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

Titers approximate pairwise

antigenic distance

0
	0	2
		0

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

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