPD in the unvaccinated cohort. Conclusion Overall, the impact of PCV10 vaccination on IPD was very high in vaccine-eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained. 1 Introduction 1 It has been estimated that Streptococcus pneumoniae (the pneumococcus) caused about 14.5 million 2 episodes of serious pneumococcal disease, including pneumonia, meningitis and febrile 3 bacteraemia, worldwide in 2000.1 The introduction of pneumococcal conjugate vaccines (PCVs) 4 since 2000 has afforded excellent direct protection for vaccinated children against invasive 5 pneumococcal disease (IPD) caused by serotypes included in the vaccines. At the same time, the 6 impact has extended to unvaccinated populations through indirect protection due to reduced 7 vaccine-type carriage in vaccinated children and the subsequently reduced transmission. However, 8 replacement in carriage and subsequent disease by serotypes not included in the vaccines has partly 9 eroded the direct and indirect benefits of vaccination across all age groups and is a growing 10 concern.2-8 11 In addition to protection against the vaccine serotypes, PCVs have been documented to provide 12 cross-protection against some vaccine-related serotypes, i.e. serotypes that belong to the same 13 serogroups as the vaccine serotypes. Previous studies have shown that the seven-valent vaccine 14 (PCV7, Prevenar, Pfizer), which included serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, reduced also 15 IPD caused by 6A IPD, but not by 19A or 6C.3,9,10 Serotype 19A IPD was among the most common 16 causes of replacement disease after PCV7 introduction.3,4,11,12 In 2010, PCV13 (Prevenar 13, Pfizer) 17 with six additional serotypes (1, 3, 5, 6A, 7F, and 19A) replaced PCV7. Recently, cross-protection 18 against 6C from the 6A component of PCV13 has been reported13 . 19 The 10-valent pneumococcal conjugate vaccine (PCV10, Synflorix, GSK Vaccines) including 20 serotypes in the PCV7 + 1, 5 and 7F was introduced into the Finnish National Vaccination 21 Programme (NVP) after a public tender in September 2010. In addition to providing protection 22 against vaccine serotypes, PCV10 also had reduced incidence of 6A and 19A IPD among vaccine23 eligible children in Finland three years after vaccine introduction into NVP.6 Here we report 24 2 updated data about the overall and indirect long-term impact of PCV10 vaccination against IPD 25 among vaccine-eligible and unvaccinated older children, with a special focus on cross-protection 26 against the vaccine-related serotypes. 27 Methods 28 The vaccination programme 29 PCV10 was introduced into the NVP in September 2010. Children born on or after June 1, 2010, 30 are eligible for vaccination with a 2+1 schedule (primary series at 3 and 5 months and a booster 31 dose at 12 months of age). There was no catch-up vaccination at PCV10 introduction. In the birth 32 cohort of 2012, the uptake of at least one dose of PCV10 was estimated at 94% based on data in the 33 National Vaccination Register.14 34 In 2009-2011, the effectiveness of PCV10 against vaccine-type IPD was investigated in a nation35 wide FinIP vaccine trial, in which over 30,000 children born 2008 through May 2010 were 36 vaccinated with PCV10.15 During the FinIP trial, the PCV10 vaccine coverage varied regionally 37 from 0 to 60%. Prior to the FinIP trial and the introduction of PCV10 into the NVP, no 38 pneumococcal conjugate or polysaccharide vaccines were routinely used for healthy children and 39 adults, and the vaccine uptake was estimated to be less than 2%. 