Journal of Theoretical Biology 526 (2021) 110795

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Journal of Theoretical Biology

journal homepage: www.elsevier.com/locate/yjtbi

Effect of population heterogeneity on herd immunity and on vaccination

decision making process
Fan Bai
Hausdorff Center for Mathematics, University of Bonn, Bonn, Germany

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

Article history: We study the influence of population heterogeneity on herd immunity level and on individual’s vaccina-
Received 13 December 2020 tion decision making process. We first formulate the mathematical model in a population with two sub-
Revised 6 May 2021 groups, based on different activity levels or different susceptibilities. The herd immunity threshold is
Accepted 30 May 2021
derived and discussed. It is calculated that the required vaccine coverage level for herd immunity in a
Available online 5 June 2021
heterogeneous mixing population can be varied significantly. The required vaccine coverage level is lower
than the classical herd immunity level, if the vaccine coverage level in the more active group or more sus-
Keywords:
ceptible group is higher than the other subgroup. It is suggested that the classical herd immunity levels
Epidemiology
Population heterogeneity
can be misleading in the process of planning mass vaccination programs. The analysis is further extended
Herd immunity to study the population with more subgroups. We then study the formal vaccination games to simulate
Optimal vaccination strategy the process of vaccination decision making, in either homogeneous or heterogeneous mixing populations.
Game theory It is proved that the Nash equilibrium in the vaccination game is not unique if population heterogeneity is
considered. Moreover, herd immunity is not achieved if individuals are solely driven by self-interests.
Ó 2021 Elsevier Ltd. All rights reserved.

1. Introduction is inferred from early observed exponential growth rate for an epi-
demic, indicated by daily data of incidence cases (Brauer, 2018b;
1.1. Population heterogeneity, herd immunity and vaccine rollout Wallinga and Lipsitch, 2006).
strategies It was argued in another important paper (Fox et al., 1971) that
the simple herd immunity threshold might not be appropriate for
Herd immunity is the indirect protection against an infectious public health. Some possible reasons are imperfect immunity,
disease. With the presence and proximity of immune individuals, heterogeneous mixing population, nonrandom vaccination and
the risk of infection among susceptible individuals is reduced the so-called ‘‘freeloaders” (Fine et al., 2011). Recently, the pan-
(Fine, 1993; Fine et al., 2011). It was initially stated in (Smith, demic COVID-19 has lead scientists to argue whether population
1970) that, given the basic reproduction number R0 , the infection heterogeneity can reduce the required herd immunity threshold
incidence will decline if the proportion of immune individuals to some degree (Britton et al., 2020; Omer et al., 2020; Fontanet
exceeded the herd immunity threshold: and Cauchemez, 2020; Anderson et al., 2020). In Britton et al.
(2020), the authors analyzed the levels of disease-induced immu-
hom 1 nity in several regions and examined the influence of heterogene-
hc ¼1 : ð1Þ
R0 ity on herd immunity. With fixed value of basic reproduction
A thorough introduction of development for the study of herd number R0 ¼ 2:5, several mathematical models with different
immunity can be found in Fine (1993), Fine et al. (2011) and structures were considered and corresponding numerical simula-
Jones and Helmreich (2020). Mathematically speaking, if we tions were performed to find the threshold value such that there
assume the proportion of immune individuals is p, then the is no second wave of epidemic. It was shown that, by considering
resulted control reproduction number is given by Rc ¼ ð1  pÞR0 age groups and different activity levels, the actual herd immunity
(Macdonald, 1957; Anderson and May, 1991). Thus, in order for level may be substantially lower than the classical herd immunity
hom level in Eq. (1). The discrepancy between two levels is greater if the
Rc 6 1, it is necessary to have p P hc in (1). The estimation of
hom
social heterogeneity is more obvious. It was also pointed out in
herd immunity threshold hc requires the quantity of R0 which Britton et al. (2020) that, the social activity heterogeneity plays a
greater role in reduced the required herd immunity than heteroge-
E-mail address: bai@hcm.uni-bonn.de

https://doi.org/10.1016/j.jtbi.2021.110795
0022-5193/Ó 2021 Elsevier Ltd. All rights reserved.
F. Bai Journal of Theoretical Biology 526 (2021) 110795

neous age-group mixing. Mainly inspired by papers (Fine et al., 2. Herd immunity in the heterogeneous mixing population
2011; Britton et al., 2020), we developed several mathematical
models to perform quantitative analysis on significant effect of We first present the simple SEIR epidemic model for homoge-
heterogeneity on herd immunity. Some statements made in neous mixing population,
Britton et al. (2020) are consistent with the analytical results in 8 0
this paper. Furthermore, it is shown that the actual required vac- >
> S ¼ bS NI
> 0
<
cine coverage for herd immunity can be varied, due to different E ¼ bS NI  rE
ð2Þ
vaccination strategies. Priority vaccinations for more active group >
>
> I0 ¼ rE  cI
: 0
(s) or more susceptible group(s) yield that the herd immunity is R ¼ cI:
much easier to achieve, so is the goal of disease eradication. It is
also worthwhile to emphasize that, vaccine rollout strategies are The population is divided into susceptible members, exposed
far more complicated than the estimates of herd immunity levels. members, infectious members and recovered members. The aver-
Prioritization of vaccinations should take many factors into age contact rate in the population is assumed to be b, the mean
account, such as the activity levels and the mortality rates in differ- exposed period is r1 and the mean infectious period is 1c. The basic
ent age groups and the characteristics of vaccines. The optimal vac- reproduction number for model (2) is R0 ¼ bc. The herd immunity
cination strategies are contextualized and need to be adapted over threshold is estimated as in Eq. (1). In the remainder of the paper,
time, especially when the supplies of vaccines are initially limited we assume that R0 is identical for models with heterogeneity
for some emerging epidemics, such as current COVID-19 (European considered.
Centre for Disease Prevention and Control, 2020).
2.1. The population with 2 subgroups

