Real-time tracking of virus evolution


Trevor Bedford (@trvrb)
31 Jan 2019
MSTP Dinner Meeting
UW

We work at the interface of virology, evolution and epidemiology

Sequencing to reconstruct pathogen evolution and spread

Epidemic process

Sample some individuals

Sequence and determine phylogeny

Sequence and determine phylogeny

Localized Middle Eastern MERS-CoV phylogeny

Cotten et al. 2013. Lancet.

Regional West African Ebola phylogeny

Park et al. 2015. Cell.

Global influenza phylogeny

Bedford et al. 2015. Nature.

Phylogenetic tracking has the capacity to revolutionize infectious disease epidemiology

Outline

  • Influenza circulation and antigenic drift
  • Zika spread in the Americas
  • "Real-time" analyses

Influenza

Influenza virion

Population turnover is extremely rapid

Clades emerge, die out and take over

Clades show rapid turnover

Dynamics driven by antigenic drift

Drift necessitates vaccine updates

H3N2 vaccine updates occur every ~2 years

Vaccine strain selection by WHO

Problem of applied evolutionary biology

Every paper in the field...

  • "These observations have implications for influenza surveillance and vaccine formulation" (Wolf et al 2006)
  • "Our results have implications for the design of vaccines to combat rapidly mutating viral diseases" (Gupta et al 2006)
  • "These results may have important implications for influenza vaccine and antiviral research" (Bhatt et al 2011)
  • "Needless to say, these results have important implications for the updating of vaccines against influenza" (Zinder et al 2013)

Disconnect between evolutionary studies and information needed by WHO

  • WHO needs specific advice, ie this strain is likely to take off, this strain is likely to die out
  • Problems of generality and timeliness

Nextflu

Project to provide a real-time view of the evolving influenza population

Nextflu pipeline

  1. Download all recent HA sequences from GISAID
  2. Filter to remove outliers
  3. Subsample across time and space
  4. Align sequences
  5. Build tree
  6. Estimate clade frequencies
  7. Infer antigenic phenotypes
  8. Export for visualization

Current H3N2 diversity

Mutations at known epitope sites

Recent clade success

Forecasting strain turnover in seasonal influenza virus

with John Huddleston, Richard Neher and others

"The future is here, it's just not evenly distributed yet"
— William Gibson

USA music industry, 2011 dollars per capita

Influenza population turnover

Fitness models can project clade frequencies


Clade frequencies $X$ derive from the fitnesses $f$ and frequencies $x$ of constituent viruses, such that

$$\hat{X}_v(t+\Delta t) = \sum_{i:v} x_i(t) \, \mathrm{exp}(f_i \, \Delta t)$$

This captures clonal interference between competing lineages

Łuksza and Lässig 2014

Current estimated clade fitnesses

Current forecast

Zika

Zika's arrival and spread in the Americas

WHO 2016

Establishment and cryptic transmission of Zika virus in Brazil and the Americas

with Nuno Faria, Nick Loman, Oli Pybus, Luiz Alcantara, Ester Sabino, Josh Quick,
Alli Black, Ingra Morales, Julien Thézé, Marcio Nunes, Jacqueline de Jesus,
Marta Giovanetti, Moritz Kraemer, Sarah Hill and many others

Faria et al. 2017. Nature.

Road trip through northeast Brazil to collect samples and sequence

Faria et al. 2017. Nature.

Case reports and diagnostics suggest initiation in northeast Brazil

Faria et al. 2017. Nature.

Phylogeny infers an origin in northeast Brazil

Faria et al. 2017. Nature.

Actionable inferences

Genomic analyses were mostly done in a retrospective manner

Dudas and Rambaut 2016

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

nextstrain.org

Rapid on-the-ground sequencing by Ian Goodfellow, Matt Cotten and colleagues













Acknowledgements

Bedford Lab: Alli Black, John Huddleston, Barney Potter, James Hadfield,
Louise Moncla, Tom Sibley, Maya Lewinsohn, Katie Kistler

Influenza: WHO Global Influenza Surveillance Network, GISAID, Richard Neher, Barney Potter, John Huddleston, Dave Wentworth, Becky Garten, Jackie Katz, Vivien Dugan, Xiyan Xu, Elizabeth Neuhaus, Sujatha Seenu

Zika: Nick Loman, Nuno Faria, Oli Pybus, Josh Quick, Kristian Andersen, Nathan Grubaugh, Alli Black, Jason Ladner, Gustavo Palacios, Sharon Isern, Gytis Dudas, Barney Potter, Esther Ellis

Nextstrain: Richard Neher, James Hadfield, Emma Hodcroft, Tom Sibley, John Huddleston, Sidney Bell, Barney Potter, Colin Megill, Charlton Callender