Mathematical Biosciences 270 (2015) 1–9

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Mathematical Biosciences
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The coexistence or replacement of two subtypes of influenza

Sarder Mohammed Asaduzzaman∗, Junling Ma, P. van den Driessche
Department of Mathematics and Statistics, University of Victoria, Victoria, BC, V8W 2Y2, Canada

a r t i c l e i n f o a b s t r a c t

Article history: A pandemic subtype of influenza A sometimes replaces but sometimes coexists with the previous seasonal
Received 10 June 2014 subtype. For example, the 1957 pandemic subtype H2N2 replaced the seasonal subtype H1N1; whereas after
Revised 10 September 2015
1977 subtypes H1N1 (from the pandemic) and H3N2 continue to coexist. In an attempt to understand these
Accepted 28 September 2015
alternatives, a hybrid model for the dynamics of influenza A is formulated. During an epidemic season the
Available online 8 October 2015
model takes into account cross-immunity of strains depending on the most recent seasonal infection. This
Keywords: cross-immunity reduces susceptibility to related strains of the seasonal subtype, and wanes with time due
Influenza drift to virus drift. The population is assumed to reach an equilibrium distribution in susceptibility after several
Influenza pandemic seasons, and then a pandemic subtype appears to which individuals in the population all have the same cross-
Cross-immunity immunity. A combination of theoretical and numerical analyses shows that for very strong cross-immunity
Reproduction number the pandemic cannot invade, whereas for strong and weak cross-immunity there is coexistence for the sea-
Vaccination
son following the pandemic, and for intermediate levels of cross-immunity the pandemic may replace the
seasonal subtype. This replacement depends on the basic reproduction numbers of seasonal and pandemic
influenza. Vaccination against the seasonal subtype is found to slightly increase this range for pandemic re-
placement, with the range increasing with increasing vaccine protection and with the length of time that
vaccine-induced immunity lasts.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction To study this replacement or coexistence, we need to model both

Influenza, caused by an RNA virus in the family of Orthomyxoviri-
dae [16], is an important cause of morbidity and mortality in humans.
Influenza outbreaks occur seasonally in each winter or as pandemic
influenza [35], with three major pandemic influenza outbreaks in the
last century [16]. A new subtype of influenza virus emerges from a
pandemic outbreak and establishes itself in humans, becoming a sea-
sonal influenza virus, and sometimes the current seasonal subtype is
replaced by this new pandemic subtype. For example, the H1N1 sub-
type emerged from the pandemic influenza in 1918 and existed in the
human population until 1957, when a new subtype H2N2 emerged
and replaced H1N1. The pandemic influenza in 1968 introduced a
new subtype H3N2, replacing the prevailing subtype H2N2. However,
the reintroduced H1N1 in 1977, after 20 years of absence in humans,
has been co-circulating with H3N2 since then [16,36]. Motivated by
these observations, we investigate under what conditions a pandemic
subtype replaces or coexists with the previous seasonal subtype in
the season following the pandemic. We focus on whether or not a
seasonal subtype can survive in the season after a pandemic.
∗ vious model [4] to seasonal recurrence of influenza epidemics. He
Corresponding author. Tel.: +12508919028.
E-mail addresses: asaduzz@uvic.ca (S.M. Asaduzzaman), junlingm@uvic.ca (J. Ma),
pvdd@math.uvic.ca (P.v.d. Driessche).
the seasonal and the pandemic epidemics, which are determined by
the evolution of the influenza virus. The virus undergoes two types
of immunologically significant evolution: antigenic drift and anti-
genic shift [16]. Antigenic drift is a rapid minor genetic variation in
currently circulating subtypes [33]. The occurrence and severity of
recurrent annual influenza epidemic outbreaks are driven by viral
antigenic drifts [33]. The immunological change that produces a naive
virus isolate is known as antigenic shift, which usually results from
the recombination of gene segments from viruses circulating in hu-
mans with virus segments from avian viruses [6].
Many theoretical studies have investigated the impact of antigenic
drift on the emergence of a novel strain of influenza A virus; see for
example [8,23]. Antigenic drift causes seasonal strains to be closely
related, but different from each other. Closely related strains give
complex cross-immunity structure induced by past infection in in-
dividuals, which in turn influences the next seasonal epidemic. Tak-
ing the past infection history of individuals into account, influenza A
in a single season was modeled by Andreasen et al. [4]. This model
has subsequently been used by many authors to study the dynam-
ics of seasonal influenza using different forms of the cross-immunity
function; see for example [1,2,24]. Andreasen [3] extended the pre-
assumed that at the beginning of each season a new strain appears
and all other strains disappear. This assumption allows a separation