1.2. Vaccination games The population under study is divided into two subgroups
based on different activity levels. The sizes of two subgroups are
Vaccination is one of the most effective methods for prevention N 1 and N 2 , respectively (see Brauer, 2008; Bai, 2020). We denote
of the spread of infectious diseases. All individuals in the popula-
k ¼ NN21 as the ratio of sizes of two subgroups. Individuals in sub-
tion are supposed to make rational decisions on whether or not
group i make bi contacts in unit time. pij is the probability that
to take vaccination. Ultimately, a certain percentage of individuals
determines to take vaccination, while the rest determine to be sus- one contact made by an individual of group i that is with an indi-
ceptible. We consider the process of decision making is one type of vidual of group j, for i; j ¼ 1; 2. We have
evolution but with a shorter time scale. Thus, evolutionary game p11 þ p12 ¼ p21 þ p22 ¼ 1;
theory is appropriate to be applied to simulate the process. The
first paper to discuss game theory and epidemiology is written and the balance relation equation (Brauer, 2008; Bai, 2020)
by Fine and Clarkson in 1986 (see Fine and Clarkson, 1986). Subse- p21 b2 N2 ¼ p12 b1 N 1 : ð3Þ
quently, several papers discussed vaccination games in infinite
population, e.g., Bauch and Earn (2004), Tassier (2013), Bai It is noted that the recovery rates for both subgroups are equal,
(2016b, 2019), Galvani et al. (2007), Reluga et al. (2006), and which suggests that the only source of heterogeneity is the differ-
Shim et al. (2012a,b). In this paper, we assume that the occurrence ent activity levels. Similar with assumptions made in Brauer (2008,
of decision making process is prior to the outbreak of the disease. 2018a,b) and Bai (2020), we set b1 > b2 , which indicates that sub-
Information about possible outcomes of infection is provided to all group 1 is more active than subgroup 2. For some study cases, sub-
individuals, and all individuals use same information to assess out- group 1 can be referred as the group of superspreaders who are
comes (Bai, 2016a; Bauch and Earn, 2004). The impact of transmis- responsible for the majority of transmissions. Different values of
sion of infection is ignored, the approach of differential games was b1 and b2 can also be interpreted as different susceptibilities. For
discuss in Reluga (2010) and many other papers. example, if subgroup 2 represents the cluster of individuals who
follow some certain public orders, such as social distancing, then
b1 > b2 still holds. It is also applicable for the cases of age hetero-
1.3. Outline geneity or combinations of different factors (see Britton et al., 2020
for full epidemic model).
The paper consists of two major parts. We first discuss the rela- The epidemic model with two subgroups is
tion between herd immunity and population heterogeneity. In this 8
>
> X2
section, the population under study is considered to have 2 sub- >
> S 0
¼ S b
I
pij Njj
>
> i i i
groups with different activity levels. With suitable setups, the herd >
> j¼1
>
>
immunity threshold relation is generated and compared with the < X 2
E0i ¼ Si bi pij Nj  rEi ð4Þ
I
classical herd immunity level. We further provide the conditions >
>
>
j
for which the herd immunity threshold level is lower by consider- >
>
j¼1
>
>
ing heterogeneity. The optimal vaccination strategy is then sug- >
> I0i ¼ rEi  cIi
>
: 0
gested. To complement the analysis, we extend the theoretical Ri ¼ cIi ;
results to the case of n subgroups, with n > 2. The second part of
the study is to formulate vaccination games. We first briefly review for i ¼ 1; 2. We apply the next generation matrix approach (van den
the results of vaccination game in the homogeneous mixing popu- Driessche and Watmough, 2002) and calculate the basic reproduc-
lation. The emphasis is however on the second vaccination game in tion number
the heterogeneous mixing population. It is proved that, Nash equi- 0 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi1
libria exist under certain conditions and are not unique. More 1 @p11 b1 þ p22 b2 ðp11 b1  p22 b2 Þ2 þ 4p12 p21 b1 b2
R0 ¼ þ A:
importantly, we conclude that the optimal vaccine coverage level 2 c c
(herd immunity level) can never be reached if all individuals are
solely driven by self-interest. To summarize the paper, we present As discussed in Brauer (2008) and Bai (2020), it is necessary to
some limitations of current research and some possible extensions make some assumptions about the nature of mixing between two
as well. subgroups in order to obtain more useful expression. One reason-
2
F. Bai Journal of Theoretical Biology 526 (2021) 110795

able assumption is the proportionate mixing, which suggests that It is also observed that if the value of R0 is larger, higher vaccine
mixing is random but constrained by the activity level. Thus, we coverage levels in both subgroups are generally required. Our next
assume step is to substitute the formulas (8) in herd immunity threshold
relation (12) to obtain
bj Nj
pij ¼ ; i; j ¼ 1; 2: ð5Þ c2 b c2 kb
b1 N1 þ b2 N2 ð1  h1 Þ ðc1 þc1 2 kÞc þ ð1  h2 Þ ðc1 þc
2
¼1
2 kÞc
ð13Þ
Then we have p11 ¼ p21 ¼: p1 and p12 ¼ p22 ¼: p2 . Furthermore, c2
ð1  h1 Þ ðc1 þc1 2 kÞ þ ð1  h2 Þ ðc1 þc
2
c2 k
¼ R10 ¼ 1  hc
hom
;
2 kÞ
the basic reproduction number R0 is
and replace the denominator ðc1 þ c2 kÞ by ðc21 þ c22 kÞ,
p1 b1 þ p2 b2
R0 ¼ : ð6Þ
c c21 c2 k hom
1 h1  2 2 2 h2 ¼ 1  hc : ð14Þ
For the rest of this paper, we use the notations p1 and p2 to c21 þ c2 k
2
c1 þ c2 k
replace the parameters p11 ; p12 ; p21 and p22 in model (4). As men- It leads to the following equation,
tioned in Brauer (2018a,b) and Bai (2020), in order to guarantee
that the basic reproduction number R0 in (6) for model (4) has hom c21 c2 k
hc ¼ h1 þ 2 2 2 h2 : ð15Þ
the same value as the model (2) with homogeneous mixing, we c21 þ c22 k c1 þ c2 k
have The classical herd immunity level can be written as the linear
b ¼ p1 b1 þ p2 b2 : ð7Þ combination of vaccine coverage levels in both subgroups. We
het
denote hc as the vaccine coverage level in the whole population
The average contact rate b is weighted by b1 and b2 . We further
to reach the herd immunity and have
assume b1 ¼ c1 b and b2 ¼ c2 b. Without loss of generality, we have
c1 > 1 and c2 < 1. Thurs, the formulas of proportionate mixing in het N1 h1 þ N2 h2 h1 þ kh2
hc ¼ ¼ : ð16Þ
Eq. (5) can be written as N1 þ N2 1þk
p1 ¼ b1 Nb11þb
N1
2 N2
c1
¼ c1 þc 2k
; hom het
Both hc and hc are in the form of linear combinations of h1
ð8Þ and h2 . We use the following theorem to summarize the compar-
p2 ¼ b1 Nb12þb
N2
2 N2
¼ c1cþc
2k
2k
:
hom het
ison between hc and hc .
We further obtain
Theorem 2.1. For a population consists of two subgroups with
c1 c2 k
b ¼ c1 b þ c2 b ; ð9Þ different activity levels, the required vaccine coverage level hc in the
het
c1 þ c2 k c1 þ c2 k
whole population to reach herd immunity is lower than the classic
which leads to the relation between heterogeneity parameters, hom
herd immunity level hc :¼ 1  R10 , if and only if the vaccine coverage
c1 þ c2 k ¼ c21 þ c22 k: ð10Þ in the more active subgroup is higher than the other subgroup. The
het hom
Once the population structure is appropriately set, we are able difference between hc and hc increases if the population hetero-
to further analyze the relation between herd immunity level and geneity is more obvious.
population heterogeneity. We assume that the vaccine coverage
levels in subgroup 1 and subgroup 2 are h1 and h2 , respectively.
hom het
If the following inequality Proof. The comparison between hc and hc depends on the rela-
c21
ð1  h1 Þp1 b1 þ ð1  h2 Þp2 b2 tion of coefficients c22 k
and 1k. We have:
61 ð11Þ
c  
hom het c21 c22 k
hc  hc ¼ h 1 þ h2
satisfies, the herd immunity can be achieved in the population as a c21 þ c22 k c21 þ c22 k
whole. We define the herd immunity threshold relation in a two-  
1 k
subgroup population as  h1 þ h2
1þk 1þk
   
