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Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics

Nature Genetics volume 51, pages 1035–1043 (2019)Cite this article

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An Author Correction to this article was published on 19 July 2019

This article has been updated

Abstract

Group A Streptococcus (GAS; Streptococcus pyogenes) is a bacterial pathogen for which a commercial vaccine for humans is not available. Employing the advantages of high-throughput DNA sequencing technology to vaccine design, we have analyzed 2,083 globally sampled GAS genomes. The global GAS population structure reveals extensive genomic heterogeneity driven by homologous recombination and overlaid with high levels of accessory gene plasticity. We identified the existence of more than 290 clinically associated genomic phylogroups across 22 countries, highlighting challenges in designing vaccines of global utility. To determine vaccine candidate coverage, we investigated all of the previously described GAS candidate antigens for gene carriage and gene sequence heterogeneity. Only 15 of 28 vaccine antigen candidates were found to have both low naturally occurring sequence variation and high (>99%) coverage across this diverse GAS population. This technological platform for vaccine coverage determination is equally applicable to prospective GAS vaccine antigens identified in future studies.

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Fig. 1: Population structure and pangenome of the 2,083 globally distributed GAS strains.
Fig. 2: Antigenic variation within vaccine targets from the 2,083 GAS genomes.
Fig. 3: Global amino acid variation mapped onto the protein crystal structure of the mature GAS streptolysin O and C5a peptidase.

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Data availability

Illumina sequence reads and draft genome assemblies were deposited to the European Nucleotide Archive under the accession numbers specified in Supplementary Table 2. GenBank accession numbers for the 30 new GAS reference genomes are provided in Supplementary Table 5. To facilitate community accessibility and interrogation of the data presented in this study, the phylogenetic tree (Fig. 1a), PopPUNK phylogroup designations and associated metadata components have been uploaded to the interactive web interface Microreact66 (https://microreact.org/project/5DEFpeck4). The PopPUNK database for assigning new genomes is available at https://doi.org/10.6084/m9.figshare.6931439.v1.

Code availability

The script for assessing antigenic variation from genome assemblies, as used in this study, is available at https://github.com/shimbalama/screen_assembly.

Change history

  • 19 July 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

This work was supported by National Health and Medical Research Council project and program grants for: Protein Glycan Interactions in Infectious Diseases and Cellular Microbiology; the Coalition to Accelerate New Vaccines Against Streptococcus (CANVAS; an Australian and New Zealand joint initiative); and The Wellcome Trust, UK. For part of this study, M.R.D. was supported by a National Health and Medical Research Council postdoctoral training fellowship (635250) and A.M. was a GENDRIVAX fellow funded by the European Union’s Seventh Framework Programme FP7/2007–2013/ under REA grant agreement number 251522. We acknowledge assistance from the sequencing and pathogen informatics core teams at The Wellcome Trust Sanger Institute. We acknowledge and thank the database curators of the S. pyogenes MLST and emm databases (especially D. Bessen). We dedicate this work to the memory of our friend and colleague Gusharan Singh Chhatwal.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Mark R. Davies, Liam McIntyre, Sebastián Duchêne, Kate A. Worthing & Richard A. Strugnell

  2. The Wellcome Trust Sanger Institute, Hinxton, UK

    Mark R. Davies, Ankur Mutreja, Matthew T. G. Holden, Sophia David, Simon R. Harris, Stephen D. Bentley, Julian Parkhill & Gordon Dougan

  3. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia

    Mark R. Davies, Tania Rivera-Hernandez, Olga Berking, Amanda J. Cork & Mark J. Walker

  4. Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia

    Mark R. Davies, Tania Rivera-Hernandez, Olga Berking, Amanda J. Cork & Mark J. Walker

  5. GSK Vaccines Institute for Global Health, Siena, Italy

    Ankur Mutreja & Allan Saul

  6. Doherty Department, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Jake A. Lacey & Steven Y. C. Tong

  7. Department of Microbiology, New York University School of Medicine, New York, NY, USA

    John A. Lees

  8. Menzies School of Health Research, Darwin, Northern Territory, Australia

    Rebecca J. Towers, Philip M. Giffard, Bart J. Currie & Steven Y. C. Tong

  9. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia

    Sebastián Duchêne

  10. Molecular Bacteriology Laboratory, Université Libre de Bruxelles, Brussels, Belgium

    Pierre R. Smeesters & Hannah R. Frost

  11. Department of Pediatrics, Queen Fabiola Childrens University Hospital, Université Libre de Bruxelles, Brussels, Belgium

