Vaccine 33 (2015) 1291–1296

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Controlling measles using supplemental immunization activities:

A mathematical model to inform optimal policy
Stéphane Verguet a,∗ , Mira Johri b,c , Shaun K. Morris d,e,f , Cindy L. Gauvreau f ,
Prabhat Jha f,g , Mark Jit h,i
a
Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA
b
International Health Unit (USI), University of Montreal Hospital Research Centre (CR-CHUM), Montreal, Québec, Canada
c
Department of Health Administration, School of Public Health, University of Montreal, Montreal, Québec, Canada
d
Division of Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, Canada
e
Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
f
Center for Global Health Research, Saint Michael’s Hospital, Toronto, Ontario, Canada
g
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
h
Modelling and Economics Unit, Public Health England, London, United Kingdom
i
Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom

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

Article history: Background: The Measles & Rubella Initiative, a broad consortium of global health agencies, has provided
Received 31 August 2014 support to measles-burdened countries, focusing on sustaining high coverage of routine immunization of
Received in revised form children and supplementing it with a second dose opportunity for measles vaccine through supplemental
17 November 2014
immunization activities (SIAs). We estimate optimal scheduling of SIAs in countries with the highest
Accepted 27 November 2014
measles burden.
Available online 23 December 2014
Methods: We develop an age-stratified dynamic compartmental model of measles transmission. We
explore the frequency of SIAs in order to achieve measles control in selected countries and two Indian
Keywords:
Measles
states with high measles burden. Specifically, we compute the maximum allowable time period between
Immunization two consecutive SIAs to achieve measles control.
Supplementary immunization activities Results: Our analysis indicates that a single SIA will not control measles transmission in any of the
Low- and middle-income settings countries with high measles burden. However, regular SIAs at high coverage levels are a viable strategy
Child health to prevent measles outbreaks. The periodicity of SIAs differs between countries and even within a single
Mathematical modeling country, and is determined by population demographics and existing routine immunization coverage.
Conclusions: Our analysis can guide country policymakers deciding on the optimal scheduling of SIA
campaigns and the best combination of routine and SIA vaccination to control measles.
© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction of under-five deaths in 2000 [2,4,5] to about 1–2% in 2010 [2,3],

measles burden remains high in a number of countries [6]. The
The fourth United Nations Millennium Development Goal aims Measles & Rubella Initiative (www.measlesrubellainitiative.org),
to reduce under-five mortality rates by two thirds between 1990 a broad consortium of global health agencies, has provided sup-
and 2015. Despite accelerated progress, with a decline from about port to measles-burdened countries in order to sustain and achieve
12 million deaths in 1990 to about 7–8 million deaths in 2010, measles mortality reductions. It has been focusing on maintaining
the goal is unlikely to be attained at current rates of decline high coverage of routine immunization of children at about 9 or
[1–3]. Measles has been a key contributor to this mortality. 12 months of age and supplementing it by a recommended second
Although measles mortality has dropped globally, from up to 5% dose for measles vaccine [7–9]. In a large number of countries, the
second dose of measles vaccine is usually included in the vaccina-
tion schedule and usually administered to children before school
∗ Corresponding author at: Department of Global Health and Population, Harvard entry [8]. In high measles-burdened countries, often, only one
T.H. Chan School of Public Health, Boston, MA, USA. dose is routinely given, but an opportunity for a second dose of
E-mail address: [email protected] (S. Verguet). measles vaccine is offered through supplemental immunization

http://dx.doi.org/10.1016/j.vaccine.2014.11.050
0264-410X/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1292 S. Verguet et al. / Vaccine 33 (2015) 1291–1296