ð1  h1 Þp1 b1 þ ð1  h2 Þp2 b2 c21 1 c2 k k
¼ 1: ð12Þ ¼ 2  h1 þ 2 2 2  h2
c c1 þ c2 k 1 þ k
2
c1 þ c2 k 1 þ k
 
The total infections contributed by subgroup 1 and subgroup 2 c2 1
¼ 2 1 2  ðh1  h2 Þ: ð17Þ
are measured by p1cb1 and p2cb2 , respectively. Three possibilities with c1 þ c2 k 1 þ k
respect to the infection contributions made by two subgroups are:   
c21 c2 c2
Because c22 k
= 1k ¼ c12 > 1, we obtain c2 þc1 2 k  1þk
1
> 0. Thus, there are
2 1 2
pi bi
1. If c > 1 for i ¼ 1; 2. Both subgroups have to be partially vacci- three possibilities:
nated, because both subgroups contribute to the total infections
hom het
significantly. 1. If h1 ¼ h2 ; hc ¼ hc ,
2. If p1cb1 > 1 and p2cb2 6 1, subgroup 1 has to be partially vaccinated. 2. if h1 >
hom
h2 ; hc >
het
hc ,
hom het
Otherwise, herd immunity can never be reached. Similar argu- 3. if h1 < h2 ; hc < hc .
ment can be made for the case of p1cb1 6 1 and p2cb2 > 1.
3. If pi bi
6 1 for i ¼ 1; 2. Partially vaccinations in either subgroup 1 When the vaccine coverage level h1 in subgroup 1 is higher than h2 ,
c
the actual vaccine doses needed for herd immunity are fewer. Eq.
or subgroup 2 or both groups possibly reach herd immunity. c1 het
This is the case typically requires the lowest vaccine coverage (17) indicates that if c2
increases, the difference between hc and
hom
level in the population. hc also increases. As desired. h

3
F. Bai
Remark.
1. Whether the required vaccine coverage is lower than the classi-
cal herd immunity level is determined by the more active group
(or equally the more vulnerable group). The incentives for indi-
viduals in such groups are therefore important.
2. The influence of population heterogeneity on herd immunity
has been studied in Britton et al. (2020). It was shown that
the age-structured community with mixing rates eventually
leads to the substantially lower herd immunity level, by a
mathematical model and several numerical simulations. The
paper discussed the context of disease-induced immunity, after
first wave of pandemic, the infection rates for subgroups with
higher activity levels or with higher susceptibilities are higher
(can be calculated by the final size relations). This is equivalent
to the scenario that such subgroups have higher vaccination
proportions, so the reason why herd immunity is lower can
be well explained.
For the purpose of reduction of economic burden, it is natural to
consider the question how to wisely allocate vaccines in the popu-
lation to achieve herd immunity with the lowest vaccine coverage
level? We formulate the following linear optimization problem.
The objective function is the overall vaccine coverage, as it is
directly related with the expenditure.
Problem 1.
þkh2
het
min hc ¼ h11þk ;
h1 ;h2
ð1h1 Þp1 b1 þð1h2 Þp2 b2
61 ð18Þ
s:t: c are 1c ¼ 5 (days) and b ¼ 0:5 (/day). Additionally, we assume the
0 6 h1 ; h2 6 1
This linear optimization problem (18) can be solved easily and
we summarize the analysis in the following theorem.
Theorem 2.2. The optimal vaccination strategy for a population with
2 subgroups is to prioritized target on the group with higher activity
level, or the group who are more vulnerable. If only vaccinating
prioritized group is not sufficient to achieve herd immunity, a certain
proportion of another group is subsequently vaccinated.
Proof. It is equal to set the first linear constraint in (18) as the
equation in (12). We then write h1 as the function of h2 ,
hom
ðc21 þ c22 kÞhc  c22 kh2
h1 ¼ : ð19Þ
c21
The objective function in (18) can be written as the function of
h2 . By calculating its first order derivative, we have
het
dhc ðc2  c22 Þk
¼ 21 > 0: ð20Þ
dh2 c1 ð1 þ kÞ
het
We conclude that hc is a monotonically increasing function of h2 .
The optimal strategy is to vaccinate subgroup 1 as priority. If herd
immunity is achieved by only vaccinating certain fraction of sub-
group 1, it is not necessary to vaccinate subgroup 2. If completely
vaccinating subgroup 1 is not sufficient for herd immunity, partial
vaccination in subgroup 2 is then needed. As desired. h
2.2. Numerical simulations
We now perform several numerical simulations to illustrate our
theoretical results. For epidemic model (4), the average mean
4
Journal of Theoretical Biology 526 (2021) 110795
infectious period is assumed to be 1
c ¼ 5 (days) and the averaged
contact rate b ¼ 0:5 (/day). The estimated basic reproduction num-
ber R0 ¼ 2:5, which is consistent with the value of R0 for current
COVID-19 pandemic. Different combinations of values of c1 ; c2
and k imply different levels of population heterogeneity. We cate-
gorize 4 possible scenarios based on whether the subgroup is a
major infection contributor or minor infection contributor, which
has been discussed. Clearly, the settings for the epidemic and pop-
ulation heterogeneity do not lead to cases that both subgroups are
minor infection contributors. For the new mutated form of the
novel coronavirus (Bai and Brauer, 2021; Hou et al., 2020), it is
believed that the infectivity is about 70% higher than previous
original forms, and this would suggest a larger value of
R0 ¼ 4:25. Both subgroups can not be minor infection contributors
simultaneously and it requires higher vaccine coverage levels in
both subgroups. On the contrary, for an epidemic with
1 < R0 < 2, it is impossible to have two major infection contribu-
tors simultaneously. Numerical results are illustrated in Fig. 1.
We illustrate another example of R0 < 2 as the complement.
The average mean infectious period is reset to be 1c ¼ 3 (days)
and other parameters are kept unchanged. So the basic reproduc-
tion number R0 ¼ 1:5. We assume the contributions from two sub-
groups are p1cb1 ¼ 0:8 and p2cb2 ¼ 0:7, respectively. We describe the
herd immunity threshold relation and the feasible region in
Fig. 2. It is observed that the feasible region area is larger than in
Fig. 1, this is generally due to the smaller value of R0 and the herd
immunity is generally easier to achieve.
het
The second numerical experiment is performed to compare hc
hom
and the classical herd immunity level hc . The parameter values
heterogeneity parameters c1 ¼ 1613
; c2 ¼ 13
1
and k ¼ 4 (similar param-
eter values were used in Bai (2020) and Brauer (2018a,b). We draw
het
the overall required vaccine coverage level hc as the function of h1
and h2 in Fig. 3. It is noted that subgroup 1 can be categorized as
the group of super spreaders and this careful setup is to conform
the 20=80 rule which states that commonly roughly 20% of the
individuals in a population are responsible for 80% of the disease
cases (Brauer, 2018b; Galvani and May, 2005). It is calculated the
hom
classical herd immunity level hc ¼ 1  R10 ¼ 60%. By considering
the population heterogeneity, the overall required vaccine cover-
age level to achieve herd immunity can be varied from 15% to
90%. If h1 ¼ 75% and h2 ¼ 0, we obtain the lowest required overall
vaccine coverage level, which further indicates the minimum of
overall necessary vaccine doses. If the vaccination program targets
on the group with higher activity level as priority, with signifi-
cantly low vaccine coverage level, the herd immunity can be
achieved. If targeting on the less active group, it requires even
hom
higher vaccine coverage level than hc in Eq. (1). This can actually
be linked to the most common COVID-19 vaccination strategies in
many countries.
We next discuss the vaccination strategies for current COVID-19
pandemic and take the European Union as an example (European
Centre for Disease Prevention and Control, 2020, 2021). Some stud-
ies showed that the susceptibilities to severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2) are lower for children and
adolescents younger than 20 years, comparing to adults older than
20 years (Davies et al., 2020; Viner et al., 2021). However, there is
no further evidence to demonstrate the difference of susceptibili-
ties for adults in different age groups. In Monod et al. (2021), it
concluded that adults aged 20–49 are responsible for approxi-
mately 65% COVID-19 infections in US, as of October 2020. This
is primarily due to the high activity level of such group. It was also
suggested in Monod et al. (2021) that, vaccinating the group of
F. Bai Journal of Theoretical Biology 526 (2021) 110795

