Real-time tracking of virus evolution
Trevor Bedford (@trvrb)
MERS spillover in the Arabian Peninsula
Ebola spread in West Africa
9 May 2019
Distinguished Scientist Seminar Series
Rocky Mountain Laboratories
Slides at: bedford.io/talks
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We work at the interface of virology, evolution and epidemiology
Sequencing to reconstruct pathogen spread
Epidemic process
Sample some individuals
Sequence and determine phylogeny
Sequence and determine phylogeny
Localized Middle Eastern MERS-CoV phylogeny
Regional West African Ebola phylogeny
Global influenza phylogeny
Phylogenetic tracking has the capacity to revolutionize epidemiology
Stuttering chains and animal-to-human spillover
Epidemic growth and human-to-human transmission
New methods for rapid phylogenetics and visualization
MERS-CoV
Middle East respiratory syndrome coronavirus (MERS-CoV)
Ongoing incidence, but lack of epidemic growth
Cases localized to the Arabian Peninsula
Hypotheses for MERS transmission
MERS-CoV spillover at the camel-human interface
with 
Gytis Dudas, Luiz Carvalho and Andrew Rambaut
Genomic dataset
- 174 virus genomes from human infections
- 100 virus genomes from camel infections
MERS tree with host state
Phylodynamic reconstruction of host state
Humans are transient hosts
Asymmetric migration rates
- 56 (48–63) camel-to-human transmission events resulting in 174 sequenced human infections
- 3 (0-12) human-to-camel transmission events
Introduction events tend to occur between April and July
Dromedary camel calving occurs between Nov and Feb
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Monte Carlo simulation
Phylogenetic clustering suggests $R_0$ below 1.0 and ~2000 human cases driven by ~600 introduction events
Critically, no evidence of increasing cluster sizes through time
Many other viruses that exhibit stuttering chains of human infection
Sylvatic introductions of yellow fever virus show similar dynamics
Ebola
Ebola epidemic of 2014-2016 was unprecedented in scope
Ebola epidemic in West Africa
Ebola epidemic within Sierra Leone
Virus genomes reveal factors that spread and sustained the Ebola epidemic
with Gytis Dudas, Andrew Rambaut, Luiz Carvalho, Marc Suchard, Philippe Lemey,
and many others
Sequencing of 1610 Ebola virus genomes collected during the 2013-2016 West African epidemic
Sequenced genomes were representative of spatiotemporal diversity
Phylogenetic reconstruction of epidemic
Tracking migration events
Factors influencing migration rates
Effect of borders on migration rates
Spatial structure at the country level
Substantial mixing at the regional level
Each introduction results in a minor outbreak
Regional outbreaks due to multiple introductions
Regional outbreaks due to multiple introductions
Ebola spread in West Africa followed a gravity model with moderate slowing by international borders, in which spread is driven by short-lived migratory clusters
The ability of single genes vs full genomes to resolve time and space in outbreak analysis
with Gytis Dudas
Accuracy vs precision
Assess accuracy and precision through an out-of-sample prediction approach to model testing. Leave out 60/600 tips and predict time and location of these tips
Maximum likelihood divergence trees
BEAST time trees
Date reconstruction
Evolutionary rate reconstruction
Location reconstruction
Estimates are generally well calibrated
Actionable inferences
Genomic analyses were mostly done in a retrospective manner
Key challenges to making genomic epidemiology actionable
- Timely analysis and sharing of results critical
- Dissemination must be scalable
- Integrate many data sources
- Results must be easily interpretable and queryable
Nextstrain
Project to conduct real-time molecular epidemiology and evolutionary analysis of emerging epidemics
with
Richard Neher,
James Hadfield,
Emma Hodcroft,
Tom Sibley,
John Huddleston,
Colin Megill,
Sidney Bell,
Barney Potter,
Charlton Callender
Nextstrain architecture
All code open source at github.com/nextstrain
Two central aims: (1) rapid and flexible phylodynamic analysis and
(2) interactive visualization
Rapid build pipeline for 1600 Ebola genomes
- Align with MAFFT (34 min)
- Build ML tree with RAxML (54 min)
- Temporally resolve tree and geographic ancestry with TreeTime (16 min)
- Total pipeline (1 hr 46 min)
Nextstrain is two things
- a bioinformatics toolkit and visualization app, which can be used for a broad range of datasets
- a collection of real-time pathogen analyses kept up-to-date on the website nextstrain.org</i>
nextstrain.org
Rapid on-the-ground sequencing in Makeni, Sierra Leone
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Newly released features
Ongoing Ebola epidemic worsening in North Kivu, DRC
Genomic epidemiology conducted by INRB/USAMRIID
Moving forward
Acknowledgements
Bedford Lab:
Alli Black,
John Huddleston,
Barney Potter,
James Hadfield,
Katie Kistler,
Louise Moncla,
Maya Lewinsohn,
Thomas Sibley,
Jover Lee,
Kairsten Fay,
Misja Ilcisin
MERS: Gytis Dudas, Andrew Rambaut, Luiz Carvalho Ebola: Gytis Dudas, Andrew Rambaut, Luiz Carvalho, Philippe Lemey, Marc Suchard, Andrew Tatem Nextstrain: Richard Neher, James Hadfield, Emma Hodcroft, Tom Sibley, John Huddleston, Sidney Bell, Barney Potter, Colin Megill, Charlton Callender Seattle Flu Study: Helen Chu, Michael Boeckh, Janet Englund, Michael Famulare, Barry Lutz, Debbie Nickerson, Mark Rieder, Lea Starita, Matthew Thompson, Jay Shendure, Jeris Bosua, Thomas Sibley, Louise Moncla, Barney Potter, Jover Lee, Kairsten Fay, Misja Ilcisin, James Hadfield, Antonio Solano