http://dx.doi.org/10.1016/j.mbs.2015.09.006
0025-5564/© 2015 Elsevier Inc. All rights reserved.
2 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9
of the time scales of the epidemic and viral drift. On the fast time
scale, the transmission dynamics of seasonal influenza was mod-
eled based on a standard susceptible-infectious-recovered model.
The cross-immunity of individuals gained from past infections was
taken into account, with the level of cross-immunity assumed to be
dependent only on the most recent infection. Cross-immunity was
assumed to reduce both the susceptibility to the next strain and the
infectivity during the infection. At the end of an epidemic season, the
final size relation was found to determine the immune structure of
individuals. On the slow time scale, the cross-immunity structure on
the fast time scale was related to the next season by a discrete season-
to-season mapping. Following the annual structure of Andreasen’s
[3] model, [7] modeled influenza drift evolution in a single season,
where the antigenic drift depends on the previous year’s epidemic
size. [17] reproduced the drift-like behavior of influenza A over many
seasons using an individual based simulation model, which showed
that short-lived cross-immunity restricts the viral diversity in the
population.
Antigenic shift leading to the emergence of pandemic influenza
has been studied by many authors; see for example [5,13,38]. Control
measures for an emergent pandemic influenza have been studied
extensively, for example, containment at the source [18,28], antivi-
ral treatment [27], the impact of social distancing [19,22], school
closures [10], travel restrictions [19,26] and entry screening [12].
Despite the existence of a large literature on influenza dynamics,
conditions under which a pandemic subtype replaces or coexists with
the previous subtype have not so far been considered. To address this
question, we formulate a hybrid model for the interaction of seasonal
influenza epidemics and a pandemic. We investigate, both theoreti-
cally and numerically, the reproduction number of the seasonal strain
for the season following the pandemic. Vaccination against seasonal
influenza may change this reproduction number. The influence of
vaccine related parameters, such as protection efficacy and duration
of vaccine-induced immunity, in the disease dynamics of influenza
has been modeled by [37]. We incorporate vaccination against sea-
sonal influenza to study its influence on subtype coexistence or re-
placement. We consider two types of vaccine-induced immunity: a
temporary one lasting for one year, and a permanent one lasting for
life.
The organization of our paper is as follows. In Section 2, we
present our model with the help of a time line diagram, and model
analysis follows in Section 3. In Section 4, the model is extended to in-
corporate vaccination against seasonal influenza, and concluding re-
marks are given in Section 5. Our main findings are that the pandemic
subtype can replace the previous seasonal subtype at only intermedi-
ate levels of cross-immunity, and vaccination at current levels makes
replacement only slightly more likely.
2. Our model
We assume that seasonal influenza has been continuing for many
seasons before the pandemic subtype causes an outbreak. Fig. 1 is
a time line of seasonal and pandemic influenza outbreaks. We as-
sume that the duration of a seasonal influenza epidemic is ts . The
broken lines in Fig. 1 correspond to summer time, and we assume
that there is no outbreak of seasonal influenza in the summer. As
in Andreasen [3], we assume that seasonal and pandemic influenza
occur on a fast time scale; whereas the cross-immunity structure
m Seasons
t1 t1 + t s t2 t2 + t s t3
Fig. 1. Time tk for k = 1, 2, . . . denotes the start of a seasonal epidemic with a duration ts (solid lines). The time between tk and tk+1 is approximately one year. The outbreak of the
pandemic influenza starts at time tb and ends at time te . The broken lines indicate no influenza outbreak.
changes on a slow time scale. The pandemic influenza starts at time
tb and ends at time te (Fig. 1), not overlapping with seasonal in-
fluenza. After this pandemic, a new strain of the previous season’s
subtype reappears at time tm+1 (Fig. 1). The persistence of the sea-
sonal strain in the season after the pandemic is determined by the
reproduction number of this seasonal strain at time tm+1 . To deter-
mine this, in Section 2.1, we model the transmission dynamics of the
seasonal influenza at time tm+1 . Since individuals who recover from
the pandemic have stronger cross-immunity than those who escaped
the pandemic infection, we keep track of infected individuals dur-
ing the pandemic influenza. To this end, in Section 2.2, we model the
dynamics of pandemic influenza between the times tb and te . We as-
sume that the distribution of fraction of susceptible individuals has
reached an equilibrium before the pandemic outbreak at time tb . To
find the equilibrium distribution of fraction of susceptible individu-
als, in Section 2.3.1 we model seasonal influenza epidemics based on
Andreasen’s [3] seasonal model between the time t1 and tm + ts be-
fore the pandemic. Knowing all these quantities, we determine if the
reproduction number of the seasonal influenza at time tm+1 after the
pandemic is greater or less than the threshold value of unity, which
determines whether or not this seasonal subtype coexists with the
pandemic subtype in the season following the pandemic.
2.1. Invasibility of the seasonal influenza after the pandemic
In this subsection, we model the transmission dynamics of a single
seasonal influenza at time tm+1 (Fig. 1) with a SIR-type model on the
fast time scale. The beginning of an epidemic in an ODE-based model
is considered as the time 0 (corresponding to tm+1 on the slow time
scale) and its end as the time ∞ (corresponding to tm+1 + ts on the
slow time scale). At the end of the pandemic, i.e., at time te , an indi-
vidual can be distinguished as either escaped or recovered from the
pandemic. Individuals who recovered from the pandemic infection
are assumed to have stronger cross-immunity, with these individu-
als less susceptible to seasonal influenza than those who escaped the
pandemic infection. Taking this into account, we assume that each
member of the population belongs to one of four classes: suscepti-
ble individuals who escaped the pandemic (S), susceptible individ-
uals who recovered from the pandemic ( S), infected and infectious
individuals (I), and recovered individuals (R). We also use these sym-
bols to represent the fraction of individuals in each class.
Individuals infected and recovered from a strain of influenza
acquire a life long immunity to this strain and a partial cross-
immunity to the strains closely related to this strain [14,21]. The
cross-immunity of an individual to the invading strain at tm+1 is
determined by the individual’s infection history. We consider only
reduced susceptibility due to this partial cross-immunity. Like An-
dreasen [3], our assumption is that infected individuals acquire the
level of cross-immunity (reduced susceptibility) from the last infec-
tion, i.e., the level of cross-immunity is only determined by the most
recent infection. To reflect the cross-immunity structure of individ-
uals in our model, susceptible individuals are divided into infinitely
(countably finite) many sub-classes according to their most recent
infection year. We denote by S0 ,  S0 the fraction of individuals in S,  S
who have never been infected by seasonal subtypes, and by Si ,  Si for i
≥ 1 the fraction of individuals in S, S who were infected i seasons ago.
The subscript i denotes the immune status of a susceptible individual.
Individuals in Si , Si have susceptibility τ i , pτ i respectively, where τ i
Pandemic (m+1)th Season
tm tm + ts tb te tm+1 tm+1 + ts
 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9 3

pandemic influenza as the time te (Fig. 1). Since there are no recov-
ered individuals at the beginning, the initial conditions for system (1)
 
are Si (0) = Si (te ), 
Si (0) = 
Si (te ) with ∞ 
i=0 Si (0) + Si (0) ≈ 1 and I(0)
positive and small in magnitude, i.e., I(0) ≈ 0.
The non-dimensional quantity R0 = βαs , called the basic repro-
duction number of seasonal influenza, is the average number of
secondary infections generated by a single infectious individual in a
completely susceptible population. In our model, from (1c), the non-
dimensional quantity
∞