Fig. 1. The feasible region in blue represents the sufficient vaccine coverage levels to eliminate the epidemic in a population of two subgroups, the basic reproduction number
R0 is 2:5. Two axes represent the vaccine coverage levels in two subgroups. The solid line in red represents the herd immunity threshold relation. Sub-figure ðaÞ indicates that
both subgroups are major infection contributors with p1cb1 > 1 and p2cc2 > 1. Sub-figure ðbÞ indicates that one subgroup is major infection contributor while the other subgroup
is minor infection contributor.

adults aged 20–49 is important in preventing transmissions, as this

strategy is potentially the optimal one to reach the herd immunity
with the least amount of vaccine doses. The priority of vaccination
strategy against COVID-19 in most European Union countries is to
protect the high-risk groups of elderly people with high hospital-
ization rates and high mortality rates. This strategy is mainly to
save life years of people and reduce the pressure of healthcare sys-
tem (European Centre for Disease Prevention and Control, 2020).
As of March 2021 (European Centre for Disease Prevention and
Control, 2021), 18 EU countries have finished vaccinating people
with age P 80 and progressed to subsequent age groups. Because
the group of elderly people generally has lower level of activity, our
analysis indicates that this type of strategy is not able to decrease
the reproduction number R0 significantly. To achieve herd immu-
nity, the aimed vaccine coverage should be much higher than the
classical herd immunity level, which is estimated in the range of
60%  70%.

2.3. Extension to more general cases

Fig. 2. R0 ¼ 1:5. Two axes represent the vaccine coverage levels in two subgroups. We further assume that a population with size N can be divided
The solid line in red represents the herd immunity threshold relation. into n > 2 subgroups, based on different activity levels or different

Fig. 3. The overall required vaccine coverage to reach herd immunity in the population with two subgroups, which depends on the vaccine coverage levels h1 and h2 in
respective subgroups. The dashed black line represents the overall required vaccine coverage when h1 and h2 satisfy the herd immunity threshold relation in Eq. (12). Its
projection on x-y plane is exactly the herd immunity threshold relation, which is represented by the purple solid line. When h1 ¼ 75% and h2 ¼ 0, the required vaccine
coverage can be as low as 15%. Under this circumstances, herd immunity is much easier to achieve than the classical herd immunity level indicated in Eq. (.1).

5
F. Bai Journal of Theoretical Biology 526 (2021) 110795

susceptibilities. Similarly, we have the epidemic model with n X

n
ð1  hi Þpi bi
subgroups,
8 i¼1
¼ 1: ð27Þ
>
> X n c
>
> S0i ¼ Si bi pj Njj
I
>
>
>
> j¼1 Our next goal is to compare the actual vaccine coverage level
>
>
< Xn het
hc with the classical herd immunity level hc
hom
in Eq. (1). We first
Ei ¼ Si bi pj Nj  rEi
0 I
ð21Þ
>
> j obtain that,
>
> j¼1
>
> X
n
>
> I0i ¼ rEi  cIi
>
> N i hi
: 0
Ri ¼ cIi ; het i¼1
hc :¼ ¼ k  h: ð28Þ
N
for i ¼ 1;    ; n. We define the vector k ¼ ðk1 ; k2 ;    ; kn Þ to represent
Pn Formula (27) leads to
the proportions of subgroups with i¼1 ki ¼ 1. The sizes of sub-
groups are therefore N ¼ ðN1 ; N 2 ;    ; Nn Þ ¼ kN. We further define ¼ v  h;
hom
hc ð29Þ
the vector c ¼ ðc1 ; c2 ;    ; cn Þ to represent the relative activity levels
with v ¼ Pn 1
het hom
of each subgroup. Without loss of generality, we assume ðc21 k1 ; c22 k2 ;    ; c2n kn Þ. hc and hc are linear combi-
c2 k
i¼1 i i
c1 > c2 >    > ci > 1 > ciþ1 >    > cn . This indicates that first i sub-
nations of h, the coefficients vectors k and v have non-negative ele-
groups are more active than the average behavior of the population,
ments and satisfy
while last n  i subgroups have lower activity levels than the aver-
age. The contact rates vector can be defined as kkk1 ¼ 1; kv k1 ¼ 1;
b ¼ ðb1 ; b2 ;    ; bn Þ ¼ bc. It is noted that the vector b can also repre-
where k  k1 is the Euclidean 1-norm. We then compare vectors k
sent different susceptibilities of subgroups. Based on these parame-
and v element by element and have
ters, the vector of probabilities that the contact is made with an
individual in subgroup i can be expressed as vi c2i
¼ :
1 ki X
n

p¼ ðc1 k1 ; c2 k2 ;    ; cn kn Þ; c2i ki
ck i¼1

The basic reproduction number R0 for model (21) can be calcu- Although we can only guarantee that vk11 > 1, it is observed that
lated by the next generation matrix approach (see Diekmann et al.,
the sequence ðvk i Þ is decreasing. The implication is that impact
2009; van den Driessche and Watmough, 2002). The next genera- i iP1

