MBE, 18(3): 2688–2712.

DOI: 10.3934/mbe.2021137
Received: 29 October 2020
Accepted: 18 February 2021
http://www.aimspress.com/journal/MBE Published: 19 March 2021

Research article
A mathematical model for Vibrio-phage interactions

Christopher Botelho1,∗ , Jude Dzevela Kong2,3 , Mentor Ali Ber Lucien4 , Zhisheng Shuai1
and Hao Wang5
1
Department of Mathematics, University of Central Florida, Orlando, Florida, 32816, USA
2
Department of Mathematics and Statistics, York University, Toronto, Ontario, M3J 1P3, Canada
3
The Canadian Center for Disease Modelling, York University, Toronto, Ontario, M3J 1P3, Canada
4
Laboratoire National de Santé Publique, Ministère de la Santé Publique et de la Population d’Haiti,
Port-au-Prince, HT6120, Haiti
5
Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, Alberta,
T6G 2G1, Canada

* Correspondence: Email: [email protected]; Tel: +1-407-823-6284; Fax:

+1-407-823-6253.
Abstract: A cholera model has been formulated to incorporate the interaction of bacteria and phage. It
is shown that there may exist three equilibria: one disease free and two endemic equilibria. Threshold
parameters have been derived to characterize stability of these equilibria. Sensitivity analysis and
disease control strategies have been employed to characterize the impact of bacteria-phage interaction
on cholera dynamics.
Keywords: cholera; bacteriophage; global stability; basic reproduction number

1. Introduction

Cholera is a gastrointestinal illness that presents with diarrhea and vomiting which, if left untreated,
may result in death. Death occurs as a result of dehydration, metabolic acidosis and uremia [1, 2].
A cholera infection is contracted upon consumption of water contaminated by the Vibrio cholerae
bacterium. An infected individual may then release additional pathogenic bacteria (V. cholerae) into
the environment by means of defecating or vomiting into or near a water source (this is referred to
as shedding). As consuming contaminated water is the main route of transmission, areas without
proper water sanitation are effected the most. These regions experience endemic cholera which appears
with seasonality. Regions that have been significantly impacted by cholera include Haiti, Dominican
Republic, Tanzania, Democratic Republic of the Congo, Somalia, Nigeria, South Sudan, Mozambique,
 2689

Iraq and Afghanistan [3,4]. With 1.3 to 4 million cases per year, cholera remains a global public health
concern [2].
While V. cholerae is the pathogen that creates a potentially devastating infection, it is not the only
microbe at play. In the environment, V. cholerae interact with bacteriophage (which we will refer to as
just phage). Phage are viruses that insert their genetic material into the bacterial cell. These phage may
be either lytic or lysogenic. A lysogenic phage integrates it genetic material into the bacterial cell’s
genome. When the bacterium replicates by means of binary fission, the phage genetic material remains
present in the bacterial daughter cells. The lysogenic cycle is a non destructive means for phage
replication. Some lysogenic phage may be beneficial to the survival of a bacterial cell. In the case of
cholera, the toxin production is attributed to the CTXϕ phage. A lytic phage inserts its genetic material
into the bacterial cell and replicates within the host cell. This causes the cell to lyse (burst) resulting
in cell death. The lytic process releases additional phage into the environment. While some phage
aid in the survival of the bacterial cell, such as the phage that are responsible for the pathogenicity of
V. cholerae, others do quite the opposite. The interaction of the bacteria and lytic phage resembles a
predator-prey type relationship.
While V. cholerae may exist in biofilms which aid in the survival of the bacterium, another mecha-
nism for cell survival is the ability of the bacterium to enter a viable but not culturable state (VBNC).
A bacterial cell enters a VBNC state when conditions are harsh. These bacteria are viable to produce
infection but do not replicate on routine media and so are not culturable. When more favorable con-
ditions present, the bacterial cell may resuscitate [5]. Such favorable conditions may be the gut of an
individual who has consumed water contaminated with bacteria in the VBNC state. Upon resuscitation,
the bacteria replicate rapidly within the gut, resulting in a cholera infection.
While cholera has plagued the developing world since the 1800s, there has been a significant amount
of research in the spread of the disease. Despite this, there has been only a few publications in mod-
elling the impact of the bacteria and phage interactions. Since the pioneering work of Codeço in
2001 [6], mathematical modelling has been used to better understand cholera and how it might be
controlled in regions that experience endemic cholera. The model developed by Codeço is an ordinary
differential equation model consisting of a human and a bacterial population. The human population is
divided amongst two explicit compartments (susceptible and infectious) and the bacteria are accounted
for in one bacterial compartment (bacterial reservoir). The bacterial compartment included the human
contribution of shedding new pathogenic bacteria into the reservoir. Codeço also explored seasonality
of the cholera by the use of a periodic function for the contact and shedding terms. While the model
Codeço developed included only three rather simple differential equations, it laid the foundation for all
models to come.
After Codeço’s work, many researchers have sought to understand the dynamics of cholera in a
more complicated setting. As a large proportion of individuals infected with cholera produce only
mild symptoms, King et al. incorporated asymptomatic infections in their model [7]. As shown in
their paper, although there might be relatively few cholera infections reported in a host population,
free-living bacteria in the environmental reservoir (aka, a reservoir environment) may be critical to the
disease’s endemicity. Models such as the one developed by Jensen et al. [8] take a different approach
to study the environmental reservoir and explore the disease dynamics influenced by the bacteria and
phage interaction. Specifically, the authors developed a model consisting of a human population, a bac-
terial population and a phage population. The human population was divided into four compartments;

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a susceptible, a recovered and two infectious compartments. The infectious compartments included
those who were phage “positive” and those who were phage “negative.” This model showed that the
presence of phage effectively reduce the bacterial concentration and thus infections, which is consistent
with the biological understanding of the bacteria-phage interactions. Kong, Davis and Wang [9] further
incorporated an immunological threshold (a minimum dose of bacteria is needed to yield an infection)
and showed that oscillating trajectories could exist in both the microbial and population scales. Notice
that different functional responses were employed for vibrio-phage interaction: Holling type I in [8]
while Holling type II in [9]. It remains unclear whether vibrio-phage interaction of Holling type I could
drive oscillation in cholear dynamics.
In this paper we investigate the cholera disease dynamics incorporating the bacteria-phage inter-
action of Holling type I. Specifically, the model consists of a human population (SIRS), a bacteria
(B) and phage population (P) to exhibit these interactions. We are able to show that no oscillating
trajectories exist in a non-reservoir environment, while oscillating trajectories could exist in both the
microbial and population scales in a reservoir environment. Our results demonstrate that a reservoir
environment could be another driven force for cholera periodicity. In addtion, strategies for controlling
cholera are discussed by conventional means (water purification, sanitary waste disposal, etc.) as well
as unconventional means (presence of phage).

