Real-time genomic surveillance of pathogen evolution and spread

Trevor Bedford (@trvrb)
27 Aug 2018
ICEID 2018
Atlanta, GA

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

    MERS spillover in the Arabian Peninsula

Epidemic growth and human-to-human transmission

    Ebola spread in West Africa
    Zika spread in the Americas

New methods for rapid phylogenetics and visualization

MERS-CoV

Middle East respiratory syndrome coronavirus (MERS-CoV)

• First identified in Saudi Arabia in 2012
• 2229 confirmed cases to date and 791 deaths
• Camels thought to be the intermediate host
• 30% of common colds due to endemic human coronaviruses

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

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

• Nipah virus (fruit bats / pigs, Southeast Asia)
• Lassa virus (rodents, West Africa)
• Avian influenza (birds, mainland China)

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

Zika

Zika's arrival and spread in the Americas

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

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

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

nextstrain.org

Rapid on-the-ground sequencing in Makeni, Sierra Leone

Newly released features

• Bacteria build pipelines using VCF rather than FASTA
• "Community" builds to promote frictionless sharing of results

Global distribution of TB lineages

Tuberculosis builds courtesy of Emma Hodcroft

Detailed spread of TB in Nunavik

Tuberculosis builds courtesy of Emma Hodcroft

Genomic epidemiology of Lassa virus in Nigeria

Data and builds courtesy of Paul Oluniyi, Christian Happi and ACEGID at Redeemer's University

Stable clustering by geography

Recent "outbreak" originates from a diverse group of viruses

Page live at nextstrain.org/community/pauloluniyi/lassa/s

Results sourced from Paul's GitHub page

Recent headway towards "actionable" genomic epidemiology

• affordable and portable full genome sequencing (ONT MinION)
• rapid phylodynamic methods (TreeTime, treedater, etc...)
• rapid distribution of results (nextstrain.org, microreact.org, virological.org)

Acknowledgements

Bedford Lab: Alli Black, Sidney Bell, Gytis Dudas, John Huddleston,
Barney Potter, James Hadfield, Louise Moncla, Tom Sibley

MERS: Gytis Dudas, Andrew Rambaut, Luiz Carvalho

Ebola: Gytis Dudas, Andrew Rambaut, Luiz Carvalho, Philippe Lemey, Marc Suchard, Andrew Tatem

Zika: Nick Loman, Nuno Faria, Oli Pybus, Josh Quick, Ingra Claro, Julien Thézé, Jaquilene de Jesus, Marta Giovanetti, Moritz Kraemer, Sarah Hill, Allison Black, Ester Sabino, Luiz Alcantara

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