activities (SIAs) [8,9]. During SIAs, children and adolescents are

targeted regardless of their previous history of measles vaccina-
tion. Periodic SIA campaigns occur nationally/sub-nationally with
use of various outreach strategies [9].
World Health Organization (WHO) analysts have reported sus-
tained decreases in measles mortality worldwide since the 2000s
[6,10]; most recently, global measles-related deaths were esti-
mated to have decreased from about 535,000 deaths in 2000
to 140,000 deaths in 2010 [6]. Despite these global reductions,
measles mortality remains substantial and concentrated in a num-
ber of high measles-burdened countries [2,3,6]. For example, India
accounted for almost 50% (about 65,000 deaths) of estimated
measles mortality in 2010, and the WHO Africa region for almost
40% (about 50,000 deaths) [6,11]. Some of these countries have
low levels of routine immunization, such as Nigeria with a 42%
coverage rate for the first dose of measles vaccine (MCV1) [12].
That being said, experience from first the Pan American Health
Organization (PAHO) and then sub-Saharan Africa has shown that
SIAs can contribute to achieving measles control in high burden
countries. Indeed, large-scale implementation of SIAs in the PAHO
region since the 1990s is thought to have contributed to the elim-
ination of the endemic transmission of measles in the Americas
[13]. The same strategy has been adapted to sub-Saharan Africa and
appeared as a major contributor for the reported drops in measles Fig. 1. Model of vaccine action. Note: S = susceptible, I = infected, R = recovered,
deaths on the African continent over the last decade [14,15]. There- VS = vaccinated susceptible, VI = vaccinated infected, VR = vaccinated recovered,
fore, it is necessary to examine the optimal strategies that can be  = force of infection,  = infectiousness period of measles,  = coverage of measles
vaccine for individuals vaccinated for the 1st time,  = effectiveness of measles vac-
implemented in order to control measles in high burden countries;
cine (85% for the first dose when vaccinating before one year of age, 95% after one
in particular, it is important to determine the appropriate use and year of age and 98% for two doses), 2 = coverage of measles vaccine for individuals
frequency of periodic SIAs in these countries. vaccinated for the 2nd time, through supplemental immunization activity (SIA) only
High measles-burden countries with limited financial resources (SIA coverage).
are confronted with difficult decisions related to measles control.
For example, these decisions involve sensitive trade-offs between or not at all (Fig. 1). We assume that vaccination gives lifetime
investing in sustainable routine immunization services and imple- protection if it successfully elicits an immune response, and that
menting repeated SIAs, as part of the overall strategy. In particular, vaccinating already infected individuals does not increase the rate
WHO recommends SIAs to be repeated every 2–4 years for those of infection clearance (i.e. the vaccine has no therapeutic action).
countries with MCV1 coverage below 80% [8]. In this paper, we The model was programmed using R statistical software version
examined the trade-offs between routine vaccination coverage 3.0.1 (www.r-project.org). Mathematical equations describing the
and SIA coverage and inter-SIA periodicity in order to achieve model are provided in the Supplementary Data (Section 1). More
measles control. Specifically, we selected countries with the highest details can be obtained from the authors upon request.
measles mortality burden globally [2,3], and estimated the opti-
mal scheduling of future measles SIAs in these countries, using a 2.2. Model parameters
dynamic compartmental model of measles transmission. The aim
is to inform country policymakers about the scheduling of SIAs to Dynamic models of infection transmission require data on age-
achieve measles control. dependent contact patterns in the population. However, empirical
data on contacts have been published for only several European
countries and Vietnam. We used well established contact sur-
2. Methods vey data from Great Britain [19] corresponding to a probability of
transmission per contact of about 3%, and in a sensitivity analy-
2.1. Modeling sis, used mixing patterns from Vietnam [20]. The probability of an
infected individual transmitting measles to a susceptible individ-
We developed DynaMICE (Dynamic Measles Immunization Cal- ual following an effective contact was set to be consistent with a
culation Engine), an age-stratified model of measles infection basic reproduction number (R0 , the number of people infected by a
transmission in vaccinated and unvaccinated individuals. The pop- single infected person in a completely susceptible population) for
ulation in the model can be susceptible to measles, infected with measles of 16 [21]. We also changed R0 to the lower value of 12 in
measles or recovered from measles (and hence have lifelong a sensitivity analysis.
immunity). The rate at which infection occurs in the susceptible The selected countries with high measles mortality bur-
population depends on the existing proportion of the population den retained were: India, Ethiopia, Nigeria, Indonesia, Mali,
that is already infected, as well as the effective contact rate between Afghanistan, Niger, Madagascar, and Burkina Faso. These countries
different age groups. Individuals age discretely, in one-year incre- were selected among the ten countries with the highest estimated
ments, at the end of each year [16], between 0 and 100 years old. burden of measles from each of two sources of estimates: the Child
Vaccinated individuals are assumed to have a reduced risk of Health Epidemiology Reference Group of WHO and UNICEF [3]
measles infection. Vaccine effectiveness is assumed to be 85% for and the Institute for Health Metrics and Evaluation [2]. The pop-
the first dose when vaccinating before one year of age, 95% after ulation age distribution by country was sourced from the United
one year of age and 98% for two doses, as suggested by a recent Nations, along with crude birth rates and death rates by country
meta-analysis [17]. Vaccines are assumed to be “all or nothing” [18], [22]; these demographic parameters were assumed to be static
so that individuals receiving the vaccine are either fully protected over time (constant population growth) to simplify long-term
 S. Verguet et al. / Vaccine 33 (2015) 1291–1296 1293

