Real-time tracking of virus evolution


Trevor Bedford (@trvrb)
24 Jun 2016
Federation Meeting of Korean Basic Medical Scientists
Incheon, Republic of Korea

Slides at bedford.io/talks/

Phylogenies

Phylogenies describe history

Phylogenies describe history

Haeckel 1879

Phylogenies describe history

Pace 1997

Phylogenies reveal process

Darwin 1859

Epidemics

Epidemic process

Sample some individuals

Sequence and determine phylogeny

Sequence and determine phylogeny

Localized Middle Eastern MERS-CoV phylogeny

Cotten et al 2013

Regional West African Ebola phylogeny

Park et al 2015

Global influenza phylogeny

Bedford et al 2015

Applications of evolutionary analysis for vaccine strain selection and charting outbreak spread

Influenza

Influenza virion

Influenza H3N2 vaccine updates

H3N2 phylogeny showing antigenic drift

H3N2 phylogeny showing antigenic drift

Drift variants rapidly take over the virus population


Timely surveillance and rapid analysis essential to understand ongoing influenza evolution

nextflu

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

All in collaboration with Richard Neher

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 frequencies
  7. Export for visualization

Up-to-date analysis publicly available at:

nextflu.org

Forecasting

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

USA music industry, 2011 dollars per capita

Influenza population turnover

Vaccine strain selection timeline

Seek to explain change in clade frequencies over 1 year

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

Predictive fitness models


A simple predictive model estimates the fitness $f$ of virus $i$ as

$$\hat{f}_i = \beta^\mathrm{ep} \, f_i^\mathrm{ep} + \beta^\mathrm{ne} \, f_i^\mathrm{ne}$$

where $f_i^\mathrm{ep}$ measures cross-immunity via substitutions at epitope sites and $f_i^\mathrm{ep}$ measures mutational load via substitutions at non-epitope sites

Łuksza and Lässig 2014

We implement a similar model based on two predictors


  1. Clade frequency change
  2. Antigenic advancement

Project frequencies forward,
growing clades have high fitness

Calculate HI drop from ancestor,
drifted clades have high fitness

Fitness model parameterization


Our predictive model estimates the fitness $f$ of virus $i$ as


$$\hat{f}_i = \beta^\mathrm{freq} \, f_i^\mathrm{freq} + \beta^\mathrm{HI} \, f_i^\mathrm{HI}$$


We learn coefficients and validate model based on previous 15 H3N2 seasons

Clade growth rate is well correlated (ρ = 0.66)

Growth vs decline correct in 84% of cases

Trajectories show more detailed congruence

Further work on predictive modeling


  1. Integrate data predictors and data sources, e.g. geography
  2. Possible to build predictive models for H1N1 and B and to forecast NA evolution

Real-time analyses are actionable and thus, may inform influenza vaccine strain selection

Outbreak analysis

Ebola

Epidemic basically contained, but resulted in >28,000 confirmed cases and >11,000 deaths

Early sequencing showed single origin of epidemic

Gire et al 2014

Continued spread through Dec 2014

Park et al 2015

At epidemic height, geographic spread of particular interest

Rambaut 2015

Later on, tracking transmission clusters of primary importance

Rambaut 2015

Evolutionary analyses helped to establish the degree of adaptive evolution occurring

Park et al 2015

Selective patterns differ across genome

Park et al 2015

Phylogeographic analyses reveal detailed patterns of spatial movement

Dudas et al 2016

Animation by Gytis Dudas

Dudas et al 2016

Important analyses, let's make them more rapid and more automated

Tracking epidemic spread in real-time:

ebola.nextstrain.org

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













Deployment of MinION sequencing to Guinea by Nick Loman, Josh Quick, Lauren Cowley and colleagues

Quick et al 2016

Zika

Virus endemic to Africa, emergence in Southeast Asia in the last century

Mackay 2016

Spread eastward through the South Pacific

Lycett 2016

Isolated epidemics in the South Pacific

Kucharski et al 2016

Single arrival into the Americas in early 2014

Faria et al 2016

Working on analysis of ongoing evolution:

nextstrain.org/zika/

ZiBRA: Project to do real-time sequencing of Zika in Brazil

Road trip through northeast Brazil to collect samples and sequence

Sequencing on the MinION nanopore sequencer













Moving forward, genetically-informed outbreak response requires:


  • Rapid sharing of sequence data, genetic context critical
  • Technologies for rapid diagnostics and sequencing
  • Technologies to rapidly conduct phylogenetic inference
  • Technologies to explore genetic relationships and inform epidemiological investigation

Future work

Acknowledgements


Influenza: WHO Global Influenza Surveillance Network, GISAID, Worldwide Influenza Centre at the Francis Crick Institute, Richard Neher, Colin Russell, Andrew Rambaut

Ebola: data producers, Gytis Dudas, Andrew Rambaut, Philipe Lemey, Richard Neher, Nick Loman, Ian Goodfellow, Paul Kellam, Danny Park, Kristian Andersen, Pardis Sabeti

Zika: data producers, Nick Loman, Nuno Faria, Andrew Rambaut, Oliver Pybus, Richard Neher, Charlton Callender, Allison Black, Luiz Alcantara and the rest of the ZiBRA team

 

Contact


  • Website: bedford.io
  • Twitter: @trvrb
  • Slides: bedford.io/talks/real-time-tracking-fmkbms/