2. Model development

We formulate a cholera model incorporating the interaction of bacteria and phage so that we
could investigate their influence on the disease dynamics. Specifically the model couples the clas-
sic Susceptible-Infectious-Recovered-Susceptible (SIRS) model of the human disease with a predator-
prey model of a Holling type I functional response for lytic phage (P) and bacteria (B). Furthermore,
we include only natural deaths (natural death rate µ) and neglect disease related deaths for simplic-
ity. This is justified as cholera is easily treated with either oral or intravenous fluids in conjunction
with antibiotics (for severe cases), and thus cholera has a relatively low death rate. The probability of
contracting an infection from consuming V. cholera contaminated water is given by the dose response
f (B) = B+H
B
. Here, H is the bacterial concentration that yields a 50% chance of infection. This dose
response is the same function used in the Codeço model [6]. We assume that there are constant births
Λ. The lytic phage interact with bacteria and result in bacterial death at a rate of b while the phage
have a gain from such bacterial death represented by χ. The bacteria replicate in the environment and
the bacterial “birth” rate is given by ν, while the natural bacterial death rate is δ. An environment is
called as a reservoir environment if ν > δ (bacteria grow in the absence of shedding from infectious
individuals); otherwise, if δ > ν, then it is called as a non-reservoir environment (bacteria die out in the
absence of the shedding from infectious individuals). Phage require a host cell (bacterium) to replicate
and so there is no replication independent of bacterial cell death. The phage deactivate at a rate m. Note
that we use the term deactivate instead of die, as a phage is a virus which does not fit the biological
definition of a living organism. In contrast to the model developed by Kong et al. [9], we include a
temporary disease induced immunity. This inclusion is important to consider as the immunity obtained
from a cholera infection may range from a few weeks to greater than 3 years, depending on severity of
infection [10–12]. This immunity is lost at a rate γ. With these considerations in mind, we have the

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following system of ordinary differential equations:





Ṡ = Λ + γR − α f (B)S − µS

I˙ = α f (B)S − (r + µ)I






= rI − (γ + µ)R

(2.1)


Ṙ

= νB + ηI − δB − bBP

Ḃ





= χbBP − mP,


Ṗ


with non-negative initial conditions. A visual representation of the model is given by the model di-
agram in Figure 1. Note that our model can be further extended to include direct transmission [13]
and the logistic growth of bacteria [14], which are ignored here, so that the impact of bacteria-phage
interaction can be highlighted. The proposed model (2.1) can be regarded as a simplification of the
model in [11]. This simplification allows for a more theoretical and deeper analysis to include global
stability results which were not included in [11].

γR
µS µI µR
Λ rI
S α f (B)S I R

ηI
χbBP
B P
νB
δB + bBP mP

Figure 1. Flow diagram from model (2.1).

A list of parameters and their descriptions can be found in Table 1, all parameters are assumed to
be positive, unless indicated otherwise. In addition, we include parameter values which are commonly
used in the literature and also will be used for our simulations in Section 9. It is important to make a
note regarding the parameter α before proceeding. In the literature, α takes on values smaller than one;
for example, α = 0.1 in [8]. However, α may be viewed as the product of the incubation rate and the
number of contaminated consumptions per day. Given that the mean incubation for cholera is about 3
days, assuming an individual consumes a considerable amount of contaminated water 3 times per day,
we set α = 31 · 3 = 1.

3. Feasible region

Set N = S + I + R, and so Ṅ = Ṡ + I˙ + Ṙ. It follows from the model (2.1) that

Ṅ + µN = Λ.

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Table 1. Model parameter values, descriptions and associated units. It is assumed that an
individual lives, on average to be 70 years old and thus µ = 70·365
1
. Moreover, the human birth
term Λ is chosen the be µN0 so that the human population remains constant.
Parameters for Bacteria-Phage Model
Parameter Description Units Value Source

f (B) probability of infection upon consumption unitless

Λ human birth rate persons·days−1 10000
70·365

µ natural human death rate days−1 1

70·365

α rate of bacterial consumption days−1 0.1 − 1 0.1 [8]

−1
r recovery rate days 0.1 − 1 WHO
γ rate in which immunity is lost days−1 0.001 − 0.03 [12]
η bacterial shedding rate bacteria·person−1 ·days−1 10 − 100 [8]
ν natural bacterial growth rate days−1 0−2
δ bacterial death rate days −1
0−1
b phage attack rate days−1 ·phage−1 0 − 0.025 [9]
χ phage gain from bacteria days−1 ·bacteria−1 80 − 100 [8]
m phage deactivation rate death−1 0.5 − 7.9 [8]
6 8
H 50% infectious dose of bacteria bacteria 10 − 10 [8]

Now, using the method of the integrating factor, we have the equation dtd {eµt N} = Λeµt . Integrating this
yields
Λ Λ
N = + (N0 − )e−µt ,
µ µ
where N0 = N(0). Letting t → ∞, we see that N(t) → Λµ . If N0 > Λµ , we see that Ṅ < 0 and so N
monotonically decreases from N0 to Λµ . Hence N≤N0 in this case. On the other hand, if N0 < Λµ , Ṅ > 0
and so N monotonically increases from N0 to Λµ . So, in this case, N≤ Λµ . Lastly, if N0 = Λµ , Ṅ = 0 and
so N = Λµ for all time. From this, we conclude that for any initial population size N0 , N is bounded.
More precisely, N≤ max{N0 , Λµ } for all time.
Now, consider the case of a non-reservoir environment (i.e., δ > ν), and set  = min{δ − ν, m} > 0.
Let E = χB + P, and so Ė = χ Ḃ + Ṗ. From (2.1), we have

Ė = χ Ḃ + Ṗ
= −χ(δ − ν)B − mP + ηχI
≤ − (χB + P) + ηχI
Λ
≤ − E + ηχ .
µ

This gives Ė+E ≤ ηχ Λµ . Again using the method of the integrating factor, we obtain dtd {Eet } ≤ ηχ Λµ et ,

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which upon integrating gives E(t) ≤ ηχΛ

µ
+ Ce−t , where C is a constant. Thus, lim supt→∞ E(t) ≤ ηχΛ
µ
.
This motivates the following lemma.
Lemma 3.1. Given the condition δ > ν, we define the feasible region by
n  Λ ηχΛ o
Γ = (S , I, R, B, P) ∈ R5+  S + I + R ≤ , χB + P ≤ ,
µ µ
which is positively invariant with respect to (2.1).
For the case δ > ν, dynamics of (2.1) within Γ will be carried out analytically in Sections 4 and 5.
For the case of a reservoir environment (i.e., ν > δ), bacteria can grow in the absence of cholera
infection, and dynamics of (2.1) could be more complicated. For example, its solutions with initial
value P(0) = 0 could be unbounded, and numeral simulations in Section 9 also show the existence of
sustained oscillations.

