International genomic definition of pneumococcal lineages, to contextualise disease, antibiotic resistance and vaccine impactResearch in context
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
Affiliations
Rebecca A. Gladstone
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK; Corresponding author.
Stephanie W. Lo
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK
John A. Lees
New York University School of Medicine, New York, NY, USA
Nicholas J. Croucher
Faculty of Medicine, School of Public Health, Imperial College London, UK
Andries J. van Tonder
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK
Jukka Corander
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK; Department of Biostatistics, University of Oslo, 0317 Oslo, Norway
Andrew J. Page
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK
Pekka Marttinen
Department of Computer Science, Helsinki Institute for Information Technology HIIT, Espoo, Finland
Leon J. Bentley
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK
Theresa J. Ochoa
Instituto de Medicina Tropical, Universidad Peruana Cayetano Heredia, Lima, Peru
Pak Leung Ho
Department of Microbiology, Carol Yu Centre for Infection, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
Mignon du Plessis
Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Johannesburg, South Africa
Jennifer E. Cornick
Malawi-Liverpool-Wellcome-Trust Clinical Research Programme, Blantyre, Malawi
Brenda Kwambana-Adams
NIHR Global Health Research Unit on Mucosal Pathogens, Division of Infection and Immunity, University College London, London, UK; WHO Collaborating Centre for New Vaccines Surveillance, Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine, Atlantic Boulevard, Fajara, PO Box 273 Banjul, the Gambia
Rachel Benisty
The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Susan A. Nzenze
Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, South Africa; Department of Science and Technology, National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, South Africa
Shabir A. Madhi
Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, South Africa; Department of Science and Technology, National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, South Africa
Paulina A. Hawkins
Rollins School Public Health, Emory University, USA
Dean B. Everett
Queens Research Institute, University of Edinburgh, UK
Martin Antonio
WHO Collaborating Centre for New Vaccines Surveillance, Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine, Atlantic Boulevard, Fajara, PO Box 273 Banjul, the Gambia; Division of Microbiology & Immunity, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
Ron Dagan
The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Keith P. Klugman
Rollins School Public Health, Emory University, USA
Anne von Gottberg
Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Johannesburg, South Africa
Lesley McGee
Centers for Disease Control and Prevention, Atlanta, USA
Robert F. Breiman
Rollins School Public Health, Emory University, USA; Emory Global Health Institute, Atlanta, USA
Stephen D. Bentley
Parasites and microbes, Wellcome Sanger Institute, Hinxton, UK
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.