population projections. The average infectious period of measles following the implementation of SIAs at regular time intervals from
was assumed to be 14 days [21]. MCV1 was assumed to be deliv- every single year to every 10 years (dotted vertical lines), with
ered before the first birthday, with the SIA measles dose being given MCV1 coverage of 74% and with the population structure of India.
to all children between six months and five years old, assuming for In this case, we see that there is resurgence of measles (occurrence
simplicity that vaccination could be given as maternally derived of incidence peaks after year 50) when the inter-SIA period is over
immunity had waned. In practice, this may be an approximation three years. Furthermore, the less frequent the SIA, the larger the
since the lower age limit is commonly 9 or 12 months, which is resurgence. Conversely, an average inter-SIA period of three years
a few months after these antibodies may have waned.1 The prob- or less suffices to control measles (no occurrence of incidence peaks
ability of receiving a MCV1 and SIA dose was assumed to be after year 50).
uncorrelated. MCV1 coverage by country was obtained from WHO Table 1 also lists the inter-SIA periods required in order to
and UNICEF [12]. Coverage figures for the SIAs were assumed to achieve measles control, estimated computationally, for selected
be of 90% among the 6–59 month-olds, a conservative estimate countries with high measles burden and 90% SIA coverage among
according to historical SIA coverage data collated by WHO [23]. 6–59 month-olds. We see that the maximum time period required
between two consecutive SIAs depends importantly on MCV1
2.3. Model analysis coverage (Pearson correlation coefficient of 0.71). For example,
countries like Ethiopia and Nigeria with lower coverage of MCV1
The dynamic compartmental model developed and presented (66% and 42%, respectively) would require SIAs about every 2 years.
above was run for 100 years with routine vaccination to reach a This national picture may however mask heterogeneities at
post-vaccination equilibrium (the last 50 years of which are shown the sub-national/state level and Table 1 also lists the periodicity
on Fig. 2), and finally run for a further 50 years with both rou- required between SIAs in order to achieve measles control with
tine and SIA vaccination. Using country-specific inputs (e.g. MCV1 current level of MCV1 coverage for two Indian states, Bihar and
coverage), we explored the potential periodicity of SIAs required Uttar Pradesh, where SIAs have been undertaken since 2010 and
in order to achieve measles control. Disease control refers to the 2011, respectively. For these two states, we see that the inter-SIA
reduction of morbidity and mortality to locally acceptable levels period required is 2 years compared with 3 years at the national
[24]. Here we define measles as being controlled if the incidence level.
of measles remains below 1 per 100,000 individuals in the entire This computational analysis is further confirmed by the analyt-
population. ical results, also presented in Table 1. Based on Eq. (1) above, Fig. 3
shows the inter-SIA period required to achieve measles control for
2.4. Analytical approach a range of SIA coverage levels, as a function of MCV1 coverage
levels, using Indian demographic inputs and R0 of 16. In the last
The computer model presented above requires considerable column of Table 1, the results are shown for the inter-SIA period
technical capacity and computing power. To enable policymakers required in order to achieve measles control, estimated analytically
to use our model for SIA planning with greater ease, we also derived through Eq. (1) and rounded down,2 for 90% SIA coverage among
a simple formula relating SIA periodicity to immunization cover- 6–59 month-olds. We see that these analytical results match the
age and population demographics. To do this, we simplified the simulation results closely.
system of differential equations representing the model of measles Finally, in the simulation model, the use of mixing data from
transmission (Supplementary Data, Section 1), removing age strat- Vietnam [20] would lengthen the measles inter-epidemic cycles
ification in order to make the equations analytically tractable [25]. considerably and increase the height of the epidemic peaks, leading
This allowed us to compute the maximum time period allowed to unrealistic inter-epidemic cycles much larger than the 1–2 year
between two consecutive SIAs that would still achieve measles cycles usually expected in low- and middle-income countries with
control, depending on MCV1 coverage, demographic parameters, higher birth rates and lower MCV1 coverage [21,26,27]. Although
measles specific parameters, and vaccine effectiveness. The max- this is not clear, reasons for this difference may include less assorta-
imum inter-SIA period allowed to achieve measles control could tive mixing (due to differences in household structure and/or birth
then be estimated as (with the formula developed in Supplemen- rates) or recall bias.
tary Data, Section 2): In addition, we varied the basic reproduction number for sensi-
S S,eff tivity analysis. Table 2 reports on the inter-SIA period required in
Tmax ∼ (1) order to achieve measles control, estimated computationally and
R
˜ 0 (1 − R R )(1 − S S,eff /2)
analytically, for the selected countries with high measles burden,
where R0 is the basic reproduction number, ṽ is the birth rate with 90% SIA coverage among 6–59 month-olds, and with a lower
adjusted for population growth (birth rate multiplied by the ratio reproduction number R0 of 12, in order to highlight a better case
between under-five population and 5–9-year-olds population),  R scenario. Expectedly, we see that the inter-SIA period to achieve
and  S are the effectiveness of MCV1 and SIA measles vaccine measles control is increased on average for all countries.
respectively, R is the coverage of MCV1, and S,eff is the effec-
tive coverage of SIA immunization (90% coverage multiplied by the
fraction of measles cases among under-fives depending on MCV1 4. Discussion
coverage and as estimated by geographical region [6]). The com-
plete details of this approach are given in the Supplementary Data Both numerical simulation and mathematical analysis indicate
(Section 2). that a single SIA will not control measles outbreaks in any of the
countries with high burden of measles. However, regular SIAs at
3. Results high coverage are able to control measles transmission, with the
periodicity of SIA campaigns determined by population demo-
Fig. 2 shows results from the computer simulation showing graphics and existing MCV1 coverage.
change in the number of infected individuals (measles incidence)