4. Disease free equilibrium and stability

Letting I = 0 and setting Ṡ = I˙ = Ṙ = Ḃ = Ṗ = 0 in (2.1), it is clear that Q0 = ( Λµ , 0, 0, 0, 0) is the

disease free equilibrium (DFE). This equilibrium always exists and lies on the boundary of Γ. We now
discuss both local stability as well as global stability of the DFE.
To explore the local stability of the DFE , we will examine the Jacobian matrix. However, before
proceeding we exchange the I and R equations to obtain a matrix with a nice structure. Note that this
arrangement does not effect the component order of the DFE as both the I and R components at DFE
are zero. The Jacobian matrix at the DFE is then given by
γ − αΛ
 
−µ 0 Hµ
0 
 0 −(γ + µ)
 
r 0 0 
JDFE =  0 0 −(r + µ) αΛ 0  .
 
Hµ
η ν − δ 0 
 
 0 0
−m
 
0 0 0 0
This matrix is block upper triangular and so three eigenvalues are −µ, −(γ + µ), −m < 0 and the
remaining two eigenvalues are given by the eigenvalues of the 2 × 2 matrix
−(r + µ) αΛ
" #
M= Hµ
. (4.1)
η ν−δ
Now, we may conclude that the remaining two eigenvalues have negative real part provided Tr(M) < 0
and Det(M) > 0. We have Det(M) = −(r + µ)(ν − δ) − Λαη Hµ
Λαη
> 0 implies Hµδ(r+µ) + δν < 1. For this
inequality to hold, it is required that δ > ν. Now, Tr(M) = −(r + µ) + ν − δ < 0. Thus, under
Λαη
the condition Hµδ(r+µ) + δν < 1, the DFE is locally stable and unstable otherwise. Now we define the
following threshold parameter
Λαη ν
RB B + . (4.2)
Hµδ(r + µ) δ
Biologically, RB describes the average number of next generation of bacteria, and accounts of both
Λαη
reproductions due to bacteria shedding from infectious individuals ( Hµδ(r+µ) ) and due to its natural

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growth ( δν ). The following result shows that RB serves as a threshold value determining whether the
disease dies out (when RB < 1). The relation between RB and the basic reproduction number R0 (a
more commonly used threshold value in the literature) will be discussed in Section 6.
Theorem 4.1. The disease free equilibrium is globally asymptotically stable if RB < 1, and is unstable
if RB > 1.
Proof. It suffices to show that the disease free equilibrium is globally asymptotically stable when RB <
1. Consider the function
r+µ r+µ
L=I+ B+ P.
η ηχ
Clearly L ≥ 0. Now, differentiating with respect to (2.1), we have

Λα (r + µ)(ν − δ)
m(r + µ)
L̇ = + B− P
Hµ η ηχ
RB − 1 m(r + µ)
= B− P.
ηδ(r + µ) ηχ
So, it is clear that when RB < 1, L̇ ≤ 0. We have that L is a Lyapunov function. Now, L̇ = 0 implies
B = P = 0. Since B = P = 0, we have Ḃ = 0 and so from the equation for Ḃ in (2.1), we see that
I = 0. Now, since I = 0, I˙ = 0 and so by the equation for I˙ in (2.1), we may conclude S = Λµ . Since
S = µλ , Ṡ = 0 and so the equation for Ṡ in (2.1) gives that R = 0. So, the largest invariant set such that
L̇ = 0 is given by {Q0 }. Thus, by LaSalle’s invariance principle [15], we conclude that Q0 is globally
asymptotically stable in Γ. 
Biologically, Theorem 4.1 implies that when the critical value RB < 1, the disease fails to persist for
any initial conditions within the feasible region. Alternatively, if RB > 1, the disease free equilibrium
is unstable. Simulations with different initial conditions have been performed, as depicted in Figure 2.
The biological meaning and importance of the critical value RB is discussed further in section 6.

80

70

60
Infectious Individuals

50

40

30

20

10

0
0 10 20 30 40 50 60 70 80
time (days)

Figure 2. Three sample trajectories of infectious individuals for model (2.1) with varying
initial conditions, provided RB < 1.

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5. Endemic equilibria and their stability

In this section, we provide detailed analysis for disease dynamics when RB > 1. First, model (2.1)
admits potentially two distinct endemic equilibria. One of the equilibria, when it exists, exists in the
absence of phage. This equilibrium will be referred to as the phage free endemic equilibrium (PFEE)
and will be denoted by QPFEE = (S ∗ , I∗ , R∗ , B∗ , 0). Another endemic equilibrium, when it exists, exists
in the presence of phage and so this equilibrium is referred to as the phage present endemic equilibrium
(PPEE) and will be denoted by QPPEE = (S ∗ , I ∗ , R∗ , B∗ , P∗ ).

5.1. Phage free endemic equilibrium and stability

For the PFEE, set P = 0, and Ṡ = I˙ = Ṙ = Ḃ = Ṗ = 0. It follows from (2.1) that

0 = Λ + γR − α f (B)S − µS (5.1)
0 = α f (B)S − (r + µ)I (5.2)
0 = rI − (γ + µ)R (5.3)
0 = (ν − δ)B + ηI. (5.4)
η
So, (5.3) gives that R∗ = γ+µ
r
I, (5.4) gives B∗ = δ−ν I∗ and so it is necessary that δ > ν, and (5.2) gives
r+µ δ−ν
S ∗ = α η H + I∗ . We now must determine when I∗ is feasible. We use S ∗ , R∗ , B∗ in (5.1) and obtain

Λαη − µ(r + µ)(δ − ν)H rµ µ(r + µ)

= I∗ +µ+ .
αη γ+µ α

For I∗ to be positive the left hand side of the above equation must be positive. That is, we must have
Λαη − µ(r + µ)(δ − ν)H > 0 which occurs when RB > 1. So, under the condition RB > 1 and δ > ν, the
phage free endemic equilibrium exists, denoted as QPFEE = (S ∗ , I∗ , R∗ , B∗ , 0).
Before proceeding, we define another threshold parameter

b ν Λαηχ(γ + µ)
+ .


RP B
δ b rµαm + µαm(γ + µ) + µχbH(r + µ)(γ + µ) + mµ(r + µ)(γ + µ)

Biologically, RP can be regarded as the phage invasion reproduction number, characterizing whether
the phage population can succeed to invade (see Theorems 5.1 and 5.2). It is straight forward to show
RP < R B .
Now, to explore the local stability of the PFEE, we again turn to the Jacobian matrix. We have

−α f (B∗ ) − µ γ − H(r+µ)(δ−ν)

 
0 η(H+B∗ )
0 
 α f (B ) −(r + µ) 0 H(r+µ)(δ−ν)
0

 ∗ η(H+B∗ )

JPFEE =  −(γ + µ)  .