Rs = R0 (τi Si (te ) + pτi
Si (te )) + R0 (S0 (te ) + p
S0 (te )) (2)
i=1

is the reproduction number that takes into account the cross-

immunity of individuals gained from seasonal infections, and the
cross-immunity between the pandemic subtype and the (m + 1)st
seasonal strain. This number determines a threshold. If Rs > 1, then
a seasonal epidemic occurs, i.e., the seasonal subtype coexists with
Fig. 2. The progress of disease dynamics in the Si 
Si IR model. Here Si , 
Si are the frac- the pandemic subtype in the season following the pandemic, and if
tion of individuals with immune status i who escaped, recovered from the pandemic, Rs < 1, then the seasonal subtype is replaced by the pandemic sub-
respectively. type [15].

satisfies a monotonic relation 0 < τ1 ≤ τ2 ≤ · · · ≤ τn ≤ · · · ≤ τ0 = 1 2.2. Dynamics of pandemic influenza

[14,29], and (1 − p) is the cross-immunity between the pandemic
subtype and any seasonal strain. We assume that all individuals in Because the quantity Rs in (2) depends on Si (te ), Si (te ), we now
the population, who were infected by influenza at least once in their model the transmission dynamics of pandemic influenza from tb to
lifetime, have the same level of susceptibility p to the pandemic te (Fig. 1), which corresponds to time zero and time infinity on the
subtype of influenza. This assumption on p is motivated by the fact fast time scale, to indicate the beginning and the end of the pan-
that influenza viruses share common proteins [35]. For example, demic outbreak. At the beginning of the pandemic influenza, there
H2N2 in 1957 and H3N2 in 1968 are re-assortments of other subtypes are no  Si classes. However, there are Si classes with the meaning in
that were previously circulating in humans [6,31]. Section 2.1. We assume that the fraction of susceptible individuals
Our model (see Fig. 2) evolves according to the ordinary differen- in Si has reached an equilibrium distribution Si∗ , for i ≥ 0, before a
tial equations (ODEs) pandemic subtype causes an outbreak. As assumed in Section 2.1, the
individuals in S0∗ have susceptibility 1 to the pandemic subtype, since
dSi
= −βs τi Si I i = 0, 1, 2, . . . , these individuals have never been infected by seasonal influenza, and
dt (1 − p) is the cross-immunity between the pandemic subtype and
d
Si
= −βs pτi Si I i = 0, 1, 2, . . . , any seasonal strain. Our pandemic influenza model is
dt
 ∞  dS0
dI  = −R0 p S0 I , (3a)
= βs (τi Si + pτiSi ) − α I , dt
dt
i=0 dSi
= −R0 p pSi I i = 1, 2, . . . , (3b)
dR dt
= αI ,

dt ∞
dI 
where α and β s denote the recovery rate and transmission rate of sea- = R0 p pSi + S0 −1 I, (3c)
sonal influenza. We ignore birth and death processes in the seasonal dt
i=1
dynamics, since for influenza the epidemiological time scale is much
λ p = R0 p I , (3d)
faster than the demographic time scale, and the number of deaths
  ∞
due to influenza is small. Thus, ∞ i=0 (Si + Si ) + I + R = 1 is a constant. and initial conditions Si (0) = Si∗ , I(0)
> 0 with ∗
≈ 1. Here, R0 p
i=0 Si
Since the equation for the fraction of recovered individuals from the is the basic reproduction number of the pandemic influenza in a com-
seasonal influenza is decoupled from the other variables, R can be de- pletely susceptible population, and λp is the force of infection on in-
termined from the other variables, so we do not need to consider the dividuals to the pandemic subtype of influenza. Note that we ignore
change in the R class. By the introduction of non-dimensional time demographics for the same reason as in Section 2.1, and also ignore
t̂ = t α , so that the infectious period is 1, the above system of ODEs death due to the pandemic because the case fatality rate of the pan-
simplifies to (dropping ˆ) demic influenza in 1918 was about 2–2.5% and it was less than 0.1%
dSi for other pandemics in the last century [32]. From (3c), the reproduc-
= −R0 τi Si I i = 0, 1, 2, . . . , (1a) tion number of the pandemic influenza, taking cross-immunity into
dt
account, is given by the non-dimensional quantity
d
Si
= −R0 pτi Si I i = 0, 1, 2, . . . , (1b) R p = R0 p ( p(1 − S0∗ ) + S0∗ ) . (4)
dt
 ∞

dI  Note that, if S0∗
is negligible, then R p ≈ pR0 p . If R p < 1, then no
= R0 (τi Si + pτi
Si ) − 1 I , (1c)
dt pandemic occurs; whereas if R p > 1, then there is a pandemic [15].
i=0
From Appendix A, the final state of the pandemic influenza at t = te
where R0 = βαs . We assume that at time 0 on the fast time scale, (t = ∞ on the fast time scale) is given by
all individuals are susceptible to the seasonal influenza according 
S0 (∞) = ψ S0∗ S0 (∞) = S0∗ (1 − ψ) ,
to their respective immune status i, and a few infectious individ-
uals are introduced into the population. Denote the end of the Si (∞) = ψ p Si∗ 
Si (∞) = S∗ (1 − ψ p )i = 1, 2, . . .
i
4 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9

