A model for the transmission of dengue

Hui Wan

Jing-an Cui

Institute of Mathematics, School of Mathematics

and Computer Sciences, Nanjing Normal University
Nanjing 210097, P.R.China
Email: wanh2046@163.com

Institute of Mathematics, School of Mathematics

and Computer Sciences, Nanjing Normal University
Nanjing 210097, P.R.China
Email: cuija@njnu.edu.cn

AbstractIn this paper, we formulate a dengue model to

explore the complex dynamics induced by antibody-dependent
enhancement (ADE). The basic reproduction number R0 is
calculated. We analyze the regions of existence and stability
for the steady state solutions. Numerical simulation manifests
that backward bifurcation may occur and there may be a stable
endemic equilibrium even if the basic reproduction number is
below 1, which implies that the basic reproduction number is
not enough to describe whether dengue will prevail or not. We
should pay more attention to the initial states.

I. I NTRODUCTION
Dengue has been known clinically for over 200 years, but
the etiology of the disease was not discovered until 1944 [10].
The infective agent is the Dengue virus of the family Flaviviridae. The two recognized species of the vector transmitting
dengue are Aedes aegypti and Aedes albopictus. The former,
which is known as the main vector, is highly anthropophilic,
thriving in crowded cities and biting primarily during the day
while the latter is less anthropophilic and inhabits rural areas.
Dengue is known to exhibit as many as four coexisting types
of serotype (strains) in a region. Once a person is infected and
recovered from one serotype, they confer life-long immunity
from that serotype. However, the antibodies that the body
develops for the first serotype will not counteract a second
infection by a different serotype. In fact, due to the nature of
the disease, the antibodies developed from the first infection
form complexes with the second serotype so that the virus
can enter more cells, increasing viral production. This effect is
known as antibody-dependent enhancement (ADE). Therefore,
the sequential infection increases the risk of more serious
disease resulting in DHF in the region where different types
of serotype coexist.
Currently vector control is the available method for the
dengue and DHF prevention and control but research on
dengue vaccines for public health use is in process. Due to
ADE, an optimal vaccination must protect against the four
types of serotype simultaneously, or the vaccinations could
increase transmission of the types of serotype not covered.
In addition, epidemiological evidence suggests that dengue
hemorrhagic fever (DHF) and dengue shock syndrome (DSS)
are associated with heterologous dengue infections occurring
at an interval of a year or more. Treatment of DHF is
complicated by the fact that it can progress from a non-specific
viral syndrome to irreversible shock and death within a few

hours, so hospitalization is required. Therefore, the coexistence

of different types of serotype is particularly dangerous.
The need for models of dengue disease has reached a
pinnacle as the transmission of this mosquito-borne virus
has increased dramatically. Some mathematical models have
been proposed. With an evaluation of the impact of ultra-low
volume (ULV) insecticide applications on dengue epidemics,
a SEIRS model is studied in [8]. Feng et al. ([9]) studied a
system that models the population dynamics of an SIR vector
transmitted disease with two pathogen strains. They argued
that the existence of competitive exclusion in this system
is product of the interplay between the host superinfection
process and frequency-dependent (vector to host) contact rates.
Esteva and Varga ([4]) studied a one-serotype dengue model
with a constant human population and variable vector population. With the assumption that the human population was
supposed to grow exponentially, the same authors proposed
another models facing only one type of serotype [5]. In
[6], they considered the impact of vertical transmission and
interrupted feeding on the dynamics of the disease. Supposing
both population size of human and vector were constant, a
multi-serotype of dengue was also studied by them ([7]). They
discussed conditions for the asymptotic stability of equilibria,
supported by analytical and numerical methods and found that
coexistence of both types of serotype was possible for a large
range of parameters. Recently, Billings and the others ([3])
formulated a multi-serotype disease model which did not include vector population to investigates the complex dynamics
induced by ADE. In this paper, they derived approximations
of the ADE parameter needed to induce oscillations and
analyzed the associated bifurcations that separate the types
of oscillations and then investigated the stability of these
dynamics by adding stochastic perturbations to the model.
Taking account of the effect of vaccination, a new multiserotype disease model was studied in [2]. After describing
the model and its steady state solutions, they modified it
to include vaccine campaigns and explored if there exists
vaccination rates that can eradicate one or more strains of a
virus with ADE. In addition, Shaw et al. ([11]) presented and
analyzed a dynamic compartmental model for multiple types
of serotype exhibiting ADE. Using center manifold techniques,
they showed how the dynamics rapidly collapsed to a lower
dimensional system.
Our interest here is to explore the effect of ADE to

978-1-4244-2902-8/09/$25.00 2009 IEEE

the transmission dynamics of multi-serotype dengue virus.