40 Influenza vaccine was introduced into the NVP in the beginning of the influenza season 2007/2008 41 for children aged 6 to 36 months. The uptake of this age group has been estimated to vary between 42 15 and 40%.14 43 Data sources and case definition 44 IPD cases were identified from the National Infectious Diseases Register (NIDR), a population45 based electronic laboratory surveillance system maintained by the National Institute for Health and 46 3 Welfare (THL). It is mandatory for all clinical microbiology laboratories to notify all isolations of 47 Streptococcus pneumoniae from blood or cerebrospinal fluid to NIDR and the process has been 48 automated to send electronic reports to the database. Furthermore, the corresponding case isolates 49 are sent to the national reference laboratory at THL for confirming the species and serotyping. 50 Currently, more than 97% of the case isolates are received.16 IPD case was defined as isolation of S. 51 pneumoniae from blood or cerebrospinal fluid. The IPD surveillance in Finland and the THL 52 laboratory methods have been described earlier.6,17 53 Vaccination status of each IPD case was verified from the National Vaccination Register and local 54 electronic vaccination cards. Data on comorbidities were obtained from the national hospital 55 discharge register (the Care Register for Health Care at THL). The study population was determined 56 by using data from the Finnish Population Information System. All register-based information was 57 linked by using the unique national personal identity code which is assigned to all permanent 58 residents in Finland. 59 IPD cases were categorized according to the causative serotype into three mutually exclusive 60 groups: PCV10 serotypes, PCV10-related serotypes (i.e. serotypes belonging to the same 61 serogroups as vaccine types; in the data: 6A, 6C, 7C, 9N, 18B, 19A, 23A, 23B), or non-PCV10 62 serotypes. The impact of PCV10 vaccination on each of the three serotype groups was evaluated. In 63 addition, the impact was assessed separately for serotypes 6A and 19A. 64 Overall impact of PCV10 vaccination in vaccine-eligible children 65 To estimate the overall impact of PCV10 vaccination on IPD, the relative reduction in the incidence 66 of IPD for each serotype group was estimated by comparing a target cohort, comprising all vaccine67 eligible children irrespective of vaccination status and born between June 2010 and September 68 2016, to a seasonand age-matched reference cohort in years 2002-2008 (Figure 1, panel A). The 69 4 children who were enrolled in the FinIP trial in years 2009-2010 were excluded from the analysis. 70 The follow-up period started at 3 months of age (the first scheduled vaccination dose) and lasted 71 until the end of December 2016 for the target cohort and December 2008 for the reference cohort. 72 The follow-up thus included children from 3 to 78 months of age. 73 To assess time trends in the age-specific risk of 19A IPD, age-specific cumulative hazards were 74 calculated for the target and reference cohorts. 75 Indirect impact of PCV10 vaccination in unvaccinated children 76 To estimate the indirect impact of PCV10 vaccination against IPD, the relative reduction in the 77 incidence of IPD for each serotype group was estimated by comparison of unvaccinated cohorts of 78 older children after and before PCV10 introduction (Figure 1, panel B). The unvaccinated target 79 cohort was chosen to comprise children born between January 2006 and May 2010. Children 80 vaccinated in the FinIP trial with PCV10 were excluded. The ageand season-matched reference 81 cohort comprised all children born between January 2000 and May 2004. The follow-up period 82 started in January 2012 (2006) and lasted until the end of December 2016 (2010) for the target 83 (reference) cohort. The follow-up included children from 19 to 131 months of age. 84 Statistical methods 85 Comparison of IPD incidence rates was performed by using Poisson regression. Vaccine impact 86 was defined as (1-incidence rate ratio)*100%, comparing the target and reference cohorts. Absolute 87 rate reductions and the corresponding confidence intervals were calculated from the parameter 88 estimates with the delta method. No adjustments were made for comorbidities or influenza 89 vaccinations in the NVP because of the small number of cases, evenly distributed comorbidities in 90 the study cohorts and the low coverage of the influenza vaccinations. Statistical significance was 91 deemed at the 5% level. Statistical software R version 3.4.218 was used for all analyses. 