where ψ =
S0 (∞)
is the fraction of susceptibles who have never been where φ denote the fraction of susceptible individuals who have
S0∗
never been infected by the seasonal influenza and escaped seasonal
infected by the seasonal influenza and escaped the pandemic, and ψ S (∞)
satisfies the implicit equation influenza in the current season, i.e., φ = S0 (0) . If R > 1, then (9a)
0
uniquely determines the value of φ . Analytically the uniqueness of
log(ψ) = R0 p [ψ p
(1 − ) + ψ − 1] .
S0∗ S0∗ (5) φ can be proved with a similar argument as for the uniqueness of ψ
This equation has a unique root ψ ∈ (0, 1) if R p > 1; see in Appendix B. Thus, for given τi , R0 and Si (0), the fraction of sus-
Appendix B. Now the basic reproduction number of seasonal in- ceptible individuals with immune status i who escaped influenza in
fluenza in (2) can be written as the current season can be found by solving φ from (9a) and using φ
∞ in (9b).

Rs = R0 τi Si∗ (ψ p + p(1 − ψ p )) + R0 S0∗ (ψ + p(1 − ψ)) . (6)
i=1 2.3.2. Season-to-season mapping
In Section 2.3.1, we found the final state of a seasonal epidemic
2.3. Dynamics of seasonal influenza before the pandemic
and determined how the immune status of individuals changes in the
seasonal dynamics of influenza. We now want to determine how the
In order to determine all Si∗ in (6), we model the dynamics of
immune status of individuals changes from the onset of one epidemic
seasonal influenza in the m seasons between the time t1 and tm + ts
season to the beginning of the next epidemic season. We ignored de-
based on the annual structure of Andreasen’s [3] seasonal model. This
mographics in the seasonal dynamics of influenza on the fast time
dynamics is influenced by the dynamics of a single season.
scale because the number of births and deaths in a single season is
negligible, but for a long time horizon, demographic events may have
2.3.1. The dynamics of single season epidemics
a significant effect on the dynamics of influenza. On the slow time
As assumed in Section 2.1, we take time tk on the slow time scale
scale, we now incorporate demographics in the dynamics of influenza
as time 0 when a seasonal epidemic begins, and time tk + ts on the
by including newborn individuals into the S0 class, since newborn in-
slow time scale as time ∞ when the epidemic is over. Unlike An-
dividuals are completely susceptible. We assume that an individual’s
dreasen [3], we do not assume that cross-immunity lasts only for a
life expectancy is exponentially distributed with parameter d, thus
finite number of seasons. Following the assumptions in Section 2.1
the survival probability of an individual is e−d .
without Si , our one season influenza epidemic model is
At the beginning of the tk season, Si (tk ) for i ≥ 1 denotes the frac-
dSi tion of susceptible individuals with immune status i and φ denotes
= −R0 τi Si I i = 0, 1, 2, . . . , (7a)
dt the fraction of individuals who have never been infected by seasonal

influenza and escaped infection during the tk season; see Fig. 1 for
∞

dI
= R0 τ i Si − 1 I , (7b) time line. The individuals with immune status i who escaped in-
dt
i=0 fluenza during the tk season acquire immune status (i + 1) at the be-
ginning of the tk+1 season because then their most recent infection is
λs = R0 I , (7c)
∞
(i + 1) seasons old; see Fig. 3. Thus the fraction of susceptible indi-
and the initial conditions are Si (0) ≥ 0 with i=0 Si (0) ≈ 1 and I(0) viduals at the beginning of the tk+1 season is
> 0. Here, λs is the force of infection on individuals to the seasonal
strain of influenza. From (7b), the reproduction number of seasonal Si+1 (tk+1 ) = φ τi Si (tk )e−d i = 1, 2, . . . , (10)
influenza, taking cross-immunity into account, is given by the quan-
where φ in season tk is a solution in (0, 1) of (9a).
tity
At the beginning of the tk+1 season, the fraction of susceptible in-
∞
 dividuals in the S1 class is determined by the fact that the individuals
R = R0 τi Si (0) . (8) from all Si classes who were infected during the tk season have re-
i=0
ceived a booster by the infection. These individuals have one year old
If R > 1, then a seasonal epidemic occurs and if R < 1, then there immune status at the beginning of the tk+1 season; see Fig. 3. Thus,
is no seasonal epidemic [15]. Following calculations as in Appendix A,

∞

when the seasonal epidemic is over the final state of this seasonal
epidemic is determined by the equations S1 (tk+1 ) = 1− φ τi Si (tk ) e−d . (11)
i=0
∞
  
log(φ) = R0 Si (0) φ τi − 1 , (9a) At the beginning of the tk season, S0 (tk ) denotes the fraction of
i=0 susceptible individuals who have never been infected. The individu-
Si (∞) = φ τi Si (0), i = 0, 1, 2, . . . , (9b) als in the S0 class who escaped influenza during the tk season remain