0 r 0 0
η ν−δ

0 0 −bB∗ 
 
χbB∗ − m
 
0 0 0 0

One of the eigenvalues is λ5 = χbB∗ − m while the remaining eigenvalues are not readily apparent. This
is again a block upper triangular matrix and so the remaining 4 eigenvalues are given by the eigenvalues

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of
−α f (B∗ ) − µ γ − H(r+µ)(δ−ν)
 
0 η(H+B∗ ) 

 α f (B∗ ) −(r + µ) H(r+µ)(δ−ν) 

0

C =  η(H+B∗ )   .
 0 r −(γ + µ) 0 
η ν−δ
 
0 0
We compute the characteristic polynomial of C and obtain the polynomial

det(C̄ − tI) = (µ + t) t3 + (r + 2µ + γ + δ − ν + α f (B∗ ))t2

+ α f (B∗ )(γ + r + µ + δ − ν) + (γ + µ)(r + µ)
H(r + µ)(δ − ν) 
+ (r + 2µ + γ)(δ − ν) − t
H + B∗
+ (γ + µ)(r + µ)(δ − ν) + α f (B∗ )(γ + r + µ)(δ − ν)
H(r + µ)(δ − ν)(γ + µ) 
− .
H + B∗
It can be show that t = −µ is a root of the polynomial and so it remains to show the roots of the third
degree factor have negative real parts. To do this, we utilize the Routh-Hurwitz criterion which states
that a third degree polynomial of the form p(t) = t3 + a1 t2 + a2 t + a3 has roots that lie in the left half of
the complex plane provided a1 , a2 , a3 > 0 and a1 a2 > a3 . Indeed, it is clear that for δ > ν, a1 , a2 , a3 > 0.
Now,

a1 a2 = α f (B∗ )(γ + r + µ + δ − ν)(γ + 2µ + r + δ − ν + α f (B∗ ))

+ (γ + µ)(r + µ + δ − ν)(γ + 2µ + r + δ − ν + α f (B∗ ))
B∗ (r + µ)(δ − ν)(γ + 2µ + r + δ − ν + α f (B∗ ))
+
H + B∗
B∗ (r + µ)(δ − ν)(γ + µ)
> α f (B∗ )(γ + r + µ)(δ − ν) + = a3
H + B∗
So, by the Routh-Hurwitz criterion, we may conclude that when QPFEE exists, λ1 , λ2 , λ3 , λ4 have nega-
tive real parts. All that is left to conclude local stability of the PFEE is determining when the eigenvalue
λ5 = χbB∗ − m < 0. Using B∗ in terms of I∗ and writing I∗ out explicitly, we obtain the the inequality
χb  (γ + µ)[Λαη − µHδ(r + µ) + µνH(r + µ)] 
−m<0
δ−ν rµα + µα(γ + µ) + µ(r + µ)(γ + µ)
which holds if and only if RP < 1. Thus we can conclude that QPFEE is locally stable provided
RP < 1 < RB . Note that the condition δ > ν is implied by RP < 1.
We now explore the global stability of the PFEE when γ = 0. That is, when recovered individuals
attain permanent immunity.
Theorem 5.1. If RP < 1 < RB and γ = 0, then QPFEE is globally asymptotically stable.
Proof. To show global stability of the PFEE, consider the function
S
I

L = S − S ∗ − S ∗ ln + I − I∗ − ln
S∗ I∗

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r + µ B
 r + µ
+ B − B∗ − B∗ ln + P.
η B∗ ηχ

It is clear that L ≥ 0. Taking the derivative with respect to t, we have

S∗ S
S∗ f (B) B f (B)S I∗ B∗ I

L̇ = µS ∗ 2 − − + α f (B∗ )S ∗ 3 − + − − −
S S∗ S f (B∗ ) B∗ f (B∗ )S ∗ I BI∗
r+µ
+ χbB∗ − m P.


ηχ

As discussed previously, χbB∗ −m < 0 provided RP < 1. It remains to show negativity of the remaining
terms in the sum. Indeed,
r
S∗ S S∗ S
+ ≥ 2· · =2
S S∗ S S∗
S∗ S
implies 2 − S
− S∗
≤ 0. We now write

S∗ f (B) B f (B)S I∗ B∗ I
3− + − − −
S f (B∗ ) B∗ f (B∗ )S ∗ I BI∗
f (B) B f (B∗ )B
= −1 + − +
f (B∗ ) B∗ f (B)B∗
S ∗ f (B∗ )B f (B)S I∗ B∗ I
+4− − − − .
S f (B)B∗ f (B∗ )S ∗ I BI∗

Now,
s
S ∗ f (B∗ )B f (B)S I∗ B∗ I S ∗ f (B∗ )B f (B)S I∗ B∗ I
+ + + =4
4
≥ 4· · · ·
S f (B)B∗ f (B∗ )S ∗ I BI∗ S f (B)B∗ f (B∗ )S ∗ I BI∗

S ∗ f (B∗ )B f (B)S I∗ B∗ I
implies 4 − − − − ≤ 0. We also have
S f (B)B∗ f (B∗ )S ∗ I BI∗

f (B) B f (B∗ )B −H(B∗ − B)2

−1 + − + = ≤ 0.
f (B∗ ) B∗ f (B)B∗ B∗ (B + H)(B∗ + H)

That is, L̇ ≤ 0 and so L is a Lyapunov function. It is clear that L̇ = 0 implies S = S ∗ , I = I∗ , B = B∗ and

P = 0. So, the largest invariant set such that L̇ = 0 is the set {QPFEE }. Thus, it follows from LaSalle’s
invariance principle [15] that QPFEE is globally asymptotically stable in Γ0 . 

Theorem 5.1 implies that when the critical values RP < 1 < RB , the phage free endemic equilibrium
is globally asymptotically stable provided γ = 0. Biologically, the infectious population persists at
the endemic level I∗ , irregardless of the initial conditions. Simulations have shown this also holds for
γ > 0, as depicted in Figure 3.

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 2698

300
I*

250

Infectious Individuals 200

150

100

50

0
0 500 1000 1500
time

Figure 3. Sample trajectories of infectious individuals for model (2.1) with varying initial
conditions settle at the phage free endemic equilibrium, provided RP < 1 < RB and γ > 0.

5.2. Phage present endemic equilibrium and stability

We now examine an equilibrium in which phage persist. To do this, we examine the equilibrium
equations

0 = Λ + γR − α f (B)S − µS (5.5)
0 = α f (B)S − (r + µ)I (5.6)
0 = rI − γR − µR (5.7)
0 = νB + ηI − δB − bBP (5.8)
0 = χbBP − mP (5.9)

with P , 0. Equation (5.9) implies B∗ = χb

m
. This and Eq (5.8) give P∗ = (ν−δ)
b
+ ηχ
m
I ∗ which is feasible
and distinct from the PFEE when (ν−δ)
b
+ ηχ
m
I ∗ > 0. From Eq (5.7), it is clear that R∗ = γ+µ
r ∗
I while it is
r+µ χbH
clear from Eq (5.6) that S = α m + 1 I . Using this in Eq (5.5), we obtain
∗ ∗

Λαm(γ + µ)
I∗ = .
rµαm + µ(γ + µ)αm + µ(r + µ)(γ + µ)χbH + mµ(r + µ)(γ + µ)

So, the only condition for existence of the PPEE is (ν−δ)

b
+ ηχ
m
I ∗ > 0. It can be shown that this inequality
holds if and only if RP > 1. It is shown in Section 8 that I ∗ ≤ I∗ , where I∗ is the infectious component
of the PFEE as discussed in the previous section.
The following theorem establishes global stability of the PPEE when recovered individuals have
permanent immunity (γ = 0).
Theorem 5.2. Suppose δ > ν and γ = 0. If RP > 1, then the phage present endemic equilibrium is
globally asymptotically stable.