tion matrix is from the most active subgroup 1 is most significant in the compar-
2 p1 b1 p2 b1 N 1 p3 b1 N 1 pn b1 N 1
3 2p 3 ison between hc
hom het
and hc . The analysis leads to the following
1 b1 p1 b2 p1 b3 p1 bn
c c N2 c N3   c Nn c c c   c
6p b N 7 6p b 7 conjecture,
6 1 2 2 p2 b2 p3 b2 N 2
  pn b2 N 2 7 6 2 1 p2 b2 p2 b3
  p2 bn 7
6 c N1 c c N3 c Nn 7 6 7
FV 1
¼6 7¼6 c c c c
7;
6 . .. .. .. 7 6 . .. .. .. 7 Conjecture 2.1. For a heterogeneous mixing population with n
6 .. . .   . 7 6 .. . .   . 7 (n > 2) subgroups which are categorized by different activity levels,
4 5 4 5
p1 bn N n p2 bn N n p3 bn N n pn bn pn b1 pn b2 pn b3 pn bn
c N1 c N2 c N3   c c c c   c
if the vaccine coverage levels in more active subgroups are higher than
in less active subgroups, the required overall vaccine coverage level in
ð22Þ
the whole population to reach herd immunity is lower than the one
where we have applied the following balance relation equation predicted by assuming homogeneity of population.
pi bj Nj ¼ pj bi Ni : ð23Þ

The next generation matrix in (22) has the zero determinant, Remark. To study a heterogeneous mixing population, the most
and the largest non-zero eigenvalue is the trace of the matrix. Thus, popular method is to divide the population into subgroups based
the basic reproduction number is on age (Mossong et al., 2008). It is assumed that the members in
pb the same subgroup have similar behavioral pattern, such as the
R0 ¼ : ð24Þ
c total number of contacts per day and the preference of contacts
in other subgroups. It requires the statistical analysis of demo-
Because the basic reproduction numbers for models (2) and (21) graphic data and certain types of social survey studies to extract
are identical, we derive the following relation between hetero- the values of parameter vectors k and c. The more accurate formula
geneity parameters, of herd immunity threshold relation (27) can be further obtained.
X
n X
n
cj kj ¼ c2j kj : ð25Þ
j¼1 j¼1 3. Vaccination game in the heterogeneous mixing populations
We assume that the vector of vaccine coverage levels in each
3.1. Review of vaccination game in the homogeneous mixing
subgroup is h ¼ ðh1 ; h2 ;    ; hn Þ, then if the following inequality
population
holds,
X
n
In a homogeneous mixing population, the vaccination game (a
ð1  hi Þpi bi two-player game) is studied by setting the elements of the follow-
i¼1
6 1; ð26Þ ing payoff matrix in Table 1, based on the fact that, prior to the
c
occurrence of vaccination, there are exact two strategies for indi-
the epidemic can be eliminated. Thus, the herd immunity threshold viduals to choose (Bai, 2016a, 2019; Bauch and Earn, 2004;
relation can be expressed as Tassier, 2013; Shim et al., 2012b). Fitness of different strategies

6
F. Bai
Table 1
Payoff matrix of the vaccination game in a homogeneous mixing population. Each
individual has to choose either strategy V (‘‘to be vaccinated”) or strategy S (‘‘not to be
vaccinated”). The payoffs in the payoff matrix are assumed to be non-positive. It is
noticed that all individuals’ decisions on whether to be vaccinated is completely
determined by payoffs.
Vaccination Game in a homogeneous mixing population
V S
V C v
S 0
can be calculated from this payoff matrix. For simplicity, we
assume that the vaccine is perfectly effective, each vaccinated indi-
vidual is fully protected by the vaccine. For the case of imperfect
vaccine, the formulation and its analysis are similar.
The payoff matrix describes four possible outcomes of the
game: one individual who chooses strategy V or S will interact with
individuals who choose different strategies with different proba-
bilities. If one individual chooses strategy V, the payoff is the cost
of the vaccination C v . This is true whether this individual is
paired with another individual with strategy V or with strategy S,
because the vaccine is considered fully effective and there is no
chance for this individual to get infected. If this individual adopts
strategy S, there are two possible outcomes. The first possibility
is to pair with another individual with strategy V. In this case, since
the other individual is protected by the vaccine and has no chance
to be infected, this individual will not be infected either, which
renders the payoff 0. The second possibility is to pair with an indi-
vidual who adopts strategy S. We further assume that for each
unvaccinated individual, the probability of being infected is pp ,
and the cost of infection is C i . Apparently, the infection probability
pp depends on the vaccine coverage level p in the whole population
(Bai, 2016a,b, 2019; Bauch and Earn, 2004). The costs of vaccina-
tion and infection are negative because they decrease the payoffs
for individuals. We define the relative cost for an individual as
Cv
Cr ¼ : ð30Þ
Ci
It is reasonable to assume that C r < 1. The property of the vac-
cination game is determined by the relative cost C r . If C r > p0 ; S is
the dominant strategy of the game. No matter how other individ-
uals play this game, choosing strategy S always has a higher payoff.
This eventually leads to the vaccine coverage level p ¼ 0 in the
population. This scenario is possibly due to the factors such as
the vaccine is too expensive or has serious side effects, or the dis-
ease is considered less serious. On the other hand, if C r < p0 , the
vaccination game is a coexistence game. There exists a fixed pH
which represents the proportion of the population who adopts
the vaccination. The estimation of pH and its comparison with
the herd immunity threshold are our primary interests.
We apply evolutionary game theory to formulate the following
replicator Eqs. (32) to simulate the decision making process.
Assume the proportion of vaccinated individuals is xv and the pro-
portion of unvaccinated individuals is xs ; fxv ; xs g ¼ fp; 1  pg (see
Bai, 2016b, 2019; Bauch and Earn, 2004; Tassier, 2013). The fitness
of two strategies can be expressed as:
f v ¼ C v xv  C v xs ¼ C v ;
f s ¼ pp C i xs ;
where f v is the fitness of individuals with strategy V and f s is the
fitness of individuals with strategy S, respectively. It is noted that
fitness is equal to payoff in our settings of vaccination game. Thus,
the replicator equations for vaccination game (1) can be expressed
as
Journal of Theoretical Biology 526 (2021) 110795
x_ v ¼ xv ðf v  f Þ;
ð32Þ
x_ s ¼ xs ðf s  f Þ;
where f denotes the average fitness of both strategies,
f ¼ xv f þ xs f :
v s
Solving the replicator equations, we are able to find that the
C v
Nash equilibrium satisfies
pp C i
Cv Cr
pH ¼ 1  ¼1 : ð33Þ
ppH C i p pH
The method to generate ppH is to formulate final size relation for
model (2) which is an implicit function of ppH and pH (we refer Bai,
2016a,b; Brauer, 2005; Brauer and Castillo-Chavez, 2012 for a rel-
atively complete understanding regarding final size relations).
Based on the assumption of C r < 1 and the infection probability
pp is a monotonically decreasing function of p (see Bai, 2016a),
hom
we conclude that the final proportion pH is unique and pH < hc .
The implication is the well-known result that the voluntary vacci-
nation programs could not guarantee herd immunity, which has
been studied in many papers, e.g. Bai (2016a, 2019), Bauch and
Earn (2004), Shim et al. (2012a), Reluga et al. (2006) and Galvani
et al. (2007). The vaccine coverage level is sub-optimal if individu-
als are driven by self-interests. The proof is graphically presented
in Fig. 4. We assumed that the basic reproduction number is
R0 ¼ 2:5.
3.2. Vaccination game in the heterogeneous mixing population
We now consider the vaccination game in a heterogeneous mix-
ing population consists of two subgroups, based on different activ-
ity levels or different susceptibilities. It is assumed that vaccination
costs C v for both subgroups are identical. Infection probabilities for
unvaccinated individuals in subgroups are p1 ðp; qÞ and p2 ðp; qÞ,
respectively. The formal vaccination game is similarly expressed
by the payoff matrix (2),
The elements in payoff matrix (2) can be interpreted similarly
as in previous subsection. We also denote C r ¼ CCv to represent
i
the relative vaccination cost.
ð31Þ
Fig. 4. The red dashed line represents the piecewise function ð1  pÞpp about
vaccine coverage level p. When p P 0:6, herd immunity is achieved. As a result, the
function value is 0 for p P 0:6. For 0 6 p 6 0:6, the function is decreasing
monotonically. If we set the relative vaccination cost C r ¼ 0:3 (the green solid
horizontal line), there exists a unique solution pH  43%. It is also observed that if
C r is smaller, or even very close to 0; pH will increase towards the herd immunity
threshold 60%, but never reach it.
7
F. Bai Journal of Theoretical Biology 526 (2021) 110795