Fig. 3. The change of immune status of the fraction of susceptible individuals from the end of the tk season to the beginning of the tk+1 season. The change of immune status of the
individuals who escaped infection is shown as a solid line and for those who recovered from the infection is shown as a dashed line. Vertical arrows show natural death at a rate d
from each Si class and horizontal arrows show birth at a rate (1 − e−d ) to the S0 class.
 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9 5

in the S0 class with the newborn individuals; see Fig. 3. Thus, change from season to season, (10)–(12) describe a discrete dynam-
ical system giving the season-to-season dynamics of influenza epi-
S0 (tk+1 ) = φ S0 (tk )e −d
+ (1 − e −d
). (12)
demics. The susceptibility τ i is taken in the form (1 − qi ), 0 ≤ q ≤ 1.
The season-to-season mapping that determines the change of im- Here q is the probability of antibodies from the previous year’s strain
mune status is given by (10)–(12); see also [3, Eqs. (9)–(11)]. The binding to the current seasonal strain of influenza. This assumption
equilibrium distribution of the fraction of susceptible individuals Si∗ , satisfies the monotonic relation stated in Section 2.1. For the simula-
is found by solving the mapping equations (10)–(12). In Section 2.2, tions, we take q = 0.75, estimated from [11], except in Fig. 5 where
we assumed that this fraction has reached an equilibrium before the we take a range of q values.
pandemic arrives. The reproduction number of seasonal influenza at In our simulations, we take a large number (m) of immune classes
equilibrium, from (8) is given by of susceptible individuals. For sufficiently large m, τm ≈ τm+1 , i.e., the
∞
 susceptibility of individuals in immune class Sm is almost equal to
R∗ = R0 τi Si∗ . (13) that in immune class Sm+1 . Thus, individuals in the immune class Sm
i=0 who escaped influenza infection during the tk season remain in the
same class at the beginning of the tk+1 season.
3. Results We numerically simulated the model to understand the seasonal
dynamics of influenza epidemics on the long time scale and to find
In this section, we first find a theoretical threshold condition on the equilibrium distribution of susceptible individuals, Si∗ . For the pa-
p for an outbreak of pandemic influenza, and if there is such an out- rameter values used in these simulations, the convergence to Si∗ is
break, we use numerical simulations to predict whether or not a sea- attained in less than 10 seasons, thus validating our assumption that
sonal subtype survives in the season following a pandemic. Si (t) approaches Si∗ before the pandemic arrives. Our numerical sim-
ulations started with an initial guess of susceptible individuals Si (0)

3.1. Theoretical results such that ni=0 Si (0) ≈ 1. Using this initial guess of Si (0), and a value
of R0 , the fraction of susceptible individuals φ who have never been
For a given value of p and R0 p , (5) can be solved to find ψ , the frac- infected by seasonal influenza and escaped infection in the current
tion of individuals who have never been infected by the seasonal in- season was determined by solving (9a). The final state of the epidemic
fluenza and escaped the pandemic infection. Eq. (5) always has a root was found from (9b). For illustration, we take d = 0.0124, which cor-
at ψ = 1, which is not biologically interesting, since ψ = 1 means responds to the life expectancy of 80.7 years in the Canadian pop-
there is no pandemic, and (5) cannot have a root at ψ = 0 as the equa- ulation [25]. The immune status of individuals at the beginning of
tion is not defined at ψ = 0. The uniqueness of ψ ∈ (0, 1) if R p > 1 the next season was determined by using the season-to-season map-
1 −S0∗
R0
p ping equations (10)–(12). The new susceptible values were then used
(see Appendix B) gives p > 1−S0∗ , which imposes a lower bound
as initial values and the cycle recomputed. This process continued
on p, the susceptibility to the pandemic subtype of influenza, for an until the equilibrium distribution of susceptible individuals Si∗ was
outbreak. achieved. We found that the equilibrium values of Si exists in [0, 1],
The reproduction number Rs of seasonal influenza after the pan- and is unique. For our choice of parameters and assumption that in-
demic given in (6), is a non-linear function of R0 , R0 p , p and ψ fectivity is not reduced by cross-immunity, we found no sustained
from (5). At the upper extreme p = 1, from (6) the value of Rs = oscillations for Si (t) (cf. [3]).

R0 ∞ i=1 τi Si + R0 S0 , which equals R in (13). At the lower extreme
∗ ∗ ∗
We used the values of Si∗ as initial susceptibles at the begin-

p = 0, from (6) the value of Rs = R0 ∞ i=1 τi Si + R0 S0 ψ̂ , where ψ̂
∗ ∗ ning of the pandemic influenza. For a given p, S0∗ and R0 p , ψ was
satisfies (5) with p = 0, i.e., log(ψ̂) = R0 p S0∗ (ψ̂ − 1). This equation found by solving (5). The reproduction number Rs of seasonal in-
fluenza after the pandemic was then computed from (6). Fig. 4
has a root ψ̂ ∈ (0, 1) if R0 p S0∗ > 1. Thus the reproduction number Rs
is a plot of the reproduction number Rs of seasonal influenza af-
of the seasonal influenza at the lower extreme p = 0 is less than R∗
ter the pandemic against p. These plots show that for small val-
if R0 p S0∗ > 1; whereas Rs is equal to R∗ if R0 p S0∗ < 1, since (5) with
ues of p, i.e., for very high cross-immunity (1 − p), there is no out-
p = 0 has only the root ψ̂ = 1. break of pandemic influenza ( Fig. 4, horizontal part in each plot).
S0∗ (ψ −ψ p )+(ψ p −1)
Differentiating (5) with respect to R0 p , ∂∂ψ
R
= h (ψ)
, Numerical simulations agree with the theoretical condition found
0p
where h (ψ ) is given in Appendix B. If there is a pandemic out- in Section 3.1 for a pandemic outbreak, i.e., the pandemic sub-
1 −S0∗
break, then from Appendix B, ψ ∈ (0, ψ̄); thus h (ψ ) > 0 on this in- type of influenza cannot cause an outbreak if p <
R0
p
. If there
1−S0∗
terval. Biologically, h (ψ ) is some positive constant multiple of one
is an outbreak of pandemic influenza, the pandemic subtype co-
minus the reproduction number of the pandemic subtype at time
exists with the seasonal subtype if Rs > 1 (Fig. 4, range of p val-
infinity. The reproduction number of the pandemic subtype at the
ues for which Rs > 1). If Rs < 1, then the range of values of p
end of the pandemic is smaller than unity, since the pandemic has min
come to an end. The numerator of ∂∂ψ R
is negative for any ψ ∈ was found numerically (Fig. 4, range of p values for which Rs < 1),
0p
with the pandemic subtype replacing the seasonal subtype when
(0, 1) giving ∂∂ψ
R0 p
< 0. Thus ψ decreases with increasing R0 p . From p belongs to this range. The replacement of the seasonal subtype
∂ Rs
 p−1 ∞  by the pandemic subtype becomes easier when the basic repro-
(6), ∂ψ = (1 − p) pψ R0 i=1 τi Si∗ + R0 S0∗ > 0, i.e., Rs increases
duction number R0 p of the pandemic subtype increases (Fig. 4,
with increasing ψ . These relations give ∂∂RRs < 0, which indicates left to right in each row); the range for pandemic influenza to re-
0p
that the reproduction number of seasonal influenza after the pan- place seasonal influenza decreases as the basic reproduction num-
demic decreases with increasing basic reproduction number R0 p of ber R0 of seasonal influenza increases (Fig. 4, top to bottom in
the pandemic subtype. each column).
Fig. 5 is a plot of the reproduction number Rs of seasonal influenza
3.2. Simulation results against p for different susceptibility τi = (1 − qi ) to the seasonal
influenza. The replacement of the seasonal subtype by the pan-
Assuming that the basic reproduction number R0 in a completely demic subtype becomes easier as the susceptibility to the seasonal
susceptible population and the cross-immunity structure τ i do not influenza decreases (Fig. 5, top to bottom), i.e., with increasing q, the
6 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9