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 2699

Proof. We again make use of a Lyapunov function. Consider the function

S
I

L = S − S ∗ − S ∗ ln ∗ + I − I ∗ − ln ∗
S I
r + µ B  r + µ P

+ B − B − B ln ∗ +
∗ ∗
P − P − P ln ∗ .
∗ ∗


η B ηχ P
Differentiating with respect to t yields

S∗ S
S∗ f (B) B f (B)S I ∗ B∗ I

L̇ = µS ∗ 2 − − ∗ + α f (B∗ )S ∗ 3 − + − − −
S S S f (B∗ ) B∗ f (B∗ )S ∗ I BI ∗
∗ ∗
 S S   S f (B∗ )B f (B)S I ∗ B∗ I 
= µS 2 −
∗
− ∗ + α f (B )S 4 −
∗
+ − −
S S S f (B)B∗ f (B∗ )S ∗ I BI ∗
H(B∗ − B)2
− α f (B∗ )S ∗ .
B (B + H)(B∗ + H)
From which, it is clear that L̇ ≤ 0. So, L is indeed a Lyapunov function. Now, L̇ = 0 implies
S = S ∗ , I = I ∗ , B = B∗ . Moreover, since B = B∗ , we have Ḃ = 0 and so by (5.9), we have that P = P∗ .
So the largest invariant set such that L̇ = 0 is {QPPEE }. Now, by LaSalle’s invariance principle, we have
that QPPEE is globally attracting Γ0 . Moreover, we have that QPPEE is locally stable by Lyapunov’s
stability theorem. These two results give that the phage present endemic equilibrium QPPEE is globally
asymptotically stable. in Γ0 . 
Recall from Sections 4 and 5.1, the condition RP > 1 implies RB > 1. Moreover, the condition ν > δ
ensures the existence of the PFEE. We now observe two feasible endemic equilibrium and one disease
free equilibrium. Theorem 5.2 states that when these conditions are satisfied, the DFE and PFEE are
unstable while the PPEE is globally asymptotically stable provided γ = 0. Biologically speaking, the
infection remains endemic, with the presence of phage, at the level I ∗ . Our simulations confirm this and
also show this still holds for γ > 0, as depicted in Figure 4. This endemic equilibrium (PPEE) gives
insight into how the phage may aid in understanding and controlling cholera infection as discussed in
Section 8.

6. Reproduction numbers

In this section we revisit the next-generation matrix method [16,17], which has been widely used in
the literature of mathematical epidemiology, and derive various reproduction numbers for our model
(2.1). The relations among these reproduction numbers and RB defined in (4.2) are discussed.
We examine the infectious sub-system of (2.1), which is given by

I˙ = α H+B S − (r + µ)I

 B

 Ḃ = (ν − δ)B − bBP + ηI,




and its linearization at the DFE

αΛ # " #
I˙ −(r + µ) µH
" # " " #
I I
= =M .
Ḃ η ν−δ B B

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 2700

80
I*

70 I*

60
Infectious Individuals

50

40

30

20

10
0 50 100 150 200 250 300
time

Figure 4. Sample trajectories of infectious individuals for model (2.1) with varying initial
conditions settle at the phage present endemic equilibrium, provided RP > 1 and γ > 0.

As shown in [14, 18, 19], the decomposition of M into a transmission matrix F and a transfer matrix
V (i.e., M = F − V) might not be unique, yielding various threshold values (aka various reproduction
numbers) that all determine the stability of the DFE. We choose the “largest” matrix F as possible,
since all other threshold values can be regarded as the corresponding target reproduction numbers as
shown in Theorem 6 in [18]. Hence, set
" αΛ #
(r + µ) 0
" #
0 µH
F= and V = ,
η ν 0 δ

and the next-generation matrix is


 0 αΛ 
µδH 
 
K = FV −1 =  . (6.1)
 η ν 
r+µ δ


The spectral radius of K provides a threshold value

s
1ν ν2 4αΛη 
RK = ρ(K) = + + . (6.2)
2 δ δ2 (r + µ)µδH

Now we apply the next generation matrix K and the corresponding weighted digraph G as depicted
in Figure 5 to derive other threshold values which are of more biological interests.
First, RB can be regarded as the average number of the secondary bacteria of a single bacterium.
Specifically, the secondary bacteria can be due to either its self reproduction (the loop B → B in G) or

Mathematical Biosciences and Engineering Volume 18, Issue 3, 2688–2712.

 2701

αΛ
µδH

ν
I B
δ

η
r+µ

Figure 5. The weighted digraph G corresponding to the next-generation matrix K.

the bacteria shedding (I → B) from the infectious individuals caused by the bacterium (B → I). Thus,
the number of the secondary bacteria becomes the sum of the weight of the loop B → B and the weight
η
of the closed walk B → I → B, that is, RB = δν + µδHαΛ
· r+µ . Notice that the weight of a closed walk is
the product of weights of all arcs in the walk.
Next, the basic reproduction number R0 , the average number of the secondary infections while
introducing a single infection in a completely susceptible host population, can be evaluated as the sum
of weights of all closed walks starting at I and ending at I in G (I → B → I, I → B → B → I,
I → B → B → B → I, · · · ), that is,
η αΛ η ν αΛ η  ν 2 αΛ
R0 = · + · · + · · + ··· (6.3)
r+µ µδH r + µ δ µδH r + µ δ µδH
η  ν  ν 2  αΛ
= · 1+ + + ··· · . (6.4)
r+µ δ δ µδH
In a non-reservoir environment (i.e., δ > ν), the geometric series in (6.4) converges, which leads to
η 1 αΛ ηαΛ
R0 = · ν · = , δ > ν. (6.5)
r+µ 1− δ
µδH µH(r + µ)(δ − ν)

In a reservoir environment (i.e., δ < ν), the geometric series in (6.4) diverges, implying that R0
approaches to infinity and expression (6.5) becomes invalid. Biologically, this means that the new
infections can be produced without introducing any single infection. Notice that the threshold value
RK defined in (6.2) has been customarily called as the “basic reproduction number” in the literature.
However, here we follow the biological interpretation of the basic reproduction number, so prefer it as
R0 defined in (6.4) (in a non-reservoir environment, which becomes (6.5)).

