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
epidemics-sitges-2017
By Sidney Bell