92 5 Ethical considerations 93 As part of its statutory tasks, the National Institute for Health and Welfare (THL) is obliged to 94 monitor the effectiveness and safety of the vaccines used in NVP. The study plan was approved by 95 the THL institutional review board (May 23, 2013). Permissions to use the register data for research 96 were obtained from the relevant register controllers at THL (THL/1090/6.02.00/2013). 97 98 Results 99 Overall impact of PCV10 vaccination in vaccine-eligible children 100 Table 1 presents the estimated overall impact of PCV10 vaccination by the serotype groups, based 101 on comparisons of the entire vaccine-eligible cohort (years 2010-2016) with its reference cohort 102 (years 2002-2008). Among children targeted for vaccination, the incidence of all IPD decreased by 103 79% (95% CI 74 to 83%) from 42.9 to 9.2 cases per 100,000 person-years. The incidence of PCV10 104 serotype IPD decreased by 94% (95% CI 91 to 96%) from 32.3 to 1.9 cases per 100,000 person105 years. There was a borderline non-significant increase in non-PCV10 serotypes (IRR 1.53, 95% CI 106 0.96 to 2.49). Figure 2 shows the evolution of the IPD incidence in children of vaccine-eligible age 107 by epidemiological year (from July to June). 108 The incidence of IPD caused by PCV10-related serotypes decreased from 6.3 to 3.8 per 100,000 109 person-years. This was mainly due to a decrease in the incidence of 6A with a relative reduction of 110 95% (95% CI 75 to 100%). There was a statistically non-significant reduction of 26% (95% CI -13 111 to 51%) in 19A. 112 Apart from the notably high incidence in the epidemiological years 2003/2004-2004/2005, the 113 incidence of 19A fluctuated over the years with some increase towards the end of the follow-up 114 6 (Figure 3). The annual numbers of cases in 0-1 and 2-5 year-olds varied, respectively, between 0-17 115 and 0-12. Cases of 19A IPD appeared to occur more often among older children aged 24-78 months 116 in the target cohort compared to the reference cohort (Figure 4, Supplement Figure 1). The presence 117 of underlying comorbidities in 19A cases was low and similar in both cohorts. The serotype118 specific changes in incidences are presented in Supplement Table 1. 119 There were six breakthrough cases defined as vaccine-type IPD more than two weeks after 120 administration of the booster dose at 12 months among the fully vaccinated children (received all 3 121 doses). The causative serotypes were 19F (2 cases), 23F (2 cases), 6B and 14. No vaccine-type IPD 122 cases occurred between two primary doses and a booster dose. 123 Indirect impact of PCV10 vaccination in unvaccinated children 124 Table 2 presents the relative and absolute rate reductions in IPD incidence, based on the 125 unvaccinated target cohort of older children (19-131 months of age) during 2012-2016 and its 126 reference cohort in the years 2006-2010. The incidence of PCV10 serotype IPD decreased by 58% 127 (95% CI 37 to 73%) from 5.9 cases in the reference cohort to 2.5 cases per 100,000 person-years in 128 the target cohort, and the incidence of all IPD by 33% (95% CI 8 to 52%) from 7.3 to 4.8 per 129 100,000 person-years (Figure 2). There was no indirect effect against the PCV10-related serotypes. 