We will show in the next section that RB and R0 are target reproduction numbers of K with specific
disease control strategies, and serve as threshold values (staying at the same side of 1). In specific, the
following result holds and follows immediately from Theorems 6 and 7 in [18].
Lemma 6.1. (i) Either RB > RK > 1 or RB = RK = 1 or 1 > RK > RB .
(ii) Suppose that δ > ν. Then either R0 > RB > RK > 1 or R0 = RB = RK = 1 or 1 > RK > RB > R0 .

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7. Target reproduction number and control strategies

The target reproduction number provides a measure of effort required to control the disease by
targeting only certain types of infectious interactions. That is, the target reproduction targets specific
entries of the next generation matrix where the (i, j) entry of K represents the effect on infections that
infectious type j has on infectious type i. When targetting multiply entries of K, we denote the target
set by S where S consists of all entries of K that are targeted. Here, the notation and methods follows
Shuai, Heesterbeek and van den Driessche [21], while the readers are referred to [18] for the recent
update. For a target set S , the target reproduction number is given by TS = ρ(KS (I − K + KS )−1 ) where
[KS ]i, j = [K]i, j if (i, j)∈S and 0 otherwise. If targeting just one entry of K, we write the targets set as the
entry being targeted. That is, if we are targeting only the (i, j) entry, we write the target reproduction
number as Ti, j .
We wish to only consider feasible strategies for disease control. These strategies are regularly
implemented in areas with endemic cholera. The control strategies include reducing the consumption
of contaminated water and reducing the shedding of bacteria into the environment.
Reducing the consumption of contaminated water considers the effect on the disease that the bacte-
ria have on the infectious population. Examples of strategies that reduce consumption of contaminated
water include water filtration devices, chemical water treatment, and improving water sanitation in-
frastructure. Control strategies of this type consider the (1, 2) entry of K defined as in (6.1). The target
Λαη
reproduction number is then given by T1,2 = Hµ(r+µ)(δ−ν) = R0 .
Reducing the amount of bacteria shed into the environment considers the effect on the disease that
infectious human population has on the bacterial population. Examples of control strategies that reduce
bacterial shedding include building proper latrines or other sanitary methods of human waste disposal.
Control strategies of this type target the (2, 1) entry of K. The target reproduction number is then given
by T1,2 = T2,1 .
Both strategies for control may be used simultaneously and p with equal effort. In this case, we
consider the target set S = {(1, 2), (2, 1)}. In this case, TS = T1,2 . So, all of the target reproduction
numbers provide an equivalent threshold.
We did not consider the target reproduction numbers T1,1 or T2,2 . The target reproduction number
T2,2 targets the (2, 2) entry of K. That is, it considers the effect that bacteria have on bacteria (bacterial
growth rate) which cannot feasibly be controlled. The target reproduction number T1,1 targets the (1, 1)
entry of K. That is, it considers the effect that the infectious human population has on the infectious
human population. Since our model does not consider human to human transmissions, we do not
consider strategies for control of this type.

8. Impact of phage on endemic equilibria

We now wish to explore how the presence of phage impacts the endemic equilibria of the model:
the phage free endemic equilibrium (S ∗ , I∗ , R∗ , B∗ , 0) and the phage present endemic equilibrium
(S ∗ , I ∗ , R∗ , B∗ , P∗ ). We will show that the infectious levels may be reduced to any desirable degree
with the appropriate phage growth. We do this by examining the impact environmental environmental
factors have on disease dynamics.

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 2703

Recall that the infectious component of the PPEE is given by

Λαm(γ + µ)
I∗ = .
rµαm + µ(γ + µ)αm + µ(r + µ)(γ + µ)χbH + mµ(r + µ)(γ + µ)
Now, considering I ∗ as a function of m, we see that I ∗ is strictly increasing in m. Also recalling the
definition of RP , we see that RP is strictly decreasing in m.
For a moment, suppose that RB > 1 and δ > ν. That is, the PFEE exists. Recall the infectious
component of the PFEE is given by
(γ + µ) Λαη − (δ − ν)µ(r + µ)H
 
I∗ = .
η(rµα + µ(µ + γ)α + µ(r + µ)(γ + µ))
By choosing
χb(γ + µ) Λαη − (δ − ν)µ(r + µ)H
 
m0 = ,
(δ − ν) rµα + µ(µ + γ)α + µ(r + µ)(γ + µ)


we see that RP (m0 ) = 1 and I ∗ (m0 ) = I∗ . Here, m0 > 0 is guaranteed by the conditions RB > 1 and
δ > ν.
Now, since RP (m) is strictly decreasing in m, we have that RP (m) > 1 for 0 < m < m0 . This gives
that I ∗ exists uniquely for m < m0 and since I ∗ (m) is strictly increasing in m, we have that I ∗ (m) < I∗ .
This motivates the following theorem.
Theorem 8.1. If RB > 1 and δ > ν, then for any  > 0, there is an 0 < m < m0 such that I ∗ (m) < 
whenever 0 < m < m .
This theorem show that the number of infectious individuals can be reduced by increasing the
phage growth rate. Biologically, this means decreasing the phage deactivation rate m. While, on the
surface, this may not seem as a feasible strategy for controlling the disease, this may be accomplished
by an addition to the phage compartment proportional to the current phage population. Consider an
addition of kP to the phage growth rate where k > 0 is a constant. Then the phage growth rate is
Ṗ = χbBP − (m − k)P and so m − k < m effectively “reducing” the phage deactivation rate.
Recalling that RB > 1 implies R0 > 1, we see that the disease remains endemic. Despite the disease
remaining endemic, the number of infectious individuals can effectively be reduced in the presence of
phage. The ultimate goal with any illness should be complete eradication. However, in regions where
cholera remains endemic, phage may aid in reducing the number of infectious individual to a more
manageable amount.

9. Simulations

Before we begin the discussion of numerical results, we must first begin by discussing reasonable
initial conditions for the model. Biologically, bacteria and phage can exist in the absence of human
shedding. However, by examining the model in (2.1), we see that Ṗ = 0 for t ≥ 0 provided P(0) = 0.
That is, an introduction of a single infectious individual to a setting absent of bacteria and phage will
result in a the equation Ṗ “dropping out” of the model. While realistically, an infectious individual
may be able to introduce bacteria and phage by means of shedding. This reality is not considered in
this model and so to remedy this, we require the initial condition P(0) > 0. This requirement may

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 2704

be justified by the fact that in areas with previous outbreaks, both bacteria and phage may exist in the
environment despite the absence of endemic cholera. We proceed with the two cases: a non-reservoir
environment (δ > ν), and a reservoir environment (ν > δ).

9.1. Non-reservoir environment (δ > ν)

To explore the disease dynamics and how they are effected by the vibrio-phage interactions when
γ , 0, we turn to numerical simulations. After an individual recovers from a cholera infection, they re-
tain immunity for a period of time. Though this serves as protection against infection from V. cholerae,
it does not last forever. As discussed in Section 2, the immunity period after a cholera infection ranges
from just a few weeks to more than 3 years. For the sake of numerical simulations, we let γ = 365 1
.
That is, we choose an immunity period of 1 year.

