Diversity of Serotype Replacement After Pneumococcal Conjugate Vaccine Implementation in Europe

Abstract

Streptococcus pneumoniae is the leading cause of bacterial infections in children, including meningitis, bacteremia, bacteremic pneumonia, empyema, and mucosal infections such as otitis media and non-bacteremic pneumonia. After the implementation of pneumococcal conjugate vaccines (PCVs), worldwide, the burden of invasive pneumococcal diseases (IPDs) and non-invasive pneumococcal diseases due to vaccine serotypes (VTs) greatly decreased in children.1Savulescu C. Krizova P. Lepoutre A. Mereckiene J. Vestrheim D.F. Ciruela P. et al.Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study.Lancet Respir Med. 2017; 5: 648-656Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar However, since 2015, several European countries have reported an increased incidence of IPDs due to non-vaccine serotypes (NVTs), which seemed variable across countries in terms of magnitude, serotypes involved, and clinical entities.1Savulescu C. Krizova P. Lepoutre A. Mereckiene J. Vestrheim D.F. Ciruela P. et al.Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study.Lancet Respir Med. 2017; 5: 648-656Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 2Ladhani S.N. Collins S. Djennad A. Sheppard C.L. Borrow R. Fry N.K. et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 3Rokney A. Ben-Shimol S. Korenman Z. Porat N. Gorodnitzky Z. Givon-Lavi N. et al.Emergence of Streptococcus pneumoniae serotype 12F after sequential introduction of 7- and 13-valent vaccines, Israel.Emerg Infect Dis. 2018; 24: 453-461Crossref PubMed Scopus (33) Google Scholar, 4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar This led to questions regarding the long-term benefit of PCVs. This commentary presents an overview of serotype replacement in pneumococcal carriage and diseases in Europe, with a focus on IPDs. The aim is to raise awareness among pediatricians and healthcare professionals of the potential factors involved in the phenomenon of serotype replacement diversity after PCV implementation. In addition, we analyze the potential factors involved in this phenomenon. We selected European observational studies assessing the impact of PCV10 and PCV13 beyond 5 years after their implementation at the population level in children. We reviewed the literature in MEDLINE via PubMed, with no time or language restriction (last search June 30, 2019). The search algorithm was based on a combination of terms related to “13-or 10-valent PCV,” “pneumococcal diseases or pneumococcal carriage,” and “impact/effect/change.” We completed this search by screening the reference lists of the selected articles. In the nasopharyngeal microbiota, following the striking collapse of VTs, several NVTs emerged, which resulted in an overall pneumococcal carriage rate close to or identical to the pre-PCV level.5Rybak A. Levy C. Bonacorsi S. Béchet S. Vié le Sage F. Elbez A. et al.Antibiotic resistance of potential otopathogens isolated from nasopharyngeal flora of children with acute otitis media before, during and after pneumococcal conjugate vaccines implementation.Pediatr Infect Dis J. 2018; 37: e72-e78Crossref PubMed Scopus (11) Google Scholar, 6Ben-Shimol S. Givon-Lavi N. Greenberg D. Dagan R. Pneumococcal nasopharyngeal carriage in children <5 years of age visiting the pediatric emergency room in relation to PCV7 and PCV13 introduction in southern Israel.Hum Vaccines Immunother. 2016; 12: 268-276Crossref Scopus (41) Google Scholar In European countries where nasopharyngeal carriage studies have been performed, the main predominant serotypes are now 15B/C, 11A, 23B, 15A, 35B, 10A, 21, and 23A.5Rybak A. Levy C. Bonacorsi S. Béchet S. Vié le Sage F. Elbez A. et al.Antibiotic resistance of potential otopathogens isolated from nasopharyngeal flora of children with acute otitis media before, during and after pneumococcal conjugate vaccines implementation.Pediatr Infect Dis J. 2018; 37: e72-e78Crossref PubMed Scopus (11) Google Scholar, 6Ben-Shimol S. Givon-Lavi N. Greenberg D. Dagan R. Pneumococcal nasopharyngeal carriage in children <5 years of age visiting the pediatric emergency room in relation to PCV7 and PCV13 introduction in southern Israel.Hum Vaccines Immunother. 