130 The incidence of 19A IPD was 0.69 and 0.74 cases per 100,000 person-years, and that of 6A IPD 131 0.00 and 0.25 cases per 100,000 person-years in the reference and target cohorts, respectively 132 (Figure 3, Supplement Table 2). The incidence of non-PCV10 serotypes was five times higher in 133 the target-cohort compared to the reference cohort, but the confidence intervals were wide and the 134 incidence remained low. 135 Discussion 136 13 15. Palmu AA, Jokinen J, Borys D, et al. Effectiveness of the ten-valent pneumococcal 272 Haemophilus Influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal 273 disease: A cluster randomised trial. Lancet. 2013;381(9862):214-222. doi: 274 https://doi.org/10.1016/S0140-6736(12)61854-6. 275 16. Siira L, Jalava J, Kaijalainen T, Ollgren J, Lyytikainen O, Virolainen A. Antimicrobial 276 resistance in relation to seroand genotypes among invasive Streptococcus Pneumoniae in Finland, 277 2007-2011. Microb Drug Resist. 2014;20(2):124-130. doi: https://doi.org/10.1089/mdr.2013.0156. 278 17. Siira L, Kaijalainen T, Lambertsen L, Nahm MH, Toropainen M, Virolainen A. From Quellung 279 to multiplex PCR, and back when needed, in pneumococcal serotyping. J Clin Microbiol. 280 2012;50(8):2727-2731. doi: https://doi.org/10.1128/JCM.00689-12. 281 18. R Core Team (2013). R: A language and environment for statistical computing. R foundation 282 for statistical computing, Vienna, Austria. https://www.r-project.org/. Updated 2017. Accessed 283 May/16, 2017. 284 19. Feikin DR, Kagucia EW, Loo JD, et al. Serotype-specific changes in invasive pneumococcal 285 disease after pneumococcal conjugate vaccine introduction: A pooled analysis of multiple 286 surveillance sites. PLoS Med. 2013;10(9):e1001517. doi: 287 https://doi.org/10.1371/journal.pmed.1001517. 288 20. Galanis I, Lindstrand A, Darenberg J, et al. Effects of PCV7 and PCV13 on invasive 289 pneumococcal disease and carriage in Stockholm, Sweden. Eur Respir J. 2016;47(4):1208-1218. 290 doi: https://doi.org/10.1183/13993003.01451-2015. 291 14 21. De Wals P, Lefebvre B, Markowski F, et al. Impact of 2+1 pneumococcal conjugate vaccine 292 program in the province of Quebec, Canada. Vaccine. 2014;32(13):1501-1506. doi: 293 https://doi.org/10.1016/j.vaccine.2013.11.028. 294 22. Huang SS, Platt R, Rifas-Shiman SL, Pelton SI, Goldmann D, Finkelstein JA. Post-PCV7 295 changes in colonizing pneumococcal serotypes in 16 Massachusetts communities, 2001 and 2004. 296 Pediatrics. 2005;116(3):e408-13. 297 23. Kellner JD, Scheifele D, Vanderkooi OG, Macdonald J, Church DL, Tyrrell GJ. Effects of 298 routine infant vaccination with the 7-valent pneumococcal conjugate vaccine on nasopharyngeal 299 colonization with Streptococcus Pneumoniae in children in Calgary, Canada. Pediatr Infect Dis J. 300 2008;27(6):526-532. doi: https://doi.org/10.1097/INF.0b013e3181658c5c. 301 24. Domingues CM, Verani JR, Montenegro Renoiner EI, et al. Effectiveness of ten-valent 302 pneumococcal conjugate vaccine against invasive pneumococcal disease in Brazil: A matched case303 control study. Lancet Respir Med. 2014;2(6):464-471. doi: https://doi.org/10.1016/S2213304 2600(14)70060-8. 305 25. Nuorti JP, Rinta-Kokko H, Toropainen M, et al. Evidence of herd protection and serotype 306 replacement in adults after universal 10-valent pneumococcal conjugate vaccination of infants in 307 Finland. 2016;10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD308 10), Glasgow, Scotland. 309 26. Palmu AA, Toropainen M, Kaijalainen T, et al. Direct and indirect effectiveness of the 10310 valent pneumococcal conjugate vaccine against carriage in a cluster randomized trial. Pediatr Infect 311 Dis J. 2017;36(12):1193-1200. doi: https://doi.org/10.1097/INF.0000000000001705. 312 15 27. Van Effelterre T, Moore M, Fierensa F, et al. A dynamic model of pneumococcal infection in 313 the United States: Implications for prevention through vaccination. Vaccine. 2010;28:3650-3660. 314 28. Beall BW, Gertz RE, Hulkower RL, Whitney CG, Moore MR, Brueggemann AB. Shifting 315 genetic structure of invasive serotype 19A pneumococci in the United States. J Infect Dis. 316 2011;203(10):1360-1368. doi: 10.1093/infdis/jir052 [doi]. 