2
Rounding down (e.g. 2.3∼2; 2.7∼2) the inter-SIA period estimated analytically
1
This choice does not materially affect the measles dynamics studied in the paper. leads to a more conservative estimate.
1294 S. Verguet et al. / Vaccine 33 (2015) 1291–1296

Fig. 2. Computer model predictions of annual measles incidence pre- and post-SIA in India, under different intervals between SIAs. Each SIA is indicated by a dotted vertical
line. R0 is 16 and SIAs are assumed to have 90% coverage among 6–59 month-olds. Note: The model was run for 100 years with routine vaccination to reach a postvaccination
equilibrium (the last 50 years of which are shown), and finally run for a further 50 years with both routine and SIA vaccination.

The model also suggests that a single SIA may give the impres- immunization campaigns [25,36–38]. Here, we build on these mod-
sion of having controlled measles due to a post-vaccination els to explore the impact and optimal timing of periodic measles
‘honeymoon’ [28] (Fig. 2). Such potentially unexpected effects can immunization campaigns, which have been the main focus of
have disastrous consequences on plans for national elimination measles control efforts in the highest burden countries. We find
or even global eradication goals. This underscores the importance that impact and optimal timing of measles SIAs varied among
of using predictive models that account for transmission events, the highest burden countries, and even within a single country
rather than relying solely on surveillance based on reported cases, (Tables 1 and 2). This suggests that a country-specific approach
to inform decision making about vaccination. to SIA timing may be most effective, with the recommended
Several models of measles transmission have been previously length of time between SIAs dependent on local demographics and
developed in order to explore the potential impact of different routine coverage. Our computer model and the associated simpli-
vaccination strategies [27,29–35], including the impact of mass fied analytical formula offer a way for country policymakers to
 S. Verguet et al. / Vaccine 33 (2015) 1291–1296 1295

Table 1
Inter-SIA period required to achieve measles control with 90% SIA coverage and R0 of 16, as a function of routine immunization coverage for the first dose of measles vaccine
and crude birth rate, for selected countries with high measles burden, and two Indian states.

Country Routine coverage for 1st Crude birth rate (per SIA period (years) SIA period (years)
dose of measles vaccine (%) 1000 population) (computational model) (analytical model)

Afghanistan 68 36 2 2
Burkina Faso 87 43 3 3
Ethiopia 66 35 2 2
India 74 23 3 3
State of Bihar 58 29 2 3
State of Uttar Pradesh 53 29 2 2
Indonesia 80 21 3 4
Madagascar 69 36 2 2
Mali 59 49 2 2
Niger 73 51 2 2
Nigeria 42 43 2 2

Table 2 within the range of the 2–4 years periods recommended by WHO
Supplemental immunization activity (SIA) period required to achieve measles con-
for countries with MCV1 coverage under 80% [8]. But, it also goes
trol with 90% SIA coverage and R0 of 12, for selected countries with high measles
burden, and two Indian states. beyond these recommendations as it provides a means to weigh
various combinations of coverage levels for MCV1 and SIAs with
Country SIA period (years) SIA period (years)
the dimension of SIA periodicity. This enables countries to identify
(computational model) (analytical model)
more locally appropriate SIA scheduling in accordance with finan-
Afghanistan 3 3 cial and operational capacity: this is especially important in the
Burkina Faso 5 5
context of resource-limited settings given that SIAs can be expen-
Ethiopia 3 3
India 3 4 sive.
State of Bihar 3 4 Nonetheless, our model has several limitations. First, we used an
State of Uttar Pradesh 2 3 average estimate of the basic reproduction number of measles, and
Indonesia 4 6
hence did not capture local variations in the intensity of measles
Madagascar 3 3
Mali 3 3 transmission (due to differences in cultural practices and social
Niger 3 3 gathering, for example). However, estimating this number sepa-
Nigeria 2 3 rately for each setting is hindered by the lack of reliable data for
measles case notifications due to underreporting and great dis-
parity in reporting quality. As sensitivity analysis, we reported
determine when measles SIAs should be implemented. They can
on the inter-SIA period required for the selected high burden
also further inform WHO guidelines on the conduct of SIAs at
countries with a lower reproduction number R0 of