    Pierre R. Smeesters & Hannah R. Frost

  12. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

    Pierre R. Smeesters, Hannah R. Frost & Andrew C. Steer

  13. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia

    David J. Price

  14. Victorian Infectious Diseases Reference Laboratory Epidemiology Unit, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    David J. Price

  15. School of Medicine, University of St Andrews, St Andrews, UK

    Matthew T. G. Holden

  16. Wellcome Trust Research Centre, Kilifi, Kenya

    Anna C. Seale

  17. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    James A. Berkley

  18. Laboratory of Bacteriology, Epidemiology Laboratory and Disease Control Division, Laboratório Central do Estado do Paraná, Curitiba, Brazil

    Rosângela S. L. A. Torres

  19. Department of Medicine, Universidade Positivo, Curitiba, Brazil

    Rosângela S. L. A. Torres

  20. Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia

    Trevor Lithgow

  21. Helmholtz Centre for Infection Research, Braunschweig, Germany

    Rene Bergmann, Patric Nitsche-Schmitz & Gusharan S. Chhatwal

  22. Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    John D. Fraser & Nicole J. Moreland

  23. Telethon Kids Institute, University of Western Australia and Perth Children’s Hospital, Perth, Western Australia, Australia

    Jonathan R. Carapetis

  24. Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Deborah A. Williamson

  25. Victorian Infectious Disease Service, The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Steven Y. C. Tong

  26. Department of Medicine, University of Cambridge, Cambridge, UK

    Gordon Dougan

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Contributions

M.R.D., G.D. and M.J.W. conceived the project. M.R.D., A.M., J.A.Lacey, J.A.Lees, S.Duchene, P.R.S., M.T.G.H., S.Y.C.T., P.M.G., A.C.S., J.A.B., G.S.C., S.D.B., R.A.S., T.L., J.D.F., N.J.M., J.R.C., A.C.S., J.P., A.S., D.A.W., B.J.C. and M.J.W. designed the experiments. M.R.D., L.M., J.A.Lacey, J.A.Lees, S.David, A.M., R.J.T., K.A.W., S.R.H., T.R.-H., H.R.F., R.S.L.A.T., O.B., A.J.C., R.B., P.N.-S., N.J.M. and D.A.W. performed the experimental protocols. M.R.D., L.M., J.A.Lacey, J.A.Lees, S.Duchene, D.J.P., A.M., P.R.S., N.J.M., G.D. and M.J.W. analyzed the experimental results. M.R.D. and M.J.W. wrote the manuscript and all authors reviewed the manuscript.

Corresponding authors

Correspondence to Mark R. Davies or Mark J. Walker.

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Competing interests

A.S. is an employee of the GSK group of companies with a commercial interest in GAS vaccine development. These companies had no influence over study design.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–14 and Supplementary Tables 1, 5, 7 and 10–12

Reporting Summary

Supplementary Table 2

GAS strains used in this study

Supplementary Table 3

List of 890 core GAS genes identified as having recombinogenic signatures as defined by fastGEAR

Supplementary Table 4

List of 416 ‘non-recombinogenic’ core GAS genes and markers of selection pressure (ratio of non-synonymous (dN) to synonymous (dS) codon subsititutions (dN/dS))

Supplementary Table 6

Frequency, size (length) and relative rates of recombination within 36 PopPUNK phylogroups

Supplementary Table 8

Position of amino acid variants within the streptolysin O (SLO) protein and the consensus sequence of the SLO mature protein (as plotted in Fig. 3a,c)

Supplementary Table 9

Position of amino acid variants within the C5a peptidase (ScpA) protein and the consensus sequence

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Davies, M.R., McIntyre, L., Mutreja, A. et al. Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics. Nat Genet 51, 1035–1043 (2019). https://doi.org/10.1038/s41588-019-0417-8

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