317 29. Goossens H, Ferech M, Coenen S, Stephens P, European Surveillance of Antimicrobial 318 Consumption Project Group. Comparison of outpatient systemic antibacterial use in 2004 in the 319 United States and 27 European countries. Clin Infect Dis. 2007;44(8):1091-1095. doi: CID41134 320 [pii]. 321 30. European Centre for Disease Prevention and Control, ECDC. Summary of the latest data on 322 antibiotic consumption in the European Union. 323 https://ecdc.europa.eu/sites/portal/files/documents/antibiotics-consumption-EU-data-2014.pdf. 324 Updated 2014. Accessed 01/26, 2018. 325 31. Palmu AA, Rinta-Kokko H, Nohynek H, Nuorti JP, Jokinen J. Impact of national ten-valent 326 pneumococcal conjugate vaccine program on reducing antimicrobial use and tympanostomy tube 327 placements in Finland. Pediatr Infect Dis J. 2018;37(1):97-102. doi: 328 10.1097/INF.0000000000001810 [doi]. 329 32. Siira L, Toropainen M, Nohynek H, Nuorti JP, Jalava J. Changes in invasive pneumococcal 330 serotypes and antimicrobial susceptibility before and after PCV10 introduction in Finland, 2005331 2014. 2016;10th International Symposium on Pneumococci and Pneumococcal Diseases, Glasgow, 332 Scotland. 333 16 33. Jalava J, Räisänen K(). Bakteerien mikrobilääkeresistenssi Suomessa. 2016;National Institute 334 for Health and Welfare, Finland. In Finnish. 335 34. Toropainen M, Siira L, Jalava J, Palmu AA, Rinta-Kokko H, Nuorti JP. Molecular 336 epidemiology and antimicrobial susceptibility of invasive serotype 19A Streptococcus Pneumoniae 337 in Finnish children, 2007–2015. 2016;10th International Symposium on Pneumococci and 338 Pneumococcal diseases, Glasgow, Scotland. 339 35. Toropainen M. Unpublished observation. 2018. 340 36. Deceuninck G, De Serres G, Boulianne N, Lefebvre B, De Wals P. Effectiveness of three 341 pneumococcal conjugate vaccines to prevent invasive pneumococcal disease in Quebec, Canada. 342 Vaccine. 2015;33(23):2684-2689. doi: https://doi.org/10.1016/j.vaccine.2015.04.005. 343 37. Lipsitch M. Vaccination against colonizing bacteria with multiple serotypes. Proc Natl Acad Sci 344 U S A. 1997;94(12):6571-6576. 345 346 347 17 Conflict of Interest Statement for all authors. 348 National Institute for Health and Welfare has received research funding from GlaxoSmithKline 349 Vaccines for the conduct of a nationwide effectiveness trial of the 10-valent pneumococcal 350 conjugate vaccine. HR-K, AAP, MT, LS, and JJ are co-investigators in these studies. The other 351 authors have no conflicts to disclose. Current study was entirely publicly funded. 352 Authorship contributions 353 HR-K coordinated the data collection, carried out the analyses, interpreted the data and drafted the 354 manuscript; AAP, KA, JPN, HN, and JJ designed the study, interpreted the data and reviewed and 355 revised the manuscript; MT, LS, and MJV supervised the microbiological data quality and reviewed 356 and revised the manuscript; and all authors approved the final manuscript as submitted. 357 358 359 18 Tables and figures 360 Table 1. Incidence rates of invasive pneumococcal disease (IPD) and the corresponding relative and 361 absolute incidence rate reductions, based on the comparison of the PCV10-eligible target cohort 362 (2010-2016) vs. a reference cohort (2002-2008). 363 364 Table 2. Incidence rates of invasive pneumococcal disease (IPD) and the corresponding relative and 365 absolute incidence rate reductions, based on the comparison of an unvaccinated target cohort (2012366 2016) vs. a reference cohort (2006-2010). 367 368 Figure 1. Target and reference cohorts for estimating the overall impact of PCV10 on IPD among 369 vaccine-eligible children (panel A) and unvaccinated children (panel B). 