Contrasting evolutionary dynamics
Dengue (serotype 2)
Influenza (H3N2)
Four (uniform?) serotypes of dengue
DENV1
DENV3
DENV4
DENV2
Each serotype is genetically diverse
DENV1
DENV3
DENV4
DENV2
Sanofi vaccine trial efficacy
varies by genotype
DENV4-I
associated with
adverse events
DENV1
DENV3
DENV4
DENV2
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?
≠
?
≠
≠
Titers approximate pairwise
antigenic distance
Experimentally measure how well sera inhibits viral plaque formation
Sera produced by 1st infection
Test viruses
Dengue serotypes look antigenically diverse
NHP sera; 3 months post primary infection
= 2-fold change in PRNT50
Katzelnick et al, Science 2015
How does
dengue evolve
antigenically?
Models of antigenic evolution
Interserotype hypothesis
Full tree hypothesis
| Pearson R | 0.79 |
| Abs. Error | 1.02 |
| 0.86 |
| 0.86 |
Between-serotype variation explains most of
dengue antigenic phenotypes
Within-serotype variation significantly contributes to dengue antigenic phenotypes
Test Error
Interserotype model
Full tree model
Each serotype of dengue contains multiple
distinct antigenic phenotypes
Genetic distance is associated
with antigenic distance
Homotypic genotypes
Heterotypic genotypes
Dengue
Flu (H3N2)
12 years
500 years
4 titer units*
11 titer units
* likely underestimated
Dengue antigenic evolution is ongoing but slow
Does antigenic diversity impact dengue population dynamics?
Serotypes cycle through populations
Genotypes
Predict clade growth
based on fitness (as before)
Lukzsa and Lassig, Nature, 2014
\propto e^{(f_i(t) + dt)}
Growth rate @
next 5 years
Population susceptibility:
Previously circulating:
Population
immunity:
Clade growth:
Fitness based on antigenic distance* from
standing population immunity
Does antigenic novelty contribute
to dengue fitness?
f_i(t) = f_{i0} - \beta 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
Fitness based on antigenic distance* from
standing population immunity
* from
interserotype
or
full-tree
titer model
Antigenic fitness drives
clade growth & decline
Interserotype model
Full tree model
Genotypes
Serotypes
Antigenic fitness drives
clade growth & decline
Flu population turnover
29% of variation explained
(1 year windows)
Dengue population flux
62% of variation explained
(5 year windows)
smbe-kyoto-2018
By Sidney Bell