2016; 12: 268-276Crossref Scopus (41) Google Scholar, 7Kandasamy R. Voysey M. Collins S. Berbers G. Robinson H. Noel I. et al.Persistent circulation of vaccine serotypes and serotype replacement after five years of UK infant immunisation with PCV13.J Infect Dis. 2019; (in press)Crossref PubMed Scopus (24) Google Scholar This distribution seems relatively similar among countries.5Rybak A. Levy C. Bonacorsi S. Béchet S. Vié le Sage F. Elbez A. et al.Antibiotic resistance of potential otopathogens isolated from nasopharyngeal flora of children with acute otitis media before, during and after pneumococcal conjugate vaccines implementation.Pediatr Infect Dis J. 2018; 37: e72-e78Crossref PubMed Scopus (11) Google Scholar, 6Ben-Shimol S. Givon-Lavi N. Greenberg D. Dagan R. Pneumococcal nasopharyngeal carriage in children <5 years of age visiting the pediatric emergency room in relation to PCV7 and PCV13 introduction in southern Israel.Hum Vaccines Immunother. 2016; 12: 268-276Crossref Scopus (41) Google Scholar, 7Kandasamy R. Voysey M. Collins S. Berbers G. Robinson H. Noel I. et al.Persistent circulation of vaccine serotypes and serotype replacement after five years of UK infant immunisation with PCV13.J Infect Dis. 2019; (in press)Crossref PubMed Scopus (24) Google Scholar If we consider IPDs as a unique clinical entity, the serotypes implicated in replacement are more diverse among countries. The Table2Ladhani S.N. Collins S. Djennad A. Sheppard C.L. Borrow R. Fry N.K. et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 3Rokney A. Ben-Shimol S. Korenman Z. Porat N. Gorodnitzky Z. Givon-Lavi N. et al.Emergence of Streptococcus pneumoniae serotype 12F after sequential introduction of 7- and 13-valent vaccines, Israel.Emerg Infect Dis. 2018; 24: 453-461Crossref PubMed Scopus (33) Google Scholar, 4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 7Kandasamy R. Voysey M. Collins S. Berbers G. Robinson H. Noel I. et al.Persistent circulation of vaccine serotypes and serotype replacement after five years of UK infant immunisation with PCV13.J Infect Dis. 2019; (in press)Crossref PubMed Scopus (24) Google Scholar, 8European Centre for Disease Prevention and ControlInvasive pneumococcal disease - annual epidemiological report for 2017. ECDC, Solna, Sweden2017https://ecdc.europa.eu/en/publications-data/invasive-pneumococcal-disease-annual-epidemiological-report-2017Google Scholar, 9Levy C. Varon E. Ouldali N. Béchet S. Bonacorsi S. Cohen R. Changes in invasive pneumococcal disease spectrum after 13 valent pneumococcal conjugate vaccine implementation.Clin Infect Dis. 2019; (in press)Crossref Scopus (14) Google Scholar, 10Desmet S. Verhaegen J. Van Ranst M. Peetermans W. Lagrou K. Switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10: a defendable approach?.Lancet Infect Dis. 2018; 18: 830-831Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 11Naucler P. Galanis I. Morfeldt E. Darenberg J. Örtqvist Å. Henriques-Normark B. Comparison of the impact of pneumococcal conjugate vaccine 10 or pneumococcal conjugate vaccine 13 on invasive pneumococcal disease in equivalent populations.Clin Infect Dis. 2017; 65: 1780-1789Crossref PubMed Scopus (89) Google Scholar, 12Weinberger R. von Kries R. van der Linden M. Rieck T. Siedler A. Falkenhorst G. Invasive pneumococcal disease in children under 16 years of age: incomplete rebound in incidence after the maximum effect of PCV13 in 2012/13 in Germany.Vaccine. 