International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact

Rebecca A. Gladstone; Stephanie W. Lo; John A. Lees; Nicholas J. Croucher; Andries J. van Tonder; Jukka Corander; Andrew J. Page; Pekka Marttinen; Leon J. Bentley; Theresa J. Ochoa; Pak Leung Ho; Mignon du Plessis; Jennifer E. Cornick; Brenda Kwambana-Adams; Rachel Benisty; Susan A. Nzenze; Shabir A. Madhi; Paulina A. Hawkins; Dean B. Everett; Martin Antonio; Ron Dagan; Keith P. Klugman; Anne von Gottberg; Lesley McGee; Robert F. Breiman; Stephen D. Bentley

doi:10.1016/j.ebiom.2019.04.021

International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact

Rebecca A. Gladstone, Stephanie W. Lo, John A. Lees, Nicholas J. Croucher, Andries J. van Tonder, Jukka Corander, Andrew J. Page, Pekka Marttinen, Leon J. Bentley, Theresa J. Ochoa, Pak Leung Ho, Mignon du Plessis, Jennifer E. Cornick, Brenda Kwambana-Adams, Rachel Benisty, Susan A. Nzenze, Shabir A. Madhi, Paulina A. Hawkins, Dean B. Everett, Martin AntonioRon Dagan, Keith P. Klugman, Anne von Gottberg, Lesley McGee, Robert F. Breiman, Stephen D. Bentley

Faculty of Health Sciences

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

Abstract

Background: Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background. Methods: Our dataset of 13,454 genomes, combined with four published genomic datasets, represented Africa (40%), Asia (25%), Europe (19%), North America (12%), and South America (5%). These 20,027 pneumococcal genomes were clustered into lineages using PopPUNK, and named Global Pneumococcal Sequence Clusters (GPSCs). From our dataset, we additionally derived serotype and sequence type, and predicted antibiotic sensitivity. We then measured invasiveness using odds ratios that relating prevalence in invasive pneumococcal disease to carriage. Findings: The combined collections (n = 20,027) were clustered into 621 GPSCs. Thirty-five GPSCs observed in our dataset were represented by >100 isolates, and subsequently classed as dominant-GPSCs. In 22/35 (63%) of dominant-GPSCs both non-vaccine serotypes and vaccine serotypes were observed in the years up until, and including, the first year of pneumococcal conjugate vaccine introduction. Penicillin and multidrug resistance were higher (p < .05) in a subset dominant-GPSCs (14/35, 9/35 respectively), and resistance to an increasing number of antibiotic classes was associated with increased recombination (R² = 0.27 p < .0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p < .05) of its antibiogram (mean misclassification error 0.28, SD ± 0.13). We detected increased invasiveness of six genetic backgrounds, when compared to other genetic backgrounds expressing the same serotype. Up to 1.6-fold changes in invasiveness odds ratio were observed. Interpretation: We define GPSCs that can be assigned to any pneumococcal genomic dataset, to aid international comparisons. Existing non-vaccine-serotypes in most GPSCs preclude the removal of these lineages by pneumococcal conjugate vaccines; leaving potential for serotype replacement. A subset of GPSCs have increased resistance, and/or serotype-independent invasiveness.

Original language	English
Pages (from-to)	338-346
Number of pages	9
Journal	EBioMedicine
Volume	43
DOIs	https://doi.org/10.1016/j.ebiom.2019.04.021
State	Published - 1 May 2019

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2019.04.021

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Gladstone, R. A., Lo, S. W., Lees, J. A., Croucher, N. J., van Tonder, A. J., Corander, J., Page, A. J., Marttinen, P., Bentley, L. J., Ochoa, T. J., Ho, P. L., du Plessis, M., Cornick, J. E., Kwambana-Adams, B., Benisty, R., Nzenze, S. A., Madhi, S. A., Hawkins, P. A., Everett, D. B., ... Bentley, S. D. (2019). International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact. EBioMedicine, 43, 338-346. https://doi.org/10.1016/j.ebiom.2019.04.021