R0p = 2 R0p = 3 R0p = 4

1.6 1.6
1.4
1.2
1.0

R0 = 2
0.8
0.6 1.4
0.4
0.2

Reproduction Number Rs
Reproduction Number Rs

0.0
1.6
1.4 1.2
1.2
1.0

R0 = 3
0.8
0.6
0.4 1.0
0.2
0.0
1.6
1.4
1.2 0.8
1.0

R0 = 4
0.8
0.6
0.4
0.2 0.6
0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
Susceptibility p Susceptibility p
Fig. 4. The curves Rs plotted as a function of p, giving the range of p values for which Fig. 5. As Fig. 4 with parameters R0 = 3, R0 p = 3 and τi = (1 − qi ) but varying q =
the seasonal subtype is replaced by the pandemic subtype or reappears after the pan- 0.65 (dashed curve), 0.75 (solid curve) and 0.85 (dotted curve), respectively.
demic. R0 and R0 p represent the basic reproduction number of seasonal influenza and
pandemic influenza, respectively. The pandemic subtype of influenza cannot invade in
the rectangular region (light shaded) for small p values but replaces the seasonal sub- Unvaccinated Vaccinated
type (dark shaded) and coexists with the seasonal subtype in the season following the (1 − )Si (tk )  Si (tk )
pandemic (not shaded) above Rs = 1 (marked by a horizontal line). Note that each plot
shown has q = 0.75 and R0 p S0∗ < 1.

Seasonal dynamics
probability of antibodies from the previous year’s strain binding to
the current seasonal strain of influenza.

4. Vaccination against seasonal influenza

In this section, we extend our seasonal model in Section 2.3.1 to
incorporate vaccination against seasonal influenza. Given the nor-
mal practice for vaccination, we assume that vaccines are adminis-
tered before the start of the seasonal epidemic. For simplicity of our
model, we ignore any age-specific effects of vaccination. Our assump-
tion is that the effective vaccination coverage (vaccine effectiveness
times vaccine coverage), which has been achieved before the begin-
ning of the seasonal influenza epidemic, reduces the available frac-
tion of susceptibles by a factor . We assume that the duration of
vaccine-induced immunity lasts for one year (Section 4.1), or for life
(Section 4.2).
4.1. Vaccination gives immunity for one year
We assume here that the effectiveness of vaccination lasts for one
year, i.e., vaccinated individuals are protected from influenza infec-
tion for the season in which they are vaccinated. The immune sta-
tus i of vaccinated individuals at the beginning of the next season is
the same as those of unvaccinated individuals who escaped influenza
infection during the season (Fig. 6). Thus, one year effective vaccine
works as if the individuals naturally escaped the influenza infection.
The transmission dynamics of our seasonal model is not changed; but
is now applied to the unvaccinated individuals. The season-to-season
dynamics of influenza is as follows:
Si+1 (tk+1 ) = (1 − )Si (tk )φ τi e−d + Si (tk )e−d
(25–41%) this increase is slight (compare with Fig. 4). However, if
∞
 vaccine coverage of 100% is achieved, then the range of p values for
S1 (tk+1 ) = (1 − ) 1 − Si (tk )φ τi e−d ,
i=0
Escaped
Recovered Si (tk +ts )
Fig. 6. The flow diagram of individuals during the seasonal epidemic when the effec-
tiveness of vaccination lasts for one year and effective vaccination fraction is .
S0 (tk+1 ) = (1 − )S0 (tk )φ e−d + S0 (tk )e−d + (1 − e−d ) , (14c)
We numerically simulated the model (14) to find the susceptible
fraction Si∗ at equilibrium. The reproduction number Rs of seasonal
influenza after the pandemic is given by
∞

Rs = (1 − )R0 τi Si∗ (ψ p + p(1 − ψ p ))
i=1
+(1 − )R0 S0∗ (ψ + p(1 − ψ)) . (15)
From data influenza vaccine has an overall effectiveness of 60%
[34] and the current seasonal influenza vaccine coverage in Canada
ranges between 25–41% across ethnic groups [30]. Following these
we choose = 0.15, 0.24 corresponding to 15 and 24% effective vac-
cination coverage of the total population. We also choose = 0.60
corresponding to 100% coverage of vaccination in the population
with the present effectiveness of vaccine. These plots in Fig. 7 of
Rs from (15) show that as vaccination against seasonal influenza
i = 1, 2, . . . , (14a) increases, the range of p values for the pandemic subtype to replace
the seasonal subtype increases but with the current vaccine coverage
(14b) the pandemic subtype to replace the seasonal subtype increases
significantly, e.g., for R0 p = 3 and R0 = 4, the pandemic subtype
 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9 7