2018; 36: 572-577Crossref PubMed Scopus (30) Google Scholar (available at www.jpeds.com) lists the relevant selected articles reporting the main replacement serotypes. In England and Wales, the overall IPD incidence increased after 2015,2Ladhani S.N. Collins S. Djennad A. Sheppard C.L. Borrow R. Fry N.K. et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar but young children were less affected.2Ladhani S.N. Collins S. Djennad A. Sheppard C.L. Borrow R. Fry N.K. et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar In infected children <2 years old, the main NVTs were 12F, 8, and 10A. A study from the United Kingdom reported an increase in incidence of serotypes 12F, 24F, and 23B in 2015.7Kandasamy R. Voysey M. Collins S. Berbers G. Robinson H. Noel I. et al.Persistent circulation of vaccine serotypes and serotype replacement after five years of UK infant immunisation with PCV13.J Infect Dis. 2019; (in press)Crossref PubMed Scopus (24) Google Scholar In Israel, Rokney et al described a steady increase in incidence of IPDs due to serotype 12F, in all age groups, including children <2 years old.3Rokney A. Ben-Shimol S. Korenman Z. Porat N. Gorodnitzky Z. Givon-Lavi N. et al.Emergence of Streptococcus pneumoniae serotype 12F after sequential introduction of 7- and 13-valent vaccines, Israel.Emerg Infect Dis. 2018; 24: 453-461Crossref PubMed Scopus (33) Google Scholar In addition, the frequency of serotype 2 in IPD increased, but with an epidemic evolution. In Germany, the main NVTs involved were serotypes 10A and 24F during 2014-2016.12Weinberger R. von Kries R. van der Linden M. Rieck T. Siedler A. Falkenhorst G. Invasive pneumococcal disease in children under 16 years of age: incomplete rebound in incidence after the maximum effect of PCV13 in 2012/13 in Germany.Vaccine. 2018; 36: 572-577Crossref PubMed Scopus (30) Google Scholar, 13Perniciaro S. Imöhl M. Fitzner C. van der Linden M. Regional variations in serotype distribution and vaccination status in children under six years of age with invasive pneumococcal disease in Germany.PLoS One. 2019; 14: e0210278Crossref Scopus (5) Google Scholar In France, there was an increase in pneumococcal meningitis incidence after 2015, mainly affecting children <2 years old.4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar This increase was related to serotype 24F, which accounted for 23% of cases in children <2 years old in 2016.4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The other main NVTs reported were 15B/C, 23B, and 12F.4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google ScholarTableSerotype distribution in IPDs in European countries 5 years after high-valence PCV implementation in childrenCountries/schedules/vaccination coveragesStudy yearsType of IPDType of studyPopulation of serotype distributionSample sizeSerotypes involved in the last available year or periodECDC 2017 report8European Centre for Disease Prevention and ControlInvasive pneumococcal disease - annual epidemiological report for 2017. ECDC, Solna, Sweden2017https://ecdc.europa.eu/en/publications-data/invasive-pneumococcal-disease-annual-epidemiological-report-2017Google Scholar2013-2017Overall IPDNational IPD surveillance system of 29 European countriesChildren <1 y old in 20175283 (10.0%)10A (8.9%)8 (8.7%)24F (8.1%)19A (6.5%)Children 1-4 y old in 201781224F (12.1%)12F (9.2%)19A (7.6%)3 (7.4%)23B (6.4%)Children <5 y old in 2017134024F (10.5%)3 (8.4%)12F (7.8%)19A (7.2%)10A (6.9%)England/Wales (Ladhani et al)2Ladhani S.N. Collins S. Djennad A. Sheppard C.L. Borrow R. Fry N.K. et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Abstract Full Text Full Text PDF PubMed Scopus (243) Google ScholarPCV7 in 2006, PCV13 in 20102, 4, 13 moVC ≥3 doses: >92% since their introduction2000-2017Overall IPDNational prospective laboratory-based surveillanceChildren <5 years old in 2016-201733112F (14.2%)8 (10.0%)10A (8.2%)15B/C (7.9%)23B (6.3%)England/Wales (Kandasamy et al)7Kandasamy R. Voysey M. Collins S. Berbers G. Robinson H. Noel I. et al.Persistent