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Now published in The Lancet

International Genomic Definition of Pneumococcal Lineages, to Contextualise Disease, Antibiotic Resistance and Vaccine Impact

88 Pages Posted: 28 Mar 2019

See all articles by Rebecca Gladstone

Rebecca Gladstone

Wellcome Genome Campus - Parasites and Microbes

Stephanie W. Lo

Wellcome Genome Campus - Parasites and Microbes

John A. Lees

New York University (NYU) - Grossman School of Medicine

Nicholas J. Croucher

Imperial College London - Department of Infectious Disease

Andries J. van Tonder

Wellcome Genome Campus - Parasites and Microbes

Jukka Corander

Wellcome Genome Campus - Parasites and Microbes

Andrew J. Page

Wellcome Genome Campus - Parasites and Microbes

Pekka Marttinen

Helsinki Institute for Information Technology

Leon J. Bentley

Wellcome Genome Campus - Parasites and Microbes

Theresa J. Ochoa

Universidad Peruana Cayetano Heredia

Pak Leung Ho

The University of Hong Kong - Queen Mary Hospital

Mignon du Plessis

National Health Laboratory Services (NHLS) - Centre for Respiratory Diseases and Meningitis

Jennifer E. Cornick

University of Malawi - Malawi-Liverpool-Wellcome Trust Clinical Research Programme

Brenda Kwambana-Adams

London School of Hygiene & Tropical Medicine - Medical Research Council Unit: The Gambia

Rachel Benisty

Ben-Gurion University of the Negev - Faculty of Health Science

Susan A. Nzenze

University of the Witwatersrand

Shabir A. Madhi

University of the Witwatersrand - Vaccines and Infectious Diseases Analytics Research Unit

Paulina A. Hawkins

Emory University - Rollins School of Public Health

Dean B. Everett

University of Edinburgh

Martin Antonio

London School of Hygiene & Tropical Medicine - Medical Research Council Unit: The Gambia

Ron Dagan

Ben-Gurion University of the Negev - Faculty of Health Science

Keith P. Klugman

Emory University - Rollins School of Public Health

Anne von Gottberg

National Health Laboratory Services (NHLS) - Centre for Respiratory Diseases and Meningitis; University of the Witwatersrand - School of Pathology

Lesley McGee

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

Robert F. Breiman

Emory University - Rollins School of Public Health

Stephen D. Bentley

Wellcome Sanger Institute - Parasites and Microbes

The Global Pneumococcal Sequencing Consortium

Independent

More...

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, relating prevalence in 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 pre-PCV.   Penicillin and multidrug resistance were higher (p<0.05) 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<0.0001). In 28/35 dominant-GPSCs, the country of isolation was a significant predictor (p<0.05) 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, equivalent to the fold change in invasiveness odds ratio between serotype 35A and 18C.

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.

Funding: 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.

Declaration of Interest: 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.

Ethical Approval: 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.

Keywords: Streptococcus pneumoniae, Pneumococcal, Whole Genome Sequencing, Population Structure, Antibiotic resistance, Invasiveness

Suggested Citation

Gladstone, Rebecca and Lo, Stephanie W. and Lees, John A. and Croucher, Nicholas J. and van Tonder, Andries J. and Corander, Jukka and Page, Andrew J. and Marttinen, Pekka and Bentley, Leon J. and Ochoa, Theresa J. and Ho, Pak Leung and du Plessis, Mignon and Cornick, Jennifer E. and Kwambana-Adams, Brenda and Benisty, Rachel and Nzenze, Susan A. and Madhi, Shabir A. and Hawkins, Paulina A. and Everett, Dean B. and Antonio, Martin and Dagan, Ron and Klugman, Keith P. and von Gottberg, Anne and McGee, Lesley and Breiman, Robert F. and Bentley, Stephen D. and Consortium, The Global Pneumococcal Sequencing, International Genomic Definition of Pneumococcal Lineages, to Contextualise Disease, Antibiotic Resistance and Vaccine Impact (March 26, 2019). Available at SSRN: https://ssrn.com/abstract=3360095 or http://dx.doi.org/10.2139/ssrn.3360095

Rebecca Gladstone (Contact Author)

Wellcome Genome Campus - Parasites and Microbes ( email )

Hinxton
United Kingdom

Stephanie W. Lo

Wellcome Genome Campus - Parasites and Microbes

Hinxton
United Kingdom

John A. Lees

New York University (NYU) - Grossman School of Medicine

550 First Ave.
VZ30, Office 626
New York, NY 10016
United States

Nicholas J. Croucher

Imperial College London - Department of Infectious Disease

United Kingdom

Andries J. Van Tonder

Wellcome Genome Campus - Parasites and Microbes

Hinxton
United Kingdom

Jukka Corander

Wellcome Genome Campus - Parasites and Microbes

Hinxton
United Kingdom

Andrew J. Page

Wellcome Genome Campus - Parasites and Microbes

Hinxton
United Kingdom

Pekka Marttinen

Helsinki Institute for Information Technology

Helsinki 00180
Finland

Leon J. Bentley

Wellcome Genome Campus - Parasites and Microbes

Hinxton
United Kingdom

Theresa J. Ochoa

Universidad Peruana Cayetano Heredia

Lima
Peru

Pak Leung Ho

The University of Hong Kong - Queen Mary Hospital

Hong Kong
China

Mignon Du Plessis

National Health Laboratory Services (NHLS) - Centre for Respiratory Diseases and Meningitis

Johannesburg
South Africa

Jennifer E. Cornick

University of Malawi - Malawi-Liverpool-Wellcome Trust Clinical Research Programme

P.O. Box 30096, Chichiri
Blantyre 3, Malawi
Blantyre
Malawi

Brenda Kwambana-Adams

London School of Hygiene & Tropical Medicine - Medical Research Council Unit: The Gambia

Atlantic Boulevard
Fajara
Gambia

Rachel Benisty

Ben-Gurion University of the Negev - Faculty of Health Science

Beer-Sheba 84105
Israel

Susan A. Nzenze

University of the Witwatersrand

1 Jan Smuts Avenue
Johannesburg, GA Gauteng 2000
South Africa

Shabir A. Madhi

University of the Witwatersrand - Vaccines and Infectious Diseases Analytics Research Unit ( email )

Paulina A. Hawkins

Emory University - Rollins School of Public Health

Atlanta, GA 30322
United States

Dean B. Everett

University of Edinburgh

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Martin Antonio

London School of Hygiene & Tropical Medicine - Medical Research Council Unit: The Gambia

Atlantic Boulevard
Fajara
Gambia

Ron Dagan

Ben-Gurion University of the Negev - Faculty of Health Science

Beer-Sheba 84105
Israel

Keith P. Klugman

Emory University - Rollins School of Public Health

Atlanta, GA 30322
United States

Anne Von Gottberg

National Health Laboratory Services (NHLS) - Centre for Respiratory Diseases and Meningitis

University of the Witwatersrand - School of Pathology

Johannesburg, 2000
South Africa

Lesley McGee

Government of the United States of America - Centers for Disease Control and Prevention (CDC)

1600 Clifton Rd., NE
Atlanta, GA 30333
United States

Robert F. Breiman

Emory University - Rollins School of Public Health

Atlanta, GA 30322
United States

Stephen D. Bentley

Wellcome Sanger Institute - Parasites and Microbes ( email )