We vary the phage deactivation rate m and see how this impacts the infectious population. As
observed in the previous analytic results, we anticipate that decreasing m will reduce the infectious
levels. Recall that the threshold number RB and the infectious equilibrium I∗ are independent of the
phage deactivation rate m and so they are constant given parameters chosen from the ranges given in
Table 1. We set ν = 0, δ = 0.33, χ = 100, η = 10, b = 0.00002, r = 51 , α = 1. So, we have RB = 1.5149
and I∗ = 46.4483. Using these chosen parameter values, we first simulate the infectious population
for 2000 days with m = 7.9. Now, using the formula for RP , we have RP = 0.6196 < 1 < RB .
We see that the trajectory for the infectious compartment settles to I∗ . We see similar behavior for
the infectious compartments when m = 4. Here, RP = 0.8748 < 1 < RB . We again see that the
infectious population eventually settles to I∗ . Again decreasing m, this time m = 1, we now observe
that 1 < RP = 1.2086 < RB and I ∗ = 21.1305. In contrast to the previous values for m, we see
that the infectious population settles to I ∗ < I∗ and phage population becomes persistent at the phage-
present endemic equilibrium, as depicted in Figure 6. It is also seen in Figure 6(a) that the decreasing
the parameter m, reduces the infectious peak through the simulations. That is, an environment that
is favorable to phage survival may help reduce the infectious peak of an outbreak, thus preventing
the healthcare system from becoming overburdened. Additionally, we observe from Figure 6(b) that
the transient behavior (peak) of the phage population appears not to be monotone, while the phage
component of the stable equilibrium (PPEE or PFEE) appears to be monotone decreasing with respect
to m.

Now, we wish to numerically examine the impact a decrease in the parameter m has on the disease
dynamics. Recall from Section 8 that there exists a value m0 such that I ∗ (m0 ) = I∗ . Moreover, recall
that the infectious level may be reduced to any desired amount by selecting an appropriate m < m0 .
Using the parameter choices given in Table 1, we consider I ∗ as a function of the phage deactivation
rate m, as depicted in Figure 7. We see that while the infectious component of the PFEE remains
constant, the infectious component of the PPEE approaches zero as m approaches zero. Specifically,
when m > m0 ≈ 2.815, RP becomes to be less than 1 and thus the phage present endemic equilibrium
vanishes.

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 2705

(a) Infectious Population (b) Phage Population

104
250 9
m=7.9 m=7.9
m=4 8 m=4
m=1 m=1
200
7
Infectious Individuals

6
150
5

phage
4
100
3

2
50

0 0
0 200 400 600 800 1000 1200 1400 1600 1800 2000 0 50 100 150 200 250
time (days) time (days)

Figure 6. Simulations for model (2.1) with varying phage deactivation rate m.

I * and I * relationship with varying m

I *(m)
60 I*
m0

50
Individuals (human)

40

30

20

10

0
0 0.5 1 1.5 2 2.5 3 3.5 4
m

Figure 7. Relationship between I ∗ of the phage present endemic equilibrium and I∗ of the
phage free endemic equilibrium with varying m.

9.2. Reservoir environment (ν > δ)

In this section we explore the case ν > δ, that is, the net rate of bacterial growth is positive in the
absence of shedding. As a consequence, the bacterial population could exist in the environment in the
absence of the human contribution of shedding. As shown previously, if ν > δ, then RP ≥ 1 (and
thus RB > 1 as well), the DFE is always unstable (Section 4), the PFEE does not exist (Section 5.1),
and the PPEE always exists (Section 5.2). Numerical simulations have shown that the model (2.1)
could admit complex dynamics. Specifically, with parameter values given in Table 1 and setting ν = 2,
δ = 1, m = 7.9 and b = 1.4e − 9, simulations, as depicted in Figure 8, show the coexistence of two
stable periodic solutions. Specifically, two solutions with different initial conditions are displayed in
the B-P-I phase space, while only trajectories for large time t of these two solutions are shown in the
B-P phage plane and in the I-t plot.

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 2706

(a) B-P-I Phase Space

(b) B-P Phase Plane (c) Infectious Population

108
3
137

2.5
136
Infectious Individuals

2 135
Bacteria

134
1.5
133

1
132

131
0.5

130
0
0 2 4 6 8 10 12 14 16 18 650 660 670 680 690 700 710
Phage 109 time (days)

Figure 8. Two stable periodic solutions coexist for model (2.1) in a reservoir environment.
Each plot displays the trajectories corresponding to two distinct initial conditions (red and
blue): (a) the whole trajectories projected in B-P-I phase space; (b) trajectories for large time
t projected in B-P phase plane; (c) the infectious component of trajectories for large time t

Mathematical Biosciences and Engineering Volume 18, Issue 3, 2688–2712.

 2707

9.3. Sensitivity analysis

The objective of this section is to discuss the sensitivity of R0 , RB , RP , outbreak peak value and
time, and the total number of infected individuals to model parameters in (2.1). To this end, we
employ the Latin Hypercube Sampling/Partial Rank Correlation Coefficient (LHS/PRCC) method [20,
27]. The selected parameters are those that can be used to inform policies such as: rate of bacterial
consumption (α), recovery rate (r), bacterial shedding rate (η), natural bacteria growth rate (ν), bacteria
death rate (δ) and phage attack rate (b). We generate 3000 samples of the model parameters, using LHS
and varying them between 75% and 125% of their estimated values. We then verify the monotonic
relationships between the parameters and the model outcomes using the PRCC. The sign of PRCC
provides a measure of the nature of the linear association and its magnitude provide a measure of the
strength of the linear association. It varies between −1 and 1. A relation between model output and a
given parameter value is consider significant if the magnitude of the PRCC is greater than 0.5. Panels
A, B and C of Figure 9 show that the bacterial death rate δ and natural growth rate ν have the strongest
relationship to RB , RP and R0 . In contrast to the shedding rate η which has among the lowest of PRCC,
δ and ν would thus be an important parameter to control in order to reduce the harm of an outbreak.
While R0 and RP are only sensitive to δ and ν, RB on the other hand is significantly sensitive to α, the
rate at which humans are consuming water from the reservoirs. The total number of infected persons at
the end of a year is sensitive to γ, α, r, ν, η, b, and m with r having one of the strongest relation (Panel
D, Figure 9). The magnitude of the outbreak peak is more sensitive to α and r (Panel E, Figure 9). The
peak time like the peak magnitude is more sensitive to α, but unlike the peak magnitude, it is as well
sensitive to H and ν (Panel F, Figure 9). These results suggest that control measures influencing the
bacterial consumption and bacterial growth rate will be more effective in minimizing the epidemic than
those concentrating on influencing the shedding rate. While improving the sanitation infrastructure of
an area is the obvious step to take to control outbreaks, monitoring and controlling the bacterial levels
in the reservoir itself is equally important. Improving the infrastructure would surely help control the
bacterial levels in the reservoir by decreasing the amount of human contamination, but V. cholerae exist
independently of humans and so other factors that influence the natural levels of bacteria in the water
need to be considered as well in intervention strategies. Controlling both parameters is important and
likely to be the most effective, but the bacterial consumption rate and bacterial growth rate are the more
influential of the three.

