Understanding Dengue Antigenic Evolution

Epidemics Conference, Nov. 2017

Sidney Bell

Bedford Lab

There are 4 serotypes of dengue, each containing substantial genetic diversity

DENV1

DENV3

DENV4

DENV2

Dengue is hyperendemic in tropical regions

Population-level cocirculation causes

more severe infections for individuals

Antigenic relationships drive

dengue outcomes

Lifelong protection

Temporary

cross-protection

Initial

response

Antigenic relationships drive

dengue outcomes

Lifelong protection

Susceptibility +/-

enhancement

After

1-3 yrs

DENV antigenic relationships

are poorly understood

Serotypes are genetically distinct

Clades are genetically distinct

Serotypes are antigenically distinct

Are clades antigenically distinct?

≠

?

≠

≠

Titers approximate pairwise

antigenic distance

Autologous Titers = 0

0
0
0

1

2

1 unit = 1 x 2-fold

​decrease in binding

2

Sera produced by

"reference virus" infection

Test viruses

Titers approximate pairwise

antigenic distance

Autologous Titers = 0

0
0.0 2.0
0.0

1.0

2.0

1 unit = 1 x 2-fold

​decrease in binding

2-fold

change

4-fold

change

4-fold

change

Antigenic Space

Antigenic cartography suggests serotypes are antigenically heterogeneous

NHP sera; 3 months post primary infection

= 2-fold change

in titer

Katzelnick et al, Science 2015

How do
dengue genotypes
map to
antigenic phenotypes?

Can we predict antigenic phenotypes from virus genotypes?

Phylogenies can describe both genetic and antigenic relationships

Quantify antigenic change along each branch, 

Neher et al, PNAS 2016

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

Titer

between

&

+         avidity +     potency

d_b

Interpolate across the tree

to estimate antigenic relationships

\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

\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

\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

Squared Error

Minimize

this

L1 norm on branch effects

L2 norm on virus avidity & serum potency

Does within-serotype genetic diversity change antigenic phenotypes?

Interserotype branch effects

All branch effects

Pearson R 0.79
Abs. Error 0.71
Sqr. Error 0.87
0.90
0.61
0.61

Between-serotype variation explains most of

dengue antigenic phenotypes

Within-serotype variation significantly contributes to dengue antigenic phenotypes

Test Error

Each serotype of dengue contains multiple

distinct antigenic phenotypes

Log2 titer distance from root

DENV1

DENV3

DENV4

DENV2

>= 10 distinct phenotypes

Genetic distance is associated

with antigenic distance

Homotypic genotypes

Heterotypic genotypes

Does intraserotype antigenic variation affect vaccine efficacy?

Log2 titer distance from Sanofi

DENV4

DENV2

Log2 titer distance from Sanofi

Does intraserotype antigenic variation affect vaccine efficacy?

How does

antigenic diversity impact dengue population dynamics?

Serotypes cycle through populations

Genotypes

Does antigenic novelty contribute to dengue clade turnover?

Population susceptibility:

Previously circulating:

Population

immunity:

Clade growth:

Predict clade growth

from antigenic novelty

Lukzsa and Lassig, Nature, 2014

\frac{x_i(t+5)}{x_i(t)} \propto e^{(f_i(t) + 5)}

Growth rate of

clade i

Measure of antigenic novelty of clade i

How antigenically distant*

is clade i from what has recently circulated?

* from

interserotype

or

full-tree

titer model

Does antigenic novelty contribute

to dengue fitness?

f_i(t) = 1 - P_i(t)

Relative frequency of j

Waning immunity

P_i(t) \propto \sum_{t-n}^{t} \gamma(n) \sum_{j} x_{j}(t) * C(D_{ij})

Antigenic distance between i and j

Lukzsa and Lassig, Nature, 2014

Does antigenic novelty contribute

to dengue fitness?

f_i(t) = 1 - P_i(t)

Relative frequency of j

Waning immunity

Probability of protection from i

given exposure to j

Lukzsa and Lassig, Nature, 2014

P_i(t) \propto \sum_{t-n}^{t} \gamma(n) \sum_{j} x_{j}(t) * C(D_{ij})

Antigenic novelty significantly

contributes to dengue viral fitness

Pearson R 0.88 0.87

Interserotype antigenic phenotypes

drive population dynamics

Summary:

1: Dengue serotypes contain moderate antigenic heterogeneity

 

2: Serotype-level antigenic relationships drive

dengue population dynamics

Acknowledgements

Trevor Bedford, Leah Katzelnick

Gytis Dudas, James Hadfield, John Huddleston, Alli Black, Barney Potter, Louise Moncla

Richard Neher, David Shaw, Duncan Ralph

Erick Matsen, Jesse Bloom, Julie Overbaugh,

Adam Geballe, Daniela Witten

Slides: The Noun Project & RevealJS

Questions?

github.com/sidneymbell/talks

                 .org/dengue