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

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

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)