Table 2
Payoff matrix of the vaccination game in the heterogeneous mixing population with two subgroups. Subscripts 1; 2 represent two subgroups. It is noted that all individuals can
not choose which subgroup they belong to, but can only choose between the adoptions of strategy V or strategy S.

Vaccination game in a population with two subgroups

V1 S1 V2 S2
V1 C v C v C v C v
S1 0 p1 ðp; qÞC i 0 p2 ðp; qÞC i
V2 C v C v C v C v
S2 0 p1 ðp; qÞC i 0 p2 ðp; qÞC i

We formulate the replicator equations to simulate the process log 11p1 ¼ ð1pÞp
c
1 b1
p1 þ ð1qÞp
c
2 b1
p2
of decision making regarding whether or not to be vaccinated. ð39Þ
The proportions of individuals who adopt strategy V in subgroup
log 11p2 ¼ ð1pÞp
c
1 b2
p1 þ ð1qÞp
c
2 b2
p2 :
1 and subgroup 2 are xv 1 and xv 2 , respectively. The proportions of It is not necessary to explicitly solve for p1 and p2 , we only need
individuals who adopt strategy S in subgroup 1 and subgroup 2 to guarantee that both p1 and p2 decrease strictly with the vaccine
are xs1 and xs2 , respectively. Thus, the replicator equations are coverage levels p and q, which is
xv_ 1 ¼ xv 1 ðf v 1  f1 Þ;
@ p1 @ p1 @ p2 @ p2
x_s1 ¼ xs1 ðf s1  f1 Þ; < 0; < 0; < 0; < 0: ð40Þ
ð34Þ @p @q @p @q
xv_ 2 ¼ xv 2 ðf  f Þ;
v2 2
x_s2 ¼ xs2 ðf s2  f2 Þ; This will be confirmed and explained in detail in the following
subsection of numerical simulations.
with fi denotes the average fitness/payoffs for individuals in sub-
group i. The payoffs can be calculated accordingly,
3.4. Numerical simulations
f v 1 ¼ C v ;
f s1 ¼ p1 ðp; qÞC i p1 ð1  pÞ  p2 ðp; qÞC i p2 ð1  qÞ; We perform the numerical simulations to show the existence of
ð35Þ
f v 2 ¼ C v ; ðpH ; qH Þ for vaccination game (2), in Eq. (36). The parameters for
f s2 ¼ p1 ðp; qÞC i p1 ð1  pÞ  p2 ðp; qÞC i p2 ð1  qÞ: the simulations are 1c ¼ 5; b ¼ 0:5; c1 ¼ 2; c2 ¼ 12 and k ¼ 8. It is cal-