@article{29ebcca9c433445bb0da7f553efc3785,

title = "International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact",

abstract = "Background: Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background. Methods: Our dataset of 13,454 genomes, combined with four published genomic datasets, represented Africa (40%), Asia (25%), Europe (19%), North America (12%), and South America (5%). These 20,027 pneumococcal genomes were clustered into lineages using PopPUNK, and named Global Pneumococcal Sequence Clusters (GPSCs). From our dataset, we additionally derived serotype and sequence type, and predicted antibiotic sensitivity. We then measured invasiveness using odds ratios that relating prevalence in invasive pneumococcal disease to carriage. Findings: The combined collections (n = 20,027) were clustered into 621 GPSCs. Thirty-five GPSCs observed in our dataset were represented by >100 isolates, and subsequently classed as dominant-GPSCs. In 22/35 (63%) of dominant-GPSCs both non-vaccine serotypes and vaccine serotypes were observed in the years up until, and including, the first year of pneumococcal conjugate vaccine introduction. Penicillin and multidrug resistance were higher (p < .05) in a subset dominant-GPSCs (14/35, 9/35 respectively), and resistance to an increasing number of antibiotic classes was associated with increased recombination (R2 = 0.27 p < .0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p < .05) of its antibiogram (mean misclassification error 0.28, SD ± 0.13). We detected increased invasiveness of six genetic backgrounds, when compared to other genetic backgrounds expressing the same serotype. Up to 1.6-fold changes in invasiveness odds ratio were observed. Interpretation: We define GPSCs that can be assigned to any pneumococcal genomic dataset, to aid international comparisons. Existing non-vaccine-serotypes in most GPSCs preclude the removal of these lineages by pneumococcal conjugate vaccines; leaving potential for serotype replacement. A subset of GPSCs have increased resistance, and/or serotype-independent invasiveness.",

author = "Gladstone, {Rebecca A.} and Lo, {Stephanie W.} and Lees, {John A.} and Croucher, {Nicholas J.} and {van Tonder}, {Andries J.} and Jukka Corander and Page, {Andrew J.} and Pekka Marttinen and Bentley, {Leon J.} and Ochoa, {Theresa J.} and Ho, {Pak Leung} and {du Plessis}, Mignon and Cornick, {Jennifer E.} and Brenda Kwambana-Adams and Rachel Benisty and Nzenze, {Susan A.} and Madhi, {Shabir A.} and Hawkins, {Paulina A.} and Everett, {Dean B.} and Martin Antonio and Ron Dagan and Klugman, {Keith P.} and {von Gottberg}, Anne and Lesley McGee and Breiman, {Robert F.} and Bentley, {Stephen D.}",

note = "Funding Information: This study was co-funded by the Bill and Melinda Gates Foundation, the Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention. Funding Information: This study was co-funded by the Bill and Melinda Gates Foundation (grant code OPP1034556 ), the Wellcome Sanger Institute (core Wellcome grants 098051 and 206194 ) and the US Centers for Disease Control and Prevention . The funding sources had no role in isolate selection, analysis, or data interpretation. The corresponding authors had full access to the data and are responsible for the final decision to submit for publication. Isolates included from Qatar were collected through research project supported by NPRP 6-496-3-127 from Qatar National Research Foundation (QNRF). Funding Information: We would like to thank all members of the GPS consortium for their collaborative spirit and determination during the monumental task of sampling, extracting and sequencing this dataset, and all contributions to experimental design and input into this manuscript. We also would like to thank members of teams 284 and 81 at the Wellcome Sanger Institute (WSI) for their advice and critique and the pathogen informatics team at the WSI for the pipelines and expertise that made genomic analysis at this scale possible. We would like to thank Diederik van de Beek and Phillip Kremer for their critical review and clinical perspective on the manuscript. This study was co-funded by the Bill and Melinda Gates Foundation, the Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention. This study was co-funded by the Bill and Melinda Gates Foundation (grant code OPP1034556), the Wellcome Sanger Institute (core Wellcome grants 098051 and 206194) and the US Centers for Disease Control and Prevention. The funding sources had no role in isolate selection, analysis, or data interpretation. The corresponding authors had full access to the data and are responsible for the final decision to submit for publication. Isolates included from Qatar were collected through research project supported by NPRP 6-496-3-127 from Qatar National Research Foundation (QNRF). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Isolates for this study were selected from retrospective bacterial collections in each country participating in GPS. Appropriate approvals for use of isolates was obtained from each institution contributing isolates. No tissue material or other biological material was obtained from humans. All information regarding these isolates was anonymised. Dr. Gladstone reports PhD studentship from Pfizer, outside the submitted work; Dr. Lees reports grants from Pfizer, outside the submitted work; Dr. Madhi reports grants from BMGF, during the conduct of the study; grants and personal fees from BMGF, grants from Pfizer, grants from GSK, grants from Sanofi, grants from BIOVAC, outside the submitted work; Dr. Dagan reports grants and personal fees from Pfizer, during the conduct of the study; grants and personal fees from MSD, personal fees from MeMed, outside the submitted work; Dr. von Gottberg reports grants and other from Pfizer, during the conduct of the study; grants and other from Sanofi, outside the submitted work; Dr. Bentley reports personal fees from Pfizer, personal fees from Merck, outside the submitted work. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = may,