circulation of vaccine serotypes and serotype replacement after five years of UK infant immunisation with PCV13.J Infect Dis. 2019; (in press)Crossref PubMed Scopus (24) Google Scholar2010-2015Overall IPDRegional prospective laboratory-based surveillanceChildren <5 y old in 201540812F (12.0%)24F (7.4%)23B (6.9%)15B/C (6.6%)22F (5.9%)France (Ouldali et al)4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google ScholarPCV7 in 2003, PCV13 in 20102, 4, 12 moVC ≥3 doses: >91% since 20112001-2016MeningitisNational prospective active laboratory and hospital-based surveillanceChildren <15 y old in 2015-201614324F (21%)15B/C (8%)23B (6%)22F (6%)12F (5%)France (Levy et al)9Levy C. Varon E. Ouldali N. Béchet S. Bonacorsi S. Cohen R. Changes in invasive pneumococcal disease spectrum after 13 valent pneumococcal conjugate vaccine implementation.Clin Infect Dis. 2019; (in press)Crossref Scopus (14) Google Scholar2011-2016Overall IPDNational prospective active laboratory-based surveillanceChildren <15 y old in 201615224F (16.1%)15B/C (7.1%)23B (7.1%)12F (6.6%)10A (6.6%)Israel (Rokney et al)3Rokney A. Ben-Shimol S. Korenman Z. Porat N. Gorodnitzky Z. Givon-Lavi N. et al.Emergence of Streptococcus pneumoniae serotype 12F after sequential introduction of 7- and 13-valent vaccines, Israel.Emerg Infect Dis. 2018; 24: 453-461Crossref PubMed Scopus (33) Google ScholarPCV7 in 2009, PCV13 in 20102, 4, 12 moVC ≥2 doses: >95% since 20112009-2016Overall IPDNational prospective active population-based surveillanceChildren <15 y old in 201611912F (26%)Belgium (Desmet et al)10Desmet S. Verhaegen J. Van Ranst M. Peetermans W. Lagrou K. Switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10: a defendable approach?.Lancet Infect Dis. 2018; 18: 830-831Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar2006-2017Overall IPDPassive laboratory-based surveillanceChildren <2 y old in 201715419A (13.6%)Sweden (Naucler et al)11Naucler P. Galanis I. Morfeldt E. Darenberg J. Örtqvist Å. Henriques-Normark B. Comparison of the impact of pneumococcal conjugate vaccine 10 or pneumococcal conjugate vaccine 13 on invasive pneumococcal disease in equivalent populations.Clin Infect Dis. 2017; 65: 1780-1789Crossref PubMed Scopus (89) Google ScholarPCV7 in 2007, PCV10 or 13 in 2010.3, 5, 12 moVC ≥3 doses: ≥97%2005-2016Overall IPDNational prospective laboratory and hospital-based surveillanceChildren <5 y old in 2013-2016120NVT (32.7%)3 (13.7%)19A (11.8%)Germany (Weinberger et al)12Weinberger R. von Kries R. van der Linden M. Rieck T. Siedler A. Falkenhorst G. Invasive pneumococcal disease in children under 16 years of age: incomplete rebound in incidence after the maximum effect of PCV13 in 2012/13 in Germany.Vaccine. 2018; 36: 572-577Crossref PubMed Scopus (30) Google ScholarPCV7 in 2001, PCV10 in 2009, PCV13 in 20102, 4, 11/14 monthsVC ≥2 doses: ≥96%1997-2016Overall IPDNational prospective laboratory and hospital-based surveillanceChildren <15 y old in 2014-201616410A (17.1%)24F (13.4%)15C (9.1%)12F (8.5%)38 (7.3%)ECDC, European Centre for Disease Prevention and Control; VC, vaccination coverage. Open table in a new tab ECDC, European Centre for Disease Prevention and Control; VC, vaccination coverage. Among European countries where PCV10 was implemented, some differences in the replacement dynamics were reported. In Belgium, PCV13 was implemented in 2011 and switched to PCV10 during 2015-2016. Since 2016, the IPD incidence due to serotype 19A has increased in children <2 years.10Desmet S. Verhaegen J. Van Ranst M. Peetermans W. Lagrou K. Switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10: a defendable approach?.Lancet Infect Dis. 2018; 18: 830-831Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This serotype became the first serotype in IPD.10Desmet S. Verhaegen J. Van Ranst M. Peetermans W. Lagrou K. Switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10: a defendable approach?.Lancet Infect Dis. 2018; 18: 830-831Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Finland introduced PCV10 in 2010. The incidence of 19A IPD did not significantly change from 2010 to 2016, but this serotype ranked first during this period.14Rinta-Kokko H. Palmu A.A. Auranen K. Nuorti J.P. Toropainen M. Siira L. et al.Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland.Vaccine. 2018; 36: 1934-1940Crossref PubMed Scopus (41) Google Scholar Also in Sweden, where PCV13 or PCV10 was implemented depending on the county, the incidence of 19A IPD did not differ among counties with PCV10 and those with PCV13.11Naucler P. Galanis I. Morfeldt E. Darenberg J. Örtqvist Å. Henriques-Normark B. Comparison of the impact of pneumococcal conjugate vaccine 10 or pneumococcal conjugate vaccine 13 on invasive pneumococcal disease in equivalent populations.Clin Infect Dis. 2017; 65: 1780-1789Crossref PubMed Scopus (89) Google Scholar Overall, for countries implementing PCV13 or PCV10, reports highlighted the marked heterogeneity both in magnitude of replacement in IPD and serotypes involved. In the 2017 annual report of the European Centre for Disease Prevention and Control,8European Centre for Disease Prevention and ControlInvasive pneumococcal disease - annual epidemiological report for 2017. ECDC, Solna, Sweden2017https://ecdc.europa.eu/en/publications-data/invasive-pneumococcal-disease-annual-epidemiological-report-2017Google Scholar based on data from 29 European countries, when summarizing serotypes implicated in IPD in children <5 years old, serotype 24F ranked first (10.6% of cases), followed by serotypes 3 (8.5%), 12F (7.8%), 19A (7.2%), and 10A (6.9%).8European Centre for Disease Prevention and ControlInvasive pneumococcal disease - annual epidemiological report for 2017. ECDC, Solna, Sweden2017https://ecdc.europa.eu/en/publications-data/invasive-pneumococcal-disease-annual-epidemiological-report-2017Google Scholar It has become evident that IPD cannot be considered a homogeneous entity; moreover, we have to assess the impact of PCV implementation on noninvasive pneumococcal disease cases. For meningitis, a systematic review15Koelman D.L.H. Brouwer M.C. van de Beek D. Resurgence of pneumococcal meningitis in Europe and Northern America.Clin Microbiol Infect. 2019; (in press)PubMed Google Scholar highlighted a marked increase in number of cases due to emerging NVTs in several countries, especially France.4Ouldali N. Levy C. Varon E. Bonacorsi S. Béchet S. Cohen R. et al.Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.Lancet Infect Dis. 2018; 18: 983-991Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 15Koelman D.L.H. Brouwer M.C. van de Beek D. Resurgence of pneumococcal meningitis in Europe and Northern America.Clin Microbiol Infect. 2019; (in press)PubMed Google Scholar By contrast, for bacteremic pneumonia and pneumonia with pleural effusion, no increase in cases was reported in France16Ouldali N. Levy C. Minodier P. Morin L. Biscardi S. Aurel M. et al.Long-term association of 13-valent pneumococcal conjugate vaccine implementation with rates of community-acquired pneumonia in children.JAMA Pediatr. 2019; 173: 362-370Crossref PubMed Scopus (24) Google Scholar and England,17Thorrington D. Andrews N. Stowe J. Miller E. van Hoek A.J. Elucidating the impact of the pneumococcal conjugate vaccine programme on pneumonia, sepsis and otitis media hospital admissions in England using a composite control.BMC Med. 2018; 16: 13Crossref PubMed Scopus (46) Google Scholar with a small increase in cases of empyema in Germany.18Liese J.G. Schoen C. van der Linden M. Lehmann L. Goettler D. Keller S. et al.Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study.Clin Microbiol Infect. 