10. Human and bacterial contribution to threshold values

We now wish to examine how human behavior and natural bacterial growth influence the threshold
values RB and RP . We explore this influence numerically by means of examining heatmaps generated
for RB and RP considering parameters that describe human contribution or involvement and natural
bacterial growth. Such parameters include the consumption rate of contaminated water, α; the rate
in which humans shed bacteria, η; and the natural bacterial growth rate, ν. We examine for what
values these parameters give threshold values greater than one. In doing this, we make biological
conclusions on how important it is to address all aspects of human behavior pertaining to shedding and
consumption. This emphasizes a holistic approach to combating cholera epidemics.
We examine the heatmap in Figure 10. Here, we see that even for a small consumption rate, if the
bacterial shedding is large enough, both RB and RP exceed the threshold value 1. Similarly, for a small

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 2708

Figure 9. Sensitivity of RB (Panel A), RP (Panel B), R0 (Panel C), outbreak peak value (Panel
D), outbreak peak time (Panel E) and the total number of people infected (Panel F) to model
parameters in (2.1).

rate in which humans shed bacteria, if the consumption rate is large, we again have RB > 1 and RP > 1.
With this in mind, we observe that both shedding and consumption must be addressed if a disease free
state is to be attained.

Now, examining the heatmaps given in Figure 11, we see that for any given bacterial replication
rate ν, increasing the shedding η, the threshold values RB and RP will cross one. We also note that we
used δ = 0.33. It is seen that when η = 0, as ν crosses 0.33, the threshold values cross one. This is due
to the term δν seen in the threshold value definitions.

11. Discussion

A new cholera model has been developed in this paper to incorporate vibrio-phage interaction of
Holling type I, which is similar to the one in Jensen, et al. [8] but different as the one in Kong et
al. [9]. Our theoretical and numerical results highlight the importance of a reservoir vs non-reservoir
environment, as the former might be a new mechanism to drive cholera periodicity. As a consequence,
it is of practical importance to understand the environmental growth of V. cholerae.
Our result supports the idea that phage can effectively reduce the number of infectious individuals.
As our model assumes bacteria grow exponentially in the absence of phage and bacterial shedding,
it is of large interests to incorporate logistic growth [14, 22]. Further studies are also necessary to
incorporate other important epidemiological features, such as the direct human-to-human transmission

Mathematical Biosciences and Engineering Volume 18, Issue 3, 2688–2712.

 2709

(a) RB (b) RP

1 15 1

12 13

1.7

3.7
0.25

85
0.9 0.9
7.

.5
3

11 12 5
2.5

5.2
.5
7
6.5 6 5

10 11

3.2
0.8 0.8

1.2
.5
2

1
5. 5 5

9.50
1.5

4.7
0.7 0.7

2.7
4

0.75
8.59 10
4. 4
0.75 5

4.
1

0.6 0.6

2.2

2
0.5
7.58
3.
0.

0.5 0.5 3
6.57

0.25
3.7
0.4
3 5.56 0.4
2. 3.2

1.
5 5

7
4.5 2
0.25

5
0.3 2 4 0.3 2.7
3.5 1.
1.5 2
1 2.2
0.2 3 0.2 0.7
2.5
0.751 2
5 1.7 1
0.5 1.5 0.5 1.2
0.1 0.1
0.751 0.25 0.751
0.25 0.5 0.5
0.25
0 0 0 0
0 20 40 60 80 100 0 20 40 60 80 100

Figure 10. Heatmap displaying the values of (a) RB and (b) RP with respect to the bacterial
consumption parameter α and shedding parameter η.

(a) RB (b) RP

1 4.5 1
3 3 4 3 4.1
3 .6 4 .3 3 .5
3 .5 4.1.2 3 .4 3 4 4
0.9 3.3.4 4
0.9 3.2.3 3.8.9
3 3 4 3.1 3
3.1.2 3 .9 3.6.7
0.8 3.7.8 0.8
3
2.9 3.5
2.9 3.5 2.8 3
2.8 3 3 2.7 3 .5
2.7 3 .6 3 .4
0.7
2.6 3 .5
0.7 2.6 3.2.3 3
2 2.5 3.3.4 3 2.5
2.4
3.1
3
0.6 2.4 3.1.2 0.6 2.3 3
2.9 2.5
2.3 2.2 2.8
2.2 2.9 2.5 2.1 2.7
0.5 2.1 2.8 0.5 2 2.6
2.7 1.9 2.5 2
1.9 2.6 2 1.8 2.4
0.4 1.8 2 2.5 0.4 1.7 2.3
1.7 2.4 1.6 2.2
1.6 2.3 1.5 1.5 2.1 1.5
0.3 1
1.2 1.3 1.4 .5 2.2 0.3 1.4
1 2.1 1.2 1.3 2
1.9
0.8 1 1.8 1
1.9 1
0.2 0.2 1.7
1.8 1.6
1.7 1.5
0.1 1.6 0.5 0.1 1.4 0.5
0.6 0.8 1.2 1.3 1.4 1.5 0.6 1.2 1.3
0.4 0.2 0.4 1
1
0 0 0 0
0 20 40 60 80 100 0 20 40 60 80 100

Figure 11. Heatmap displaying the values of (a) RB and (b) RP with respect to the bacterial
replication parameter ν and shedding parameter η.

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(i.e., a fast pathway or a short cycle of transmission) [13, 23, 24, 26], hyperinfectivity [25], and the
immunological threshold (a minimum dose of bacteria is required to yield an infection) [9]. Infectious
individuals shed not only bacteria to the environment, also a certain amount of phage. The resulting
model will lose the phage-free endemic equilibrium, and more quantitative studies, incorporating real
biological and epidemiological data, are needed to investigate the impact of vibrio-phage interaction
on disease dynamics. Last but not least, as discussed in the Introduction, an important piece of the
biological puzzle is the ability for the bacteria to enter a viable but not culturable state (VBNC). A
future work on mathematical models incorporating VBNC could provide us a better understanding of
cholera transmission and control.

Acknowledgments

This research was partially supported by the Natural Science and Engineering Research Council
of Canada (NSERC) through Discovery Grant RGPIN-2020-03911 (HW), Accelerator Grant RGPAS-
2020-00090 (HW), and by the National Science Foundation (NSF) through the grant DMS 1716445
(ZS). C. Botelho acknowledges that this work is a continuation of his M.S. thesis completed at the
University of Central Florida and also acknowledges the support of the ORC Doctoral Fellowship. The
authors thank the editor and reviewers for their helpful feedback.

Conflict of interest

The authors declare there is no conflict of interest.

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