day = "1",

doi = "10.1016/j.ebiom.2019.04.021",

language = "English",

volume = "43",

pages = "338--346",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

Gladstone, RA, Lo, SW, Lees, JA, Croucher, NJ, van Tonder, AJ, Corander, J, Page, AJ, Marttinen, P, Bentley, LJ, Ochoa, TJ, Ho, PL, du Plessis, M, Cornick, JE, Kwambana-Adams, B, Benisty, R, Nzenze, SA, Madhi, SA, Hawkins, PA, Everett, DB, Antonio, M, Dagan, R, Klugman, KP, von Gottberg, A, McGee, L, Breiman, RF & Bentley, SD 2019, 'International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact', EBioMedicine, vol. 43, pp. 338-346. https://doi.org/10.1016/j.ebiom.2019.04.021

TY - JOUR

T1 - International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact

AU - Gladstone, Rebecca A.

AU - Lo, Stephanie W.

AU - Lees, John A.

AU - Croucher, Nicholas J.

AU - van Tonder, Andries J.

AU - Corander, Jukka

AU - Page, Andrew J.

AU - Marttinen, Pekka

AU - Bentley, Leon J.

AU - Ochoa, Theresa J.

AU - Ho, Pak Leung

AU - du Plessis, Mignon

AU - Cornick, Jennifer E.

AU - Kwambana-Adams, Brenda

AU - Benisty, Rachel

AU - Nzenze, Susan A.

AU - Madhi, Shabir A.

AU - Hawkins, Paulina A.

AU - Everett, Dean B.

AU - Antonio, Martin

AU - Dagan, Ron

AU - Klugman, Keith P.

AU - von Gottberg, Anne

AU - McGee, Lesley

AU - Breiman, Robert F.

AU - Bentley, Stephen D.

N1 - Funding Information: This study was co-funded by the Bill and Melinda Gates Foundation, the Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention. Funding Information: This study was co-funded by the Bill and Melinda Gates Foundation (grant code OPP1034556 ), the Wellcome Sanger Institute (core Wellcome grants 098051 and 206194 ) and the US Centers for Disease Control and Prevention . The funding sources had no role in isolate selection, analysis, or data interpretation. The corresponding authors had full access to the data and are responsible for the final decision to submit for publication. Isolates included from Qatar were collected through research project supported by NPRP 6-496-3-127 from Qatar National Research Foundation (QNRF). Funding Information: We would like to thank all members of the GPS consortium for their collaborative spirit and determination during the monumental task of sampling, extracting and sequencing this dataset, and all contributions to experimental design and input into this manuscript. We also would like to thank members of teams 284 and 81 at the Wellcome Sanger Institute (WSI) for their advice and critique and the pathogen informatics team at the WSI for the pipelines and expertise that made genomic analysis at this scale possible. We would like to thank Diederik van de Beek and Phillip Kremer for their critical review and clinical perspective on the manuscript. This study was co-funded by the Bill and Melinda Gates Foundation, the Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention. This study was co-funded by the Bill and Melinda Gates Foundation (grant code OPP1034556), the Wellcome Sanger Institute (core Wellcome grants 098051 and 206194) and the US Centers for Disease Control and Prevention. The funding sources had no role in isolate selection, analysis, or data interpretation. The corresponding authors had full access to the data and are responsible for the final decision to submit for publication. Isolates included from Qatar were collected through research project supported by NPRP 6-496-3-127 from Qatar National Research Foundation (QNRF). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Isolates for this study were selected from retrospective bacterial collections in each country participating in GPS. Appropriate approvals for use of isolates was obtained from each institution contributing isolates. No tissue material or other biological material was obtained from humans. All information regarding these isolates was anonymised. Dr. Gladstone reports PhD studentship from Pfizer, outside the submitted work; Dr. Lees reports grants from Pfizer, outside the submitted work; Dr. Madhi reports grants from BMGF, during the conduct of the study; grants and personal fees from BMGF, grants from Pfizer, grants from GSK, grants from Sanofi, grants from BIOVAC, outside the submitted work; Dr. Dagan reports grants and personal fees from Pfizer, during the conduct of the study; grants and personal fees from MSD, personal fees from MeMed, outside the submitted work; Dr. von Gottberg reports grants and other from Pfizer, during the conduct of the study; grants and other from Sanofi, outside the submitted work; Dr. Bentley reports personal fees from Pfizer, personal fees from Merck, outside the submitted work. Publisher Copyright: © 2019 The Authors