p1 and p2 were defined previously in Eq. (8), to represent the culated that p1 ¼ 13 and p2 ¼ 23. Furthermore, we have
probabilities that the contact is made with an individual in sub-
groups 1 and 2, respectively. Solving replicator Eqs. (34), the final p1 b1 5 p2 b1 10 p1 b2 5 p2 b2 5
¼ ; ¼ ; ¼ ; ¼ ;
proportions pH and qH are implicitly expressed in the following c 3 c 3 c 12 c 6
equation,
and the basic reproduction number is R0 ¼ 2:5.
p1 ðpH ; qH Þp1 ð1  pH Þ þ p2 ðpH ; qH Þp2 ð1  qH Þ ¼ C r : ð36Þ p1 ðp; qÞp1 ð1  pÞ þ p2 ðp; qÞp2 ð1  qÞ is a function of p and q. We vary
We are interested in two following questions: whether ðpH ; qH Þ the values of pair ðp; qÞ 2 ½0; 12 to draw the surface and observe
is unique? Whether ðpH ; qH Þ is in the feasible region which results how this function depends on different values of p and q. It is shown
in herd immunity? To answer these questions, we ought to analyze in Fig. 5 that the function value monotonically decreases as p or q
the properties of infection probabilities p1 and p2 first. increasing, which confirms the inequalities in Eq. (40). The function
value becomes 0 once p and q satisfy the herd immunity threshold
Remark. As expressed in Eq. (35), the payoffs/fitness for unvac- relation. The maximum of function value occurs when p ¼ q ¼ 0,
cinated or vaccinated individuals in both subgroups are identical. and the maximum is approximately 0:7. Thus, if the relative cost
Theoretically, the vaccination game (2) can be reduced to a C r is greater than 0:7, all individuals are tend to be unvaccinated
classical 2-player game. in order to gain higher personal payoffs. If and only if C r < 0:7, there
exists the final fractions ðpH ; qH Þ. However, such fractions form a
curve on the 2-dimensional plane and the uniqueness of Nash equi-
3.3. Incorporation of the epidemic model librium does not hold anymore.
If we pick different values of C r 2 ð0; 0:7Þ, different curves for
To precisely calculate infection probabilities p1 and p2 , we predicted vaccine coverage levels can obtained, which are pre-
derive final size relations based on the epidemic model (4) with sented in Fig. 6. However, the herd immunity level curve can never
two subgroups. The corresponding final size relations are be reached. This indicates that, in a heterogeneous mixing popula-
h i h i tion, herd immunity can not be achieved if individuals are solely
ð0Þ
log SS11ð1Þ ¼ p1cb1 S1 ð0ÞS1 ð1Þ
N1
þ p2cb1 S2 ð0ÞS2 ð1Þ
N2 driven by self-interest.
h i h i ð37Þ We are also interested in how individual’s behavior changes if
ð0Þ S1 ð0ÞS1 ð1Þ S2 ð0ÞS2 ð1Þ
log SS22ð1Þ ¼ p1cb2 N1
þ p2cb2 N2
: the disease is more contagious, for instance, when there exists
the new mutated form of coronavirus in current COVID-19 pan-
If we explicitly involve the vaccine coverage levels p and q, the
demic (Bai and Brauer, 2021; Hou et al., 2020). We assume
above relations lead to
h i h i b ¼ 0:85 to account for higher infectivity and have R0 ¼ 4:25.
ð0Þ
log SS11ð1Þ ¼ ð1pÞp
c
1 b1 S1 ð0ÞS1 ð1Þ
S1 ð0Þ
þ ð1qÞp
c
2 b1 S2 ð0ÞS2 ð1Þ
S2 ð0Þ
The predicted vaccine coverage levels in both subgroups are pre-
h i h i ð38Þ sented in Fig. 7. Interestingly, the upper limit of tolerance regards
ð0Þ
log SS22ð1Þ ¼ ð1pÞp
c
1 b2 S1 ð0ÞS1 ð1Þ
S1 ð0Þ
þ ð1qÞp
c
2 b2 S2 ð0ÞS2 ð1Þ
S2 ð0Þ
: relative cost of vaccine increases above 0:8. For same value of C r ,
vaccination intents in both subgroups are increasing when people
Because p1 ¼ S1 ð0ÞS 1 ð1Þ
S1 ð0Þ
and p2 ¼ S2 ð0ÞS 2 ð1Þ
S2 ð0Þ
, we further obtain are facing more contagious diseases.
8
F. Bai
Fig. 5. The surface represents the function p1 ðp; qÞp1 ð1  pÞ þ p2 ðp; qÞp2 ð1  qÞ with
ðp; qÞ 2 ½0; 12 .
Fig. 6. The vaccine coverage levels in both subgroups are associated with different
values of relative vaccination cost C r . It is observed that if C r decreases, the vaccine
coverage level curves will approach but never reach the herd immunity level curve,
which is marked in red.
Fig. 7. R0 ¼ 4:25 with a larger value of b ¼ 0:85. The vaccine coverage levels in
both subgroups are associated with different values of relative vaccination cost C r .
These expected coverage levels are also sub-optimal.
9
Journal of Theoretical Biology 526 (2021) 110795
4. Conclusion and future work
We have formulated mathematical models to study the impact
of population heterogeneity on herd immunity. For the case that
the population consists of two subgroups, the herd immunity
threshold relation was derived. It was shown that if the proportion
of vaccinated individuals in the more active group is higher, the
het
required overall vaccine coverage hc is lower than the classical
hom
herd immunity level hc . We then formulated the linear optimiza-
tion problem to minimize the vaccination cost in the population.
The solution to this optimization problem showed that the optimal
vaccination strategy is to vaccinate the more active group or more
vulnerable group. It was argued that the optimal strategy still
holds if more complicated heterogeneity is considered. However,
the design of vaccination strategies needs to take many factors into
consideration, such as the fiscal expenditure, the pressure of
healthcare system and characteristics of candidate vaccines. We
also suggested that the required overall vaccine coverage might
hom
be much higher that hc for current COVID-19 vaccination cam-
paigns. In the second part of study, game theory was applied to
study the vaccination decision making process. We summarized
previous studies on vaccination game in a homogeneous mixing
population, showed that the Nash equilibrium is unique but the
final proportion of vaccinated individuals is sub-optimal if individ-
uals are solely driven by self-interests. The studies were then
extended to the heterogeneous mixing population. By applying
replicator equations, Nash equilibrium can be obtained. It was
proved that the uniqueness of Nash equilibrium does not hold
for such case, and the final proportions are still sub-optimal.
There are many questions need further considerations. First the
heterogeneity is actually much more complex, it can be the combi-
nation of different activity levels, different age groups, different
susceptibilities, different infectivities and many other factors.
Improved parameterisation of epidemic models are possibly
obtained by large-scale social experiments or even surveys (see
Mossong et al., 2008). The assumed division based on activity
levels is also oversimple. It is discussed in Lloyd-Smith et al.
(2005) that the degree of infectiousness may follow one type of
continuous distributions in the population. Then if the infectious
period is assumed to be exponential distributed, it is more reason-
able to assume that the contact rate is continuously distributed.
Another difficulty in modeling heterogeneous mixing population
is the comparison of susceptibilities in different groups. The second
question of interest is to improve the vaccination game in the
heterogeneous mixing population. It is reasonable to assume that
the relative vaccination costs for subgroups are varied. The side
effects of vaccine might be higher for certain subgroups and lower
for others, the costs of infection are obviously higher for elderly
individuals. However, the different values of relative costs will