For the sake of mathematical tractability, only two types of
serotype is considered. Since the mosquito dynamics operates
on a much faster time-scale than the human dynamics, the
mosquito population can be considered to be at equilibrium
with respect to changes in the human population. In this paper,
we suppose that the human population is variable while the
vector population is constant, which has not been considered
in the multi-serotype dengue model mentioned above.
II. F ORMULATION OF THE MODEL
We formulate a compartmental model for the spread of
dengue fever in the human and mosquito population with the
total population sizes at time t are given by Nh (t) and Nv (t),
respectively.
For the human population: Sh is the number of individuals
susceptible to serotype 1 and 2; Ihj is the number of primary
infective human with serotype j; Rhj is the number of recovered human from serotype j, susceptible to serotype k; Ijk is
the number of secondary infective human with serotype k; Rh
is the number of human recovered from secondary infection of
either types of serotype, and immune to both types of serotype.
h > 0 is the human input (birth) rate. h > 0 is the natural
death rates. ej 0 is the disease-induced death rate produced
by serotype j. j > 0 is the rate at which human hosts with
serotype j recover. hj > 0 is the proportion of bites on human
that produce an infection of serotype j. Since viral production
is increased during a secondary infection due to ADE, we
introduce an ADE parameter, k , to mimic primary infections
with serotype j increase susceptibility to serotype k. In order
to study the effect of ADE, we are considering the situation
of k 1, where k = 1 implies that there is no ADE while
k > 1 implies ADE will increase the susceptibility of the host
to the second serotype. All the subscripts j and k mentioned
in this paragraph satisfy j, k = 1, 2 and j = k.
For the mosquito population: the three compartments represent susceptible vectors Sv , infectious vectors Ivj with
serotype j (j = 1, 2) respectively. Due to its short life span,
we assume that once a mosquito is infected with one kind
of serotype it never recover from the infection, and therefore
it cannot be reinfected with different types of serotype. Then,
secondary infections may take place only in human. Our model
also excludes the immature mosquitoes since they do not
participate in the infection cycle and are, thus, in the waiting
period, which limits the vector population growth. We assume
that, in a given period of time, the mosquito population is
constant and equal to Nv , with birth and death rate constants
equal to v . vj is the probability that a mosquito which
bites an infectious people with serotype j becomes infectious,
j = 1, 2.
The biting rate b of mosquitoes is the average number of
bites per mosquito per day. This rate depends on a number of
factors, in particular, climatic ones, but for simplicity in this
paper we assume b constant.
With the preceding assumptions and parameters, using standard incidence rate, the two-serotype dengue model with ADE

is governed by the following equations:

dSh /dt = h bh1 Iv1 Sh /Nh bh2 Iv2 Sh /Nh h Sh ,

dIhj /dt = bhj Ivj Sh /Nh (h + j )Ihj ,

dRhj /dt = j Ihj h Rhj k bhk Ivk Rhj /Nh ,

dIjk /dt = k bhk Ivk Rhj /Nh (h + k + ek )Ijk ,

dRh /dt = 1 I21 + 2 I12 h Rh ,

dSv /dt = v Nv bv1 (Ih1 + I21 )Sv /Nh

bv2 (Ih2 + I12 )Sv /Nh v Sv ,

dI
/dt
= bvj (Ihj + Ikj )Sv /Nh v Ivj ,
vj

dNh /dt = h h Nh e1 I21 e2 I12 ,

(A.1)
where j, k = 1, 2, j = k and Nh = Sh + Ih1 + Ih2 + I12 +
I21 + Rh1 + Rh2 + Rh and Nv = Sv + Iv1 + Vv2 are total
number of human and mosquitoes respectively.
The first quadrant in the Sh Ih1 Ih2 Rh1 Rh2 I12 I21 Rh
Sv Iv1 Vv2 Nh space is positively invariant for system (A.1)
since the vector field on the boundary does not point to the
exterior. Whats more, since dNh /dt < 0 for Nh > h /h
and Nv is constant, all trajectories in the first quadrant enter
or stay inside the region
D+ = {(Sh , Ih1 , Ih2 , Rh1 , Rh2 , I12 , I21 , Nh , Iv1 , Iv2 ) | Nh
 h /h , Sv + Iv1 + Vv2 = Nv }.
The continuity of the right-hand side of (A.1) implies that
unique solution exists on a maximal interval. Since solutions
approach, enter or stay in D+ , they are eventually bounded
and hence exist for t > 0. Therefore, the initial value problem
for system (A.1) is mathematically well posed and biologically
reasonable since all variables remain nonnegative.
In order to reduce the number of parameters and simplify
system (A.1), we normalize the human and mosquito vector
I
Rhj
h
, ihj = hhj
population sh = hS/
/h , rhj = h /h , ijk =
h
Ijk
h /h ,

Sv
h
h
rh = hR/
, nh = hN/
, sv = N
, ivj = Nvjv and
v
h
h
v
m = hN/
, where j, k = 1, 2, j = k.
h
It follows from the relations rh = nh sh ih1 ih2
rh1 rh2 i12 i21 and sv = 1 iv1 iv2 that the original
model (A.1) can be reduced to the following nonlinear system

mbh1
mbh2
dsh

= h
iv1 sh
iv2 sh h sh ,

dt
n
nh
h

mbhj
dihj

=
ivj sh (j + h )ihj ,

nh
dt

drhj
mbhk

= j ihj h rhj k
ivk rhj

dt
nh
dijk
mbhk

= k
ivk rhj (h + k + ek )ijk ,

dt
nh

dnh

= h h nh e1 i21 e2 i12 ,

dt

divj = bvj (ihj + ikj ) (1 iv1 iv2 ) v ivj ,

dt
nh
(A.2)

where j, k = 1, 2, j = k. Note that all trajectories in the first

quadrant enter or stay inside the region
= {(sh , ih1 , rh1 , iv1 , ih2 , rh2 , iv2 , i21 , i12 , nh ) | 0  sh ,
0  ihk , 0  ijk , 0  rhk , 0  ivk ,
sh + ih1 + ih2 + i12 + i21 + rh1 + rh2  1, iv1 + iv2  1,
j, k = 1, 2, j = k}.
III. T HE BOUNDARY E QUILIBRIA
According to the concept of next generation matrix (Diekmann et al., 1990 [1]) and reproduction number presented in
van den Driessche and Watmough (2002) [12], by calculation,
we can get the basic reproduction number


(A.3)
R0 = max{ R1 , R2 },
where

mb2 hk vk
Rk =
, k = 1, 2.
v (h + k )

(A.4)

Thus, according to our analysis, for the boundary Equilibria,

we have the following results:
Theorem III.1. For the model (A.1), the disease-free equilibrium E0 always exists; there also exists a boundary equilibrium Ek if and only if Rk > 1, k = 1, 2. E1 is the state
where only serotype 1 is present and E2 is the state where
only serotype 2 is present.
The stability of the disease-free equilibrium E0 is given by
the following theorem:
Theorem III.2. If R0 < 1 (R0 > 1), E0 is locally asymptotically stable (unstable).
Consider now the stability of the boundary equilibria
Ek , k = 1, 2. Note that E1 and E2 only make biological sense
when R1 > 1 and R2 > 1, respectively. For E1 and E2 , we
have the following theorem:
Theorem III.3. E1 is locally asymptotically stable when
R1 > 1 and
R1
R2 <
.
(A.5)
1 + 2 (R1 1)
Similarly, E2 is locally asymptotically stable when R2 > 1
and
R2
,
(A.6)
R1 <
1 + 1 (R2 1)
where
j =

j v k (h + j )
,
(h bvk + v h + v k )(h + j + ej )

(A.7)

j, k = 1, 2, j = k.
Remark III.4. In the case where R1 = R2 , we find that the
boundary equilibria, E1 and E2 , are never stable. In addition,
E1 and E2 cannot be stable simultaneously, which implies that
only one serotype for which Rk is bigger will exist eventually
if the two serotypes can not coexist when R0 > 1.