2019; 25: 857-864Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar These different trends between these clinical entities agree with a recent study comparing the spectrum of IPD over time in the PCV13 era and the specific tropism of VTs and NVTs.9Levy C. Varon E. Ouldali N. Béchet S. Bonacorsi S. Cohen R. Changes in invasive pneumococcal disease spectrum after 13 valent pneumococcal conjugate vaccine implementation.Clin Infect Dis. 2019; (in press)Crossref Scopus (14) Google Scholar The frequency of pneumonia greatly decreased but not that of meningitis or bacteremia without source.9Levy C. Varon E. Ouldali N. Béchet S. Bonacorsi S. Cohen R. Changes in invasive pneumococcal disease spectrum after 13 valent pneumococcal conjugate vaccine implementation.Clin Infect Dis. 2019; (in press)Crossref Scopus (14) Google Scholar Finally, the incidence of noninvasive pneumonia and otitis media seems not affected by the serotype replacement.19Wiese A.D. Huang X. Yu C. Mitchel E.F. Kyaw M.H. Griffin M.R. et al.Changes in otitis media episodes and pressure equalization tube insertions among young children following introduction of the 13-valent pneumococcal conjugate vaccine: a birth-cohort based study.Clin Infect Dis. 2019; (in press)Crossref Scopus (11) Google Scholar, 20Fortanier A.C. Venekamp R.P. Hoes A.W. Schilder A.G.M. Does pneumococcal conjugate vaccination affect onset and risk of first acute otitis media and recurrences? A primary care-based cohort study.Vaccine. 2019; 37: 1528-1532Crossref Scopus (13) Google Scholar Several data have suggest that the PCV implemented (PCV10 or PCV13) may affect the distribution of NVTs in IPD.1Savulescu C. Krizova P. Lepoutre A. Mereckiene J. Vestrheim D.F. Ciruela P. et al.Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study.Lancet Respir Med. 2017; 5: 648-656Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 10Desmet S. Verhaegen J. Van Ranst M. Peetermans W. Lagrou K. Switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10: a defendable approach?.Lancet Infect Dis. 2018; 18: 830-831Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Vaccine schedules or vaccine coverage also can affect the evolution of pneumococcal epidemiology, but they do not seem very different across European countries (Table). Because antibiotic use also induces a selective pressure on pneumococcal strains from nasopharyngeal microbiota and because some NVT strains are resistant to antibiotics, the level of antibiotic consumption in a country undoubtedly plays a role,21Ouldali N. Cohen R. Levy C. Gelbert-Baudino N. Seror E. Corrard F. et al.Pneumococcal susceptibility to antibiotics in carriage: a 17 year time series analysis of the adaptive evolution of non-vaccine emerging serotypes to a new selective pressure environment.J Antimicrob Chemother. 2019; (in press)Crossref Scopus (7) Google Scholar with large differences in antibiotic use in Europe. Ten years ago, after PCV7 implementation, the emergence of multidrug-resistant serotype 19A was worrying in many countries. This increase seemed more marked in countries with a high antibiotic consumption, which offered an ecologic advantage for this serotype. Similarly, we hypothesize that the prevalence of penicillin non-susceptible serotype 24F has significantly increased in France, in part because of high antibiotic consumption. Several other epidemiologic factors pre-existing to PCV implementation must be considered (Figure; available at www.jpeds.com). In the pre-PCV7 era, the variability in prevalence of NVTs was notable throughout Europe and obviously has affected the serotype distribution after PCV implementation consecutive to the collapse of VTs.22Lewnard J.A. Hanage W.P. Making sense of differences in pneumococcal serotype replacement.Lancet Infect Dis. 2019; 19: e213-e220Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Furthermore, young children, the main pneumococcus carriers, are largely involved in its transmission. Thus, the factors affecting both carriage and transmission (day care center attendance, birth rate, crowding, etc) can play a role in