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Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event

Nature Genetics volume 44, pages 352–355 (2012)Cite this article

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Abstract

Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age1. The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States2,3 provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination4, showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases.

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Figure 1: Resequencing of pneumococcal vaccine escape recombinants: comparison of recombinant and putative recipient and donor sequences.
Figure 2: Spread of the P1 vaccine escape recombinant in the United States during 2003–2007.

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Acknowledgements

The authors gratefully acknowledge the clinicians, microbiologists and investigators of the ABCs program of the Emerging Infections Program Network. We thank X. Didelot for contributions to the analysis of Illumina genomic data. This work was funded by the Wellcome Trust (079126/Z/06/Z). T.E.A.P. and D.W.C. are funded by the UK National Health Service (NHS) National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Senior Investigator Awards. P.D. is funded by a Wellcome Trust Core Award Grant (090532/Z/09/Z) and is supported, in part, by a Wolfson Royal Society Merit Award. R.B. is supported by the NHS NIHR Oxford Biomedical Research Centre and the UK Clinical Research Collaboration (UKCRC) (MRC UK G0800778 and Wellcome Trust 087646/2/08/Z). A.B.B. is a Wellcome Trust Career Development Fellow (083511/Z/07/Z). Genetic and epidemiological data are available from the authors.

Author information

Author notes

  1. Tanya Golubchik and Angela B Brueggemann: These authors contributed equally to this work.

  2. Peter Donnelly, Derrick W Crook and Rory Bowden: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Statistics, University of Oxford, Oxford, UK

    Tanya Golubchik, Teresa Street, Thien Ho, Peter Donnelly & Rory Bowden

  2. Department of Zoology, University of Oxford, Oxford, UK

    Angela B Brueggemann & Rosalind M Harding

  3. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA

    Robert E Gertz Jr, Ruth Link-Gelles, Bernard Beall & Matthew R Moore

  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Chris C A Spencer, Eleni Giannoulatou, Peter Donnelly & Rory Bowden

  5. Nuffield Department of Medicine, Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

    Tim E A Peto, Derrick W Crook & Rory Bowden

Authors
  1. Tanya Golubchik
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Contributions

B.B. and R.E.G. collected isolates. A.B.B., B.B., R.B., D.W.C., P.D., T.G., R.M.H. and T.E.A.P. planned experiments. A.B.B., B.B., R.L.-G., M.R.M. and T.E.A.P. collected and analyzed epidemiological data. A.B.B., R.E.G., T.G. and T.S. performed molecular typing. T.G., T.H. and T.S. prepared DNA and performed microarray-based sequencing. T.G., A.B.B., R.B., P.D., C.C.A.S. and E.G. analyzed molecular data. R.B., P.D. and D.W.C. wrote the manuscript. A.B.B., B.B., T.G., M.R.M. and T.E.A.P. contributed to writing the manuscript.

Corresponding author

Correspondence to Peter Donnelly.

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Competing interests

D.C. and T.P. are in receipt of a research grant for pneumococcal surveillance from Pfizer. A.B.B. is in receipt of grant funding from GlaxoSmithKline Biologicals and Pfizer (Wyeth) Vaccines.

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Supplementary Tables 1–8, Supplementary Figures 1–3 and Supplementary Note (PDF 588 kb)

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Golubchik, T., Brueggemann, A., Street, T. et al. Pneumococcal genome sequencing tracks a vaccine escape variant formed through a multi-fragment recombination event. Nat Genet 44, 352–355 (2012). https://doi.org/10.1038/ng.1072

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