Noting that, using R1 and R2 as parameters, in the plane

of R1 R2 ,
Rk
,
(A.8)
Rj =
1 + j (Rk 1)
(j, k = 1, 2, j = k) is a hyperbola when k = 1, otherwise, it
is a straight line. It is easy to see that the stability regions of
E1 and E2 become smaller as 1 and 2 increase. Since j
will increase with the increasing of j , we can conclude that
the effect of antibody-dependent enhancement (ADE) reduce
the possibility of the permanence of only one type of serotype,
which is more dangerous for dengue because of the risk for
DHF/DSS and the higher mortality rates and transmissibility
for second infections.
IV. E NDEMIC EQUILIBRIA AND BACKWARD BIFURCATION
Due to the complexity of this system, it is not easy to
analyze the existence and stability of the endemic equilibrium
E3 .
0.04

0.04

0.03

0.03

ih1
0.02

ih2
0.02

0.01

0.01

2000

4000 t

6000

8000

(a) The time course of

ih1 .

2000

4000 t

6000

8000

(b) The time course of

ih2 .

Fig. 1. A stable endemic equilibrium where both types of serotype are present
when R0 < 1. The units of time is day and 1 = 2 = 50, h = 0.0015,
v = 1/14, h1 = 0.02, h2 = 0.02, v1 = v2 = 0.15, m = 5,
e1 = e2 = 0.04, 1 = 2 = 1/14, b = 0.5. Note that R0 0.848 and
1 = 2 30.960.

Now, we consider the situation when R0 < 1. By Theorem

III.2, the DFE is always existing and local stable when R0 < 1.
To begin exploring the dynamics numerically, we set h =
0.0015, v = 1/14, h1 = h2 = 0.02, v1 = v2 = 0.15,
m = 5, e1 = e2 = 0.04, 1 = 2 = 1/14, b = 0.5. Note that
R1 = R2 0.848 < 1. For symmetry, ih1 = ih2 , iv1 = iv2 ,
rh1 = rh2 , i21 = i12 at the endemic equilibrium, if it exists.
Thus, we can evaluate the existence for a endemic equilibrium.
Interestingly, by calculation and numerical simulation, there
exists a threshold condition for the ADE parameter j . If
j is big enough, for example, let 1 = 2 = 50, there
are two endemic equilibria. One is E01 where sh 0.801,
ih1 0.00204, rh1 0.0135, i12 0.00111, nh 0.941,
iv1 0.0035 and the other is E02 where sh 0.891,
ih1 0.00112, rh1 0.0132, i12 0.000535, nh 0.971,
iv1 0.00179. In addition, the former is a locally stable
endemic equilibria (see Fig. 1), which implies the global
stability of E0 is impossible and backward bifurcation is
induced by ADE. The basic reproductive number itself is not
enough to describe whether dengue will prevail or not in this
situation. We should pay more attention to the effect of ADE
and the initial state of the disease.

V. D ISCUSSIONS
In this paper, we have formulated a model to study the
dynamics of a two-serotype dengue with ADE. The basic
reproduction number was produced. We analyzed the system
and found regions of stability for the steady state solutions.
The effect of ADE was studied.
According to our analysis, ADE shrank the area of parameter space in which only one type of serotype was present and
enlarged the area in which both types of serotype were present,
which was not desirable because of the risk for DHF/DSS
and the higher mortality rates and transmissibility for second
infection. Numerical simulation manifested if the parameter
of ADE was big enough, there existed a endemic equilibrium,
which implied that the global stability of E0 was impossible.
ADE induced complex dynamics.
By the definition of R0 , it was independent to the ADE
parameter. Nevertheless, due to ADE , the susceptibility was
increased when a new kind of serotype entered a population in
which some individuals have had previous dengue infections.
Therefore, the basic reproduction number obtained by just
fitting a time series may give an incorrect estimation of the
true number of secondary cases produced by a primary case
in a fully susceptible population.
Because of the effect of ADE, endemic equilibria might
exist even if R0 < 1 and there might be backward bifurcation.
This was a new result which implied that the basic reproduction number was not enough to describe whether dengue will
prevail or not. We should pay more attention to the initial
states.

[11] Shaw, L. B., Billings, L., Schwartz, I. B., 2007. Using dimension
reduction to improve outbreak predictability of multistrain diseases. J.
Math. Biol. 55, 1-19.
[12] van den Driessche, P., Watmough, J., 2002. Reproduction numbers and
sub-threshold endemic equilibria for compartmental models of disease
transmission. J. Math. Biosci. 180, 29-48.
[13] World
Health
Organization
website,
2008,
<http://www.who.int/csr/disease/dengue/>.

ACKNOWLEDGMENT
Research is supported by the National Natural Science
Foundation of China (10771104).
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