complicate the analysis and may cause the non-existence of Nash
equilibrium. With better understandings of population hetero-
geneity, the mathematical models can be parameterised more
properly and the control strategies can be more accurately
designed.
CRediT authorship contribution statement
Fan Bai: Conceptualization, Methodology, Software, Formal
analysis, Resources, Writing - original draft, Writing - review &
editing, Visualization, Project administration, Funding acquisition.
Acknowledgements
The work is funded by the Post-doctoral fellowship offered by
Hausdorff Center for Mathematics and the University of Bonn.
F. Bai
The author thanks two reviewers for very constructive comments
to improve this work.
References
Anderson, R.M., May, R.M., 1991. Infectious diseases of humans: dynamics and
control. Oxford University Press, Oxford.
Anderson, R.M., Vegvari, C., Truscott, J., Collyer, B.S., 2020. Challenges in creating
herd immunity to SARS-CoV-2 infection by mass vaccination. Lancet 396
(10263), 1614–1616.
Bai, F., 2016a. Uniqueness of Nash equilibrium in vaccination games. J. Biol. Dyn. 10
(1), 395–415.
Bai, F. 2016b. Vaccination models in infectious diseases. PhD thesis, University of
British Columbia..
Bai, F., 2019. Modeling vaccination decision making process in a finite population.
Math. Biosci. 311, 82–90.
Bai, F., 2020. Evaluating different epidemiological models with the identical basic
reproduction number R0 . J. Biol. Dyn. 14 (1), 849–870.
Bai, F., Brauer, F., 2021. The effect of face mask use on COVID-19 models.
Epidemiologia 2 (1), 75–83.
Bauch, C.T. and Earn, D.J.D. 2004. Vaccination and the theory of games. Proc. Natl.
Acad. Sci., 101(36), 13391–13394..
Brauer, F., 2005. The kermack–McKendrick epidemic model revisited. Math. Biosci.
198 (2), 119–131.
Brauer, F., 2008. Epidemic models with heterogeneous mixing and treatment. Bull.
Math. Biol. 70 (7), 1869–1885.
Brauer, F. 2018a. Early estimates of epidemic final sizes. J. Biol. Dyn., 1–8..
Brauer, F., 2018b. The final size of a serious epidemic. Bull. Math. Biol. 81 (3), 869–
877.
Brauer, F., Castillo-Chavez, C., 2012. Mathematical Models in Population Biology and
Epidemiology. Springer, New York.
Britton, T., Ball, F., Trapman, P., 2020. A mathematical model reveals the influence of
population heterogeneity on herd immunity to SARS-CoV-2. Science 369
(6505), 846–849.
Davies, N.G., Klepac, P., Liu, Y., Prem, K., Jit, M., Eggo, R.M., 2020. Age-dependent
effects in the transmission and control of COVID-19 epidemics. Nat. Med. 26 (8),
1205–1211.
Diekmann, O., Heesterbeek, J.A.P., Roberts, M.G., 2009. The construction of next-
generation matrices for compartmental epidemic models. J. R. Soc. Interface 7
(47), 873–885.
European Centre for Disease Prevention and Control. 2020. COVID-19 vaccination
and prioritisation strategies in the EU/EEA. 22 December 2020. ECDC:
Stockholm..
European Centre for Disease Prevention and Control. 2021. Overview of the
implementation of COVID-19 vaccination strategies and vaccine deployment
plans in the EU/EEA. 29 March 2021. ECDC: Stockholm..
Fine, P.E.M., 1993. Herd immunity: History, theory, practice. Epidemiol. Rev. 15 (2),
265–302.
Fine, P.E.M., Clarkson, J.A., 1986. Individual versus public priorities in the
determination of optimal vaccination policies. Am. J. Epidemiol. 124 (6),
1012–1020.
Fine, P., Eames, K., Heymann, D.L., 2011. herd immunity: A rough guide. Clin. Infect.
Dis. 52 (7), 911–916.
Fontanet, A., Cauchemez, S., 2020. COVID-19 herd immunity: where are we? Nat.
Rev. Immunol. 20 (10), 583–584.
10
Journal of Theoretical Biology 526 (2021) 110795
Fox, J.P., Elveback, L., Scott, W., Gatewood, L., Ackerman, E., 1971. Herd immunity:
basic concept and relevance to public health immunization practice. Am. J.
Epidemiol. 94 (3), 179–189.
Galvani, A.P., May, R.M., 2005. Dimensions of superspreading. Nature 438 (7066),
293–295.
Galvani, A.P., Reluga, T.C., Chapman, G.B., 2007. Long-standing influenza vaccination
policy is in accord with individual self-interest but not with the utilitarian
optimum. Proc. Nat. Acad. Sci. 104 (13), 5692–5697.
Hou, Y.J., Chiba, S., Halfmann, P., Ehre, C., Kuroda, M., Dinnon, K.H., Leist, S.R.,
Schäfer, A., Nakajima, N., Takahashi, K., Lee, R.E., Mascenik, T.M., Graham, R.,
Edwards, C.E., Tse, L.V., Okuda, K., Markmann, A.J., Bartelt, L., de Silva, A.,
Margolis, D.M., Boucher, R.C., Randell, S.H., Suzuki, T., Gralinski, L.E., Kawaoka,
Y., and Baric, R.S. 2020. SARS-CoV-2 d614g variant exhibits efficient replication
ex vivo and transmission in vivo. Science, eabe8499..
Jones, D., Helmreich, S., 2020. A history of herd immunity. Lancet 396 (10254), 810–
811.
Lloyd-Smith, J.O., Schreiber, S.J., Kopp, P.E., Getz, W.M., 2005. Superspreading and
the effect of individual variation on disease emergence. Nature 438 (7066),
355–359.
Macdonald, G., 1957. The epidemiology and control of malaria. Oxford University
Press, London.
Monod, M., Blenkinsop, A., Xi, X., Hebert, D., Bershan, S., Tietze, S., Baguelin, M.,
Bradley, V.C., Chen, Y., Coupland, H., Filippi, S., Ish-Horowicz, J., McManus, M.,
Mellan, T., Gandy, A., Hutchinson, M., Unwin, H.J.T., van Elsland, S.L., Vollmer, M.
A.C., Weber, S., Zhu, H., Bezancon, A., Ferguson, N.M., Mishra, S., Flaxman, S.,
Bhatt, S., and Ratmann, O. 2021. Age groups that sustain resurging COVID-19
epidemics in the united states. Science, page eabe8372..
Mossong, J., Hens, N., Jit, M., Beutels, P., Auranen, K., Mikolajczyk, R., Massari, M.,
Salmaso, S., Tomba, G.S., Wallinga, J., Heijne, J., Sadkowska-Todys, M., Rosinska,
M., Edmunds, W.J., 2008. Social contacts and mixing patterns relevant to the
spread of infectious diseases. PLoS Med. 5, (3) e74.
Omer, S.B., Yildirim, I., Forman, H.P., 2020. Herd immunity and implications for
SARS-CoV-2 control. JAMA 324 (20), 2095.
Reluga, T.C., 2010. Game theory of social distancing in response to an epidemic.
PLoS Comput. Biol. 6, (5) e1000793.
Reluga, T.C., Bauch, C.T., Galvani, A.P., 2006. Evolving public perceptions and
stability in vaccine uptake. Math. Biosci. 204 (2), 185–198.
Shim, E., Chapman, G.B., Townsend, J.P., Galvani, A.P., 2012a. The influence of
altruism on influenza vaccination decisions. J. R. Soc. Interface 9 (74), 2234–
2243.
Shim, E., Grefenstette, J.J., Albert, S.M., Cakouros, B.E., Burke, D.S., 2012b. A game
dynamic model for vaccine skeptics and vaccine believers: Measles as an
example. J. Theor. Biol. 295, 194–203.
Smith, C.E.G., 1970. Prospects for the control of infectious disease. Proc. R. Soc. Med.
63(11P2):1181–1190..
Tassier, T., 2013. The economics of epidemiology. Springer, Heidelberg.
van den Driessche, P., Watmough, James, 2002. Reproduction numbers and sub-
threshold endemic equilibria for compartmental models of disease
transmission. Math. Biosci. 180 (1–2), 29–48.
Viner, R.M., Mytton, O.T., Bonell, C., Melendez-Torres, G.J., Ward, J., Hudson, L.,
Waddington, C., Thomas, J., Russell, S., van der Klis, F., Koirala, A., Ladhani, S.,
Panovska-Griffiths, J., Davies, N.G., Booy, R., Eggo, R.M., 2021. Susceptibility to
SARS-CoV-2 infection among children and adolescents compared with adults.
JAMA Pediatrics 175 (2), 143.
Wallinga, J., Lipsitch, M., 2006. How generation intervals shape the relationship
between growth rates and reproductive numbers. Proc. R. Soc. B: Biol. Sci. 274
(1609), 599–604.