Sidney Bell

20 Feb 2019

Center for Viral
Systems Biology 

San Diego, CA

Understanding
antigenic evolution

+ resources for
   open science

Antigenic variation changes what the virus looks like to your immune system

Measles

Antigenically uniform

Flu

Antigenically

diverse

Lifelong protection

Temporary cross-protection

Influenza & Dengue

Influenza antigenic evolution

 

Trevor Bedford, Richard Neher & John Huddleston

Population turnover is extremely rapid

Dynamics driven by antigenic drift

Necessitates vaccine updates every ~2 years

Vaccine strain selection by WHO

Which viruses are

antigenically novel?

Measuring antigenic relationships

Measuring antigenic relationships

Titers approximate pairwise

antigenic distance

0
0 2
0

1

2

2-fold

change

4-fold

change

4-fold

change

Antigenic Distance

\propto

log2(Titer)

Distance

Multidimensional scaling

Antigenic cartography

Smith et al 2004

Source and impact of

antigenic change?

Evolutionary basis of antigenic change

Neher et al, PNAS 2016

0 1 2
1 0 2
2 2 0
\approx \sum{d_b}

Titer

between

&

+         avidity +     potency

d_{1}
d_{2}
d_{3}
d_{4}

1.0

0.5

0.5

0.5

Phylogenetic model of

antigenic evolution

\hat{T_{ij}} = \sum{d_b} + v_i + s_j
\sum_{i,j}(\hat{T_{ij}} - T{ij})^2 + \lambda \sum_{b}d_b + \gamma \sum_{i} v_i^2 + \delta \sum_{j} s_j^2

Learn these

Minimize

this

Predict titers

Neher et al, PNAS 2016

Phylogenetic model of

antigenic evolution

\hat{T_{ij}} = \sum{d_b} + v_i + s_j
\sum_{i,j}(\hat{T_{ij}} - T{ij})^2 + \lambda \sum_{b}d_b + \gamma \sum_{i} v_i^2 + \delta \sum_{j} s_j^2

dTiter on each branch

Virus

avidity

Serum

potency

Predict titers

Neher et al, PNAS 2016

Phylogenetic model of

antigenic evolution

Interpolate across the tree

to estimate antigenic relationships

Neher et al, PNAS 2016

Interpolate across the tree

to estimate antigenic relationships

Neher et al, PNAS 2016

Model is highly predictive of

withheld titer values

Neher et al, PNAS 2016

How does
antigenic evolution

relate to

population dynamics?

Population susceptibility:

Previously circulating:

Population

immunity:

Clade growth:

How does antigenic evolution relate to population dynamics?

Predict clade growth

based on antigenic fitness

Lukzsa and Lassig, Nature, 2014

\propto e^{(f_i(t) + dt)}

Growth rate @

next year

Ensemble model of

antigenic fitness

f_i \propto

John Huddleston

Antigenic drift

Epitope mutations

Clade expansion

Protein function

+

+

+

Prospective trajectories from

ensemble model of antigenic fitness

John Huddleston

Clade growth rates are well-predicted

John Huddleston

Clade growth vs decline is also well-predicted

John Huddleston

Unlikely to supplant expert predictions, but useful for vaccine candidate selection

So... how well does this generalize?

Contrasting evolutionary dynamics

Dengue (serotype 2)

Influenza (H3N2)

Four (uniform?) serotypes of dengue

Each serotype is genetically diverse

Sanofi vaccine trial efficacy

varies by genotype

Juraska et al, PNAS 2018

Lifelong protection

Temporary

cross-protection

Initial

response

Original antigenic sin drives

dengue case outcomes

After

1-3 yrs

 

Increased risk

DENV antigenic relationships

are poorly understood

Serotypes are genetically distinct

Clades are genetically distinct

Serotypes are antigenically distinct

Are clades antigenically distinct?

?

How does

dengue evolve

antigenically?

Measuring antigenic relationships

Neutralization

+

+

Replication

Neutralizing antibodies block virus replication

Titers measure antigenic distance

Antigenic similarity = how much sera is required to neutralize viral replication?

Serum

Test viruses

1x

2x

4x

(relative to autologous)

X

X

X

X

X

X

--

Log2

0

1

2

Titer

Titers approximate pairwise

antigenic distance

Experimentally measure how well sera inhibits viral plaque formation

Sera produced by 1st infection

Test viruses

Dengue titers are confusing

Non-human primate sera; 3 months post primary infection

Katzelnick et al, Science 2015

Antigenic distance

(less cross immunity)

Dengue serotypes look antigenically diverse

NHP sera; 3 months post primary infection

= 2-fold change    in PRNT50

Katzelnick et al, Science 2015

Where does this variation come from? Does it matter?

Neher et al, PNAS 2016

0 1 2
1 0 2
2 2 0
\approx \sum{d_b}

Titer

between

&

+         avidity +     potency

d_{1}
d_{2}

1.5

0.5

Substitution-based model of

antigenic evolution

MRCVGIGSRDFVE...
MRCVGVGNRDHVE...

Model is highly predictive of

withheld titer values

Pearson R^2 = 0.78
RMSE = 0.75

Antigenic mutations occur between and within serotypes

Each serotype of dengue contains multiple

distinct antigenic phenotypes

How does

antigenic diversity

impact dengue

population dynamics?

Serotypes cycle through populations

Bell et al., bioRxiv 2018

Does antigenic fitness

predict serotype growth & decline?

Lukzsa and Lassig, Nature 2014

\propto e^{(f_i(t) * dt)}

Growth rate @

next 5 years

How antigenically distant

is          from what has recently circulated?

Antigenic novelty drives

viral fitness and serotype turnover

Bell et al., bioRxiv 2018

Dengue

Flu (H3N2)

12 years

500 years

4 titer units*

11 titer units

* likely underestimated

Dengue antigenic evolution is ongoing but slow

Methods summary & further reading:

Antigenic cartography

Visualize antigenic space via a low-dimensional embedding

Smith et al, Science 2004
 

Evolution-based models

Assign antigenic change to branches or substitions, interpolate across dataset

Neher et al, PNAS 2016

 

Population dynamics

Antigenic fitness & clade turnover

Luksza and Lassig, Nature 2014

Acknowledgements

Slides: The Noun Project & RevealJS

Influenza: Trevor Bedford, Richard Neher, John Huddleston

Dengue: Trevor Bedford, Leah Katzelnick, Gytis Dudas, James Hadfield, John Huddleston, Alli Black, Barney Potter, Louise Moncla, Richard Neher

CZI comp bio: Jeremy Freeman, Deep Ganguli, Nick Sofroniev, Genevieve Haliburton, Ambrose Carr

Tools for Open Science

Or: the tools I wish I knew about when I started

Git + github: version control for reproducibility

(and so you can't irreparably break anything)

Gitkraken: to make git less confusing

Protocols.io: version, share,

collaborate, cite & adapt protocols

Figshare: version, cite & share datasets

ARTICnetwork: resources for

genomic epidemiology

Nextstrain: interactive, shareable explorer for pathogen genomic data

bioRxiv: sharing manuscripts early

Rxivist: finding awesome preprints

Biorender & Noun Project:

better visual communication

Questions?

@sidneymbell

phylo-workshop-san-diego-2019

By Sidney Bell

phylo-workshop-san-diego-2019

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