R0p = 2 R0p = 3 R0p = 4 R0p = 2 R0p = 3 R0p = 4

1.6 1.6
1.4 1.4
1.2 1.2
1.0 1.0

R0 = 2

R0 = 2
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
Reproduction Number Rs

Reproduction Number Rs
0.0 0.0
1.6 1.6
1.4 1.4
1.2 1.2
1.0 1.0

R0 = 3

R0 = 3
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
1.6 1.6
1.4 1.4
1.2 1.2
1.0 1.0

R0 = 4

R0 = 4
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
Susceptibility p Susceptibility p

Fig. 7. As Fig. 4, but with vaccination giving immunity for one year. Vaccine efficacy Fig. 9. As Fig. 7, except that vaccination gives lifetime immunity.
in preventing seasonal influenza infection is 60% and effective vaccination coverage
is 15% (solid line), 24% (dotted line) and 60% (dashed line). Compare with Fig. 4 (no
vaccination).
S0 (tk+1 ) = (1 − )S0 (tk )φ e−d + S0 (tk )e−d + (1 − e−d ) . (16c)
Fig. 9 is a plot of the reproduction number Rs from (15) (with
different Si∗ ) of seasonal influenza after the pandemic against p val-
replaces the seasonal subtype, whereas at the current vaccine cover- ues for different values of R0 and R0 p . As in Section 4.1, we choose
age the pandemic subtype cannot replace the seasonal subtype. Also = 0.15, 0.24 and 0.60 corresponding to 15, 24 and 60% effective vac-
if R0 = 2, then 100% vaccine coverage prevents a seasonal epidemic. cination coverage of the total population. The qualitative behavior of
these plots (Fig. 9) is the same as those for the model when vaccine-
4.2. Vaccination fives lifetime immunity induced immunity lasts for one year ( Fig. 7). However, the range of
p values for the pandemic subtype to replace the seasonal subtype
Empirical studies [11,20]) found that the effectiveness of vaccina- increases with longer vaccine induced immunity.
tion lasts for more than one year. We assume that the effectiveness
of vaccination lasts for many years, i.e., vaccinated individuals are 5. Concluding remarks
protected from influenza infection for life (Fig. 8). We assume that
the duration and protection efficacy of naturally-acquired immunity We have developed a hybrid model for studying the interaction
and vaccine-induced immunity are the same for the subsequent sea- between an influenza A pandemic subtype and a seasonal subtype
sonal epidemic. When vaccine gives the lifetime immunity, vaccina- with several strains. During a seasonal epidemic or pandemic, time
tion is working as if the vaccinated individuals have recovered from is taken as continuous giving a system of ODEs; whereas for the
influenza infection. The season-to-season dynamics of influenza is as season-to-season mapping, time is discrete. Seasonal epidemics are
follows: modeled by a modification of Andreasen’s system [3], which assumes
that the cross-immunity of an individual to the challenging seasonal
Si+1 (tk+1 ) = (1 − )Si (tk )φ τi e−d i = 1, 2, . . . , (16a)
strain is determined by the last season that an individual was in-

fected. This assumption is valid if the seasonal influenza phylogeny
∞
 ∞

S1 (tk+1 ) = (1 − ) 1 − Si (tk )φ τi e−d + Si (tk )e−d , (16b) is linear, which is supported by data [9,17]. Based on the observation
that pandemics and seasonal epidemics do not overlap in time, the
i=0 i=1
pandemic is assumed to occur between two seasonal epidemics,
with the infection history distribution having reached equilibrium
before the pandemic starts. Cross-immunity between the seasonal
Vaccinated Unvaccinated
subtype and the pandemic subtype is assumed to be independent of
 Si (tk ) (1 − )Si (tk )
the infection history for the seasonal strains.
We found that a larger basic reproduction number R0 for the
seasonal subtype makes it harder for the pandemic to replace the
Seasonal dynamics seasonal one. In fact, a larger seasonal basic reproduction number
increases the equilibrium seasonal reproduction number R∗ , but
does not effect the population level cross-immunity caused by the
pandemic to the seasonal strain after the pandemic. Thus the sea-
Escaped sonal reproduction number Rs after the pandemic increases. On the
Recovered Si (tk +ts ) other hand, a larger basic reproduction number R0 p for the pandemic
makes replacement easier. Intuitively, a larger pandemic basic repro-
Fig. 8. The flow diagram of individuals during the seasonal epidemic when the ef-
duction number increases the fraction infected by the pandemic, and
fectiveness of vaccine gives lifetime immunity and the effective vaccination fraction thus increases the population level cross-immunity to the seasonal
is . strain after the pandemic.
8 S.M. Asaduzzaman et al. / Mathematical Biosciences 270 (2015) 1–9