the serotype replacement.22Lewnard J.A. Hanage W.P. Making sense of differences in pneumococcal serotype replacement.Lancet Infect Dis. 2019; 19: e213-e220Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Dynamic models may be suitable to better assess the specific role of each factor in the complex phenomenon of replacement. The link between the serotype distribution in carriage and diversity in pneumococcal disease strongly depends on the respective disease potential of each serotype.23Balsells E. Dagan R. Yildirim I. Gounder P.P. Steens A. Muñoz-Almagro C. et al.The relative invasive disease potential of Streptococcus pneumoniae among children after PCV introduction: a systematic review and meta-analysis.J Infect. 2018; 77: 368-378Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Of note, serotypes 12F and 24F, the predominant emerging NVTs causing IPD in children in Europe, have high disease potential. Indeed, even a small increase in carriage prevalence can have a strong impact on IPD incidence and serotype distribution,23Balsells E. Dagan R. Yildirim I. Gounder P.P. Steens A. Muñoz-Almagro C. et al.The relative invasive disease potential of Streptococcus pneumoniae among children after PCV introduction: a systematic review and meta-analysis.J Infect. 2018; 77: 368-378Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar which may explain why countries with similar overall carriage distribution can exhibit various trends in IPD serotype distribution. Furthermore, recent studies showed that among pneumococcal isolates of a given serotype, several clonal lineages can be represented, with a likely difference in their disease potential.22Lewnard J.A. Hanage W.P. Making sense of differences in pneumococcal serotype replacement.Lancet Infect Dis. 2019; 19: e213-e220Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 24Lo S.W. Gladstone R.A. van Tonder A.J. Lees J.A. du Plessis M. Benisty R. et al.Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study.Lancet Infect Dis. 2019; 19: 759-769Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Conversely, these studies also revealed that one single lineage can result in a country-specific different serotype.24Lo S.W. Gladstone R.A. van Tonder A.J. Lees J.A. du Plessis M. Benisty R. et al.Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study.Lancet Infect Dis. 2019; 19: 759-769Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar After more than 5 years of PCV10 or PCV13 implementation, the serotype-replacement scenario still seems highly dynamic. Regardless, the magnitude and diversity of serotype replacement invite us to consider next-generation PCVs. The PCV15 formulation includes serotypes 22F and 33F, which to date may not represent a high disease burden in Europe in young children. Nevertheless, an expected better immunogenicity of this vaccine against serotype 3, which remains highly prevalent, gives hope for a greater impact on pneumococcal disease.25Hurtado K. Platt H. Shekar T. et al.A phase 2, double-blind, randomized, multicenter trial to evaluate the safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (pcv15) compared to pcv13 in healthy infants.in: Paper presented at the 37th Annual Meeting of the European Society for Paediatric Infectious Diseases, Abstract N° ESPID19-0162. May 6-11. 2019Google Scholar PCV20, with 5 additional serotypes (8, 10A, 11A, 12F, 15B), might have substantial benefit in countries reporting a recent increase in IPD incidence in children. Neither next-generation PCVs nor the pneumococcal polysaccharidic 23-valent vaccine include serotype 24F in their formulation, which could become a major issue for European countries in the near future. Lastly, assessing the impact of next-generation PCVs cannot be limited to IPDs. We thank Dr Shalom Ben-Shimol from The Pediatric Infectious Disease Unit, Soroka University Medical Center, Beer-Sheva, Israel, for sharing data.