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Prediction of post-vaccine population structure of Streptococcus pneumoniae using accessory gene frequencies

View ORCID ProfileTaj Azarian, View ORCID ProfilePamela P Martinez, Brian J Arnold, Lindsay R Grant, Jukka Corander, View ORCID ProfileChristophe Fraser, View ORCID ProfileNicholas J Croucher, Laura L Hammitt, Raymond Reid, Mathuram Santosham, Robert C Weatherholtz, Stephen D Bentley, Katherine L O’Brien, View ORCID ProfileMarc Lipsitch, View ORCID ProfileWilliam P Hanage
doi: https://doi.org/10.1101/420315
Taj Azarian
1Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL
2Center for Communicable Disease Dynamics, Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston MA
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Pamela P Martinez
2Center for Communicable Disease Dynamics, Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston MA
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Brian J Arnold
2Center for Communicable Disease Dynamics, Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston MA
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Lindsay R Grant
3Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Jukka Corander
4Helsinki Institute for Information Technology, Department of Mathematics and Statistics, University of Helsinki, 00014 Helsinki, Finland
5Department of Biostatistics, University of Oslo, 0317 Oslo, Norway
6Infection Genomics, The Wellcome Trust, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Christophe Fraser
7Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF, UK
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Nicholas J Croucher
8MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK
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Laura L Hammitt
3Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Raymond Reid
3Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Mathuram Santosham
3Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Robert C Weatherholtz
3Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Stephen D Bentley
6Infection Genomics, The Wellcome Trust, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Katherine L O’Brien
3Center for American Indian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Marc Lipsitch
2Center for Communicable Disease Dynamics, Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston MA
9Department of Immunology and Infectious Diseases, T.H. Chan School of Public Health, Harvard University, Boston MA
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William P Hanage
2Center for Communicable Disease Dynamics, Department of Epidemiology, T.H. Chan School of Public Health, Harvard University, Boston MA
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Abstract

Predictions of how a population will respond to a selective pressure are valuable, especially in the case of infectious diseases, which often adapt to the interventions we use to control them. Yet attempts to predict how pathogen populations will change, for example in response to vaccines, are challenging. Such has been the case with Streptococcus pneumoniae, an important human colonizer and pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use recent advances in knowledge of negative-frequency dependent selection (NFDS) acting on frequencies of accessory genes (i.e., flexible genome) to predict the changes in the pneumococcal population after intervention. Implementing a deterministic NFDS model using the replicator equation, we can accurately predict which pneumococcal lineages will increase after intervention. Analyzing a population genomic sample of pneumococci collected before and after vaccination, we find that the predicted fitness of a lineage post-vaccine is significantly and positively correlated with the observed change in its prevalence. Then, using quadratic programming to numerically solve the frequencies of non-vaccine type lineages that best restored the pre-vaccine accessory gene frequencies, we accurately predict the post-vaccine population composition. Additionally, we also test the predictive ability of frequencies of core genome loci, a subset of metabolic loci, and naïve estimates of prevalence change based on pre-vaccine lineages frequencies. Finally, we show how this approach can assess the migration and invasion capacity of emerging lineages, on the basis of their accessory genome. In general, we provide a method for predicting the impact of an intervention on pneumococcal populations and other bacterial pathogens for which NFDS is a main driving force.

Footnotes

  • Pamela P Martinez pmartinez{at}hsph.harvard.edu, Brian J Arnold brianjohnarnold{at}gmail.com, Lindsay R Grant lgrant10{at}jhu.edu, Jukka Corrander jukka.corander{at}medisin.uio.no, Christophe Fraser christophe.fraser{at}bdi.ox.ac.uk, Nicholas J Croucher n.croucher{at}imperial.ac.uk, Laura Hammitt lhammitt{at}jhu.edu, Raymond Reid rreid2{at}jhu.edu, Mathuram Santosham msantosham{at}jhu.edu, Robert R Weatherholtz rweathe1{at}jhu.edu, Stephen D Bentley sdb{at}sanger.ac.uk, Katherine L O’Brien klobrien{at}jhu.edu, Marc Lipsitch mlipsitc{at}hsph.harvard.edu, William P Hanage whanage{at}hsph.harvard.edu

  • ↵* Co-senior authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 18, 2018.
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Prediction of post-vaccine population structure of Streptococcus pneumoniae using accessory gene frequencies
Taj Azarian, Pamela P Martinez, Brian J Arnold, Lindsay R Grant, Jukka Corander, Christophe Fraser, Nicholas J Croucher, Laura L Hammitt, Raymond Reid, Mathuram Santosham, Robert C Weatherholtz, Stephen D Bentley, Katherine L O’Brien, Marc Lipsitch, William P Hanage
bioRxiv 420315; doi: https://doi.org/10.1101/420315
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Prediction of post-vaccine population structure of Streptococcus pneumoniae using accessory gene frequencies
Taj Azarian, Pamela P Martinez, Brian J Arnold, Lindsay R Grant, Jukka Corander, Christophe Fraser, Nicholas J Croucher, Laura L Hammitt, Raymond Reid, Mathuram Santosham, Robert C Weatherholtz, Stephen D Bentley, Katherine L O’Brien, Marc Lipsitch, William P Hanage
bioRxiv 420315; doi: https://doi.org/10.1101/420315

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