Our model and results are given in terms of p, which is the suscep- Integrating the above equations from time tb (0 on the fast time
tibility of individuals to the pandemic subtype, but it is instructive to scale) to t gives
interpret the results in terms of the cross-immunity 1 − p between  p
S0 (t )
the seasonal and pandemic subtype. Very strong cross-immunity be- Si (t ) = Si (0) , i = 1, 2, . . . . (A.1)
tween the pandemic and the seasonal subtype prevents the invasion S0 (0)
of the pandemic, because the pandemic reproduction number is re-
At the end of the pandemic, i.e., at time te (∞ on the fast time
duced below unity. As 1 − p decreases, the pandemic may occur, but
scale), the fraction of susceptibles who have never been infected by
does not confer a large enough population level cross-immunity to
the seasonal influenza and escaped the pandemic infection is denoted
prevent the invasion of the next seasonal epidemic, causing the pan- S (∞)
by ψ = 0S∗ . Then the equations
demic and seasonal subtypes to coexist in the season following the 0
pandemic. As cross-immunity decreases further, the pandemic in-
S0 (∞) = ψ S0∗ and Si (∞) = ψ p Si∗ , i = 1, 2, . . . (A.2)
creases, and eventually may cause large enough population cross-
immunity to prevent the next seasonal strain invading. If this oc- relate the final state of the pandemic for individuals with immune
curs, the pandemic replaces the seasonal strain. However, as 1 − p status i to seasonal influenza in terms of the fraction of susceptibles
decreases close to zero, the pandemic and the seasonal subtypes be- at the beginning of the pandemic and the fraction of individuals who
come essentially independent; thus, small cross-immunity causes the have never been infected by the seasonal influenza. Using (A.2), the
pandemic and seasonal subtype to coexist. This means that the pan- derivative of the force of infection λp in (3d) can be written in the
demic may replace the seasonal subtype for only intermediate levels following form
of cross-immunity. ∞
 p
We considered vaccination against seasonal influenza, as this is dλ p 1 pR0 p  S0 (t )
= − Si (0) − R0 p ,
currently available in Canada and many other countries; however, we dS0 S0 (t ) S0 (t ) S0 (0)
i=1
have not considered vaccination against the pandemic subtype, as a
vaccine is unlikely to be produced early enough to give significant re- with solution
  ∞
 p 
duction of the pandemic. We found that vaccination reduces seasonal S (t )  S0 (t )
reproduction numbers, and thus replacement by the pandemic sub- λ p (t ) − λ p (0) = log 0 − R0 p Si (0) −1
S0 (0) S0 (0)
type occurs more easily. However, for current levels of vaccine cov- i=1

erage and efficacy in Canada, this reduction is negligible. With the
current vaccine efficacy of 60%, if vaccination uptake could be raised
to 100%, then reduction of the seasonal reproduction number is sig-
nificant and the pandemic subtype is more likely to replace the sea-
sonal subtype.
Our model takes account of only the season following a pandemic.
If both subtypes coexist in that season, then understanding the in-
teraction and competition between the two subtypes in subsequent
seasons requires further modeling.
Qualitatively our model may be able to explain the replacement of
the seasonal subtype H1N1 by the pandemic subtype H2N2 in 1957.
The pandemic subtype H2N2 was a reassortment from H1N1 [16,36].
Thus it is reasonable to assume that the cross-immunity between this
pandemic subtype and the seasonal subtype H1N1 was at an interme-
diate level. The pandemic subtype H3N2 in 1968, also a reassortment
from the previous subtype H2N2 [16,36], similarly replaced the sea-
sonal subtype H2N2. The subtype H1N1 was not directly descended
from H3N2, thus in 1977 the cross-immunity between the pandemic
subtype H1N1 and the prevailing seasonal subtype H3N2 could be
weak, leading to their coexistence. Our model agrees qualitatively
with the above observations.
Our theoretical framework is based on the assumption of homo-
geneous mixing of the whole population. Further investigation is
needed to understand the influence of inhomogeneous mixing. In ad-
dition, age dependent immunity, vaccination uptake and effective-
ness should be considered in future models.
Acknowledgment
This research is partially supported by NSERC Discovery grants to
JM and PvdD. The authors thank two anonymous reviewers for help-
ful comments.
Appendix A
We calculate analytically the final state of the pandemic influenza
by observing from (3a) and (3b) that
dSi pSi
= , i = 1, 2, . . . .
dS0 S0
−R0 p (S0 (t ) − S0 (0)).
The force of infection λp (0) at the beginning of the pandemic is
very small since only a few infectious individuals are introduced into
the population, so it can be taken as zero. When the pandemic is
over at t = ∞, the force of infection is also zero because no one is
infectious anymore. Thus at t = ∞, ψ must satisfy the implicit equa-
tion (5). If R p > 1, then (5) uniquely determines the value of ψ ; see
Appendix B. Thus, for given values of p, S0∗ and R0 p , (5) determines
the value of ψ , and the final state of the pandemic influenza can be
found using ψ and p in (A.2).
Appendix B
To show that (5) has a unique root ψ ∈ (0, 1), consider
h(ψ) = log(ψ) − R0 p [ψ p (1 − S0∗ ) + S0∗ ψ − 1].
Then (i) h(1) = 0, (ii) limψ →0+ h(ψ) = −∞ and (iii)
h (ψ) = ψ1 [1 − R0 p ( pψ p (1 − S0∗ ) + ψ S0∗ )], which gives h (1) =

1 − R0 p ( p(1 − S0∗ ) + S0∗ ) = 1 − R p . Thus (5) has at least one root ψ ∈
(0, 1) if h (1) < 0, i.e., R p > 1. Now consider
g(ψ) = 1 − R0 p ( pψ p (1 − S0∗ ) + ψ S0∗ ) .
Then, limψ →0+ g(ψ) = 1 and g(1) = 1 − R p < 0 if R p > 1. The
term R0 p ( pψ p (1 − S0∗ ) + ψ S0∗ ) is a monotonic increasing function for
ψ ∈ (0, 1). Thus g(ψ ) has a unique root ψ̄ ∈ (0, 1), which implies
that h(ψ ) has a unique critical point ψ̄ ∈ (0, 1). Since (i) and (ii) hold,
h(ψ ) is concave down for ψ ∈ (0, 1), which completes the proof of the
uniqueness of ψ ∈ (0, 1).
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