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background: Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background. Methods: Our dataset of 13,454 genomes, combined with four published genomic datasets, represented Africa (40%), Asia (25%), Europe (19%), North America (12%), and South America (5%). These 20,027 pneumococcal genomes were clustered into lineages using PopPUNK, and named Global Pneumococcal Sequence Clusters (GPSCs). From our dataset, we additionally derived serotype and sequence type, and predicted antibiotic sensitivity. We then measured invasiveness using odds ratios that relating prevalence in invasive pneumococcal disease to carriage. Findings: The combined collections (n = 20,027) were clustered into 621 GPSCs. Thirty-five GPSCs observed in our dataset were represented by >100 isolates, and subsequently classed as dominant-GPSCs. In 22/35 (63%) of dominant-GPSCs both non-vaccine serotypes and vaccine serotypes were observed in the years up until, and including, the first year of pneumococcal conjugate vaccine introduction. Penicillin and multidrug resistance were higher (p < .05) in a subset dominant-GPSCs (14/35, 9/35 respectively), and resistance to an increasing number of antibiotic classes was associated with increased recombination (R2 = 0.27 p < .0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p < .05) of its antibiogram (mean misclassification error 0.28, SD ± 0.13). We detected increased invasiveness of six genetic backgrounds, when compared to other genetic backgrounds expressing the same serotype. Up to 1.6-fold changes in invasiveness odds ratio were observed. Interpretation: We define GPSCs that can be assigned to any pneumococcal genomic dataset, to aid international comparisons. Existing non-vaccine-serotypes in most GPSCs preclude the removal of these lineages by pneumococcal conjugate vaccines; leaving potential for serotype replacement. A subset of GPSCs have increased resistance, and/or serotype-independent invasiveness.

AB - Background: Pneumococcal conjugate vaccines have reduced the incidence of invasive pneumococcal disease, caused by vaccine serotypes, but non-vaccine-serotypes remain a concern. We used whole genome sequencing to study pneumococcal serotype, antibiotic resistance and invasiveness, in the context of genetic background. Methods: Our dataset of 13,454 genomes, combined with four published genomic datasets, represented Africa (40%), Asia (25%), Europe (19%), North America (12%), and South America (5%). These 20,027 pneumococcal genomes were clustered into lineages using PopPUNK, and named Global Pneumococcal Sequence Clusters (GPSCs). From our dataset, we additionally derived serotype and sequence type, and predicted antibiotic sensitivity. We then measured invasiveness using odds ratios that relating prevalence in invasive pneumococcal disease to carriage. Findings: The combined collections (n = 20,027) were clustered into 621 GPSCs. Thirty-five GPSCs observed in our dataset were represented by >100 isolates, and subsequently classed as dominant-GPSCs. In 22/35 (63%) of dominant-GPSCs both non-vaccine serotypes and vaccine serotypes were observed in the years up until, and including, the first year of pneumococcal conjugate vaccine introduction. Penicillin and multidrug resistance were higher (p < .05) in a subset dominant-GPSCs (14/35, 9/35 respectively), and resistance to an increasing number of antibiotic classes was associated with increased recombination (R2 = 0.27 p < .0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p < .05) of its antibiogram (mean misclassification error 0.28, SD ± 0.13). We detected increased invasiveness of six genetic backgrounds, when compared to other genetic backgrounds expressing the same serotype. Up to 1.6-fold changes in invasiveness odds ratio were observed. Interpretation: We define GPSCs that can be assigned to any pneumococcal genomic dataset, to aid international comparisons. Existing non-vaccine-serotypes in most GPSCs preclude the removal of these lineages by pneumococcal conjugate vaccines; leaving potential for serotype replacement. A subset of GPSCs have increased resistance, and/or serotype-independent invasiveness.

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U2 - 10.1016/j.ebiom.2019.04.021

DO - 10.1016/j.ebiom.2019.04.021

M3 - Article

C2 - 31003929

AN - SCOPUS:85064282117

VL - 43

SP - 338

EP - 346

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -

International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impact

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ASJC Scopus subject areas

UN SDGs

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