370 371 Figure 2. Incidence rates of invasive pneumococcal disease (IPD) in age groups <2 years (panel A) 372 and 2-5 years (panel B) by serotype group in epidemiological years 6/2002–6/2017. 373 374 Figure 3. Incidence rates of 19A and 6A IPD in age groups <2 years (panel A) and 2-5 years (panel 375 B) in epidemiological years 6/2002–6/2017. 376 377 Figure 4. Incidence of all IPD (first panel) and 19A IPD (second panel) in the PCV10-eligible target 378 and reference cohorts by age group. 379 380 381 19 Supplement table 1. Incidence rates of invasive pneumococcal disease (IPD) of individual PCV10 382 serotypes and the corresponding relative and absolute incidence rate reductions, based on the 383 comparison of the PCV10-eligible target cohort (2010-2016) vs. a reference cohort (2002-2008). 384 385 Supplement table 2. Incidence rates of invasive pneumococcal disease (IPD) of individual PCV10 386 serotypes and the corresponding relative and absolute incidence rate reductions, based on the 387 comparison of an unvaccinated target cohort (2012-2016) vs. a reference cohort (2006-2010). 388 389 Supplement Figure 1. Age-specific cumulative hazards of 19A IPD in the PCV10-eligible target 390 cohort and the reference cohort. 391 392 393 Table 1. Incidence rates of invasive pneumococcal disease (IPD) and the corresponding relative and absolute incidence rate reductions, based on the comparison of the PCV10-eligible target cohort (2010-2016) vs. a reference cohort (2002-2008). Table 2. Incidence rates of invasive pneumococcal disease (IPD) and the corresponding relative and absolute incidence rate reductions, based on the comparison of an unvaccinated target cohort (20122016) vs. a reference cohort (2006-2010). Table 1. Incidence per 100,000 person-years (N) Target cohort vs. reference cohort Reference cohort 2002-2008* Target cohort 2010-2016** Relative rate reduction, % (95% CI) Absolute rate reduction per 100,000 person-years (95% CI) Follow-up yrs 1211504 Follow-up yrs 1243145 Any culture confirmed IPD 42.9 (520) 9.2 (114) 78.6 (73.9, 82.6) 33.8 (29.7, 37.8) PCV10 serotypes 32.3 (391) 1.9 (23) 94.3 (91.5, 96.3) 30.4 (27.1, 33.7) PCV10-related serotypes 6.3 (76) 3.8 (47) 39.7 (13.7, 58.4) 2.5 (0.72, 4.3) Non-PCV10 serotypes 2.3 (28) 3.5 (44) -53.1 (-148.6, 4.1) -1.2 (-2.6, 0.12) Not known 2.1 (25) 0 (0) NA NA *Age 3-78 months, born Jun 2002 – Sep 2008 **Age 3-78 months, born Jun 2010 – Sep 2016 NA = not applicable Table 2. Serotype group Incidence per 100,000 person-years (N) Unvaccinated target cohort vs. reference cohort Reference cohort 2006-2010* Target cohort 2012-2016** Relative rate reduction, % (95% CI) Absolute rate reduction per 100,000 person-years (95% CI) Follow-up yrs 1309618 Follow-up yrs 1221933 Any culture confirmed IPD 7.3 (95) 4.8 (59) 33.4 (8.2, 52.1) 2.4 (0.52, 4.3) PCV10-serotypes 5.9 (77) 2.5 (30) 58.2 (37.1, 73.0) 3.4 (1.8, 5) PCV10-related serotypes 0.69 (9) 1.2 (15) -78.6 (-325.3, 20.5) -0.54 (-1.3, 0.23) Non-PCV10 serotypes 0.23 (3) 1.2 (14) -400.2 (-2069.8, -63.3) -0.92 (-1.8, -0.26) Not known 0.46 (6) 0 (0) NA NA *Age 19-131 months, born Jan 2000 – May 2004 **Age 19-131 months, born Jan 2006 – May 2010 NA = not applicable Age 0 1 2 3 4 5 6 7 8 9 10 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Year (A) PCV10−eligible target cohort 2010 to 2016 Reference cohort 2002 to 2008 Unvaccinated target cohort 2012 to 2016 Reference cohort 2006 to 2010 0 1 2 3 4 5 6 7 8 9 10 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Year (B) Epidemiological year Incidence/100,000 person−years 20 40 60 80 7/2002 7/2003 7/2004 7/2005 7/2006 7/2007 7/2008 7/2009 7/2010 7/2011 7/2012 7/2013 7/2014 7/2015 7/2016 7/2017 FinIP PCV10 (A) Age−group 0−1 years Epidemiological year 20 40 60 80 7/2002 7/2003 7/2004 7/2005 7/2006 7/2007 7/2008 7/2009 7/2010 7/2011 7/2012 7/2013 7/2014 7/2015 7/2016 7/2017 FinIP PCV10 (B) Age−group 2−5 years Serotype groups Any IPD PCV10 PCV10−related Non−PCV10−related