Real-time genomic surveillance of pathogen evolution and spread


Trevor Bedford (@trvrb)
5 Jun 2017
Global Infectious Disease Seminar
Center for Infectious Disease Research

Spread of plague in 14th century

Spread of swine flu in 2009

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

Outline

  • Influenza evolution and forecasting
  • Ebola spread in West Africa
  • Zika spread in the Americas
  • "Real-time" analyses

Influenza

Influenza virion

Population turnover (in H3N2) is extremely rapid

Clades emerge, die out and take over

Clades show rapid turnover

Dynamics driven by antigenic drift

Drift variants emerge and rapidly take over in the virus population


This causes the side effect of evading existing vaccine formulations

Drift necessitates vaccine updates

H3N2 vaccine updates occur every ~2 years

Timely surveillance and rapid analysis essential to vaccine strain selection

nextflu

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

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 clade frequencies
  7. Infer antigenic phenotypes
  8. Export for visualization

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

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

We implement a similar model based on two predictors


  1. Clade frequency change
  2. Antigenic advancement

Clade growth rate is well correlated (ρ = 0.66)

Growth vs decline correct in 84% of cases

Trajectories show more detailed congruence

Trajectories show more detailed congruence

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

Ebola

Tracking geographic spread of 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

Phylogenetic reconstruction of evolution and spread

Initial emergence from Guéckédou

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

Regional outbreaks due to multiple introductions

Each introduction results in a minor outbreak

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

Zika

Zika's arrival and spread in the Americas

Tracking origins of the Zika epidemic

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

Road trip through northeast Brazil to collect samples and sequence

Case reports and diagnostics suggest initiation in northeast Brazil

Phylogeny infers an origin in northeast Brazil

Local spread of Zika in Florida

with Nathan Grubaugh, Kristian Andersen, Jason Ladner, Gustavo Palacios, Sharon Isern, Oli Pybus, Moritz Kraemer, Gytis Dudas, Amanda Tan, Karthik Gangavarapu, Michael Wiley, Stephen White, Julien Thézé, Scott Michael, Leah Gillis, Pardis Sabeti, and many others

Outbreak of locally-acquired infections focused in Miami-Dade county

Phylogeny shows a surprising degree of clustering

Clustering suggests fewer, longer transmission chains and higher R0

Flow of infected travelers greatest from Caribbean

Genomic epidemiology of Zika in the US Virgin Islands

with Allison Black, Barney Potter, Esther Ellis, Brett Ellis, Kristian Andersen,
Nathan Grubaugh, Leora Feldstein, and others

Preliminary analysis of 20 genomes shows multiple introductions to USVI

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

Key challenges

  • 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


Richard Neher, Trevor Bedford, James Hadfield,
Colin Megill, Sidney Bell, Charlton Callender,
Barney Potter, Sarah Murata,

Nextstrain architecture

All code open source at github.com/nextstrain

nextstrain.org

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













Desired analytics are pathogen specific and tied to response measures

Acknowledgements


Influenza: WHO Global Influenza Surveillance Network, Worldwide Influenza Centre at the Francis Crick Institute, Richard Neher, Colin Russell, Boris Shraiman

Ebola: Gytis Dudas, Andrew Rambaut, Luiz Carvalho, Philippe Lemey, Marc Suchard, Andrew Tatem, Nick Loman, Ian Goodfellow, Matt Cotten, Paul Kellam, Kristian Andersen, Pardis Sabeti, many others

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

Nextstrain: Richard Neher, James Hadfield, Colin Megill, Sidney Bell, Charlton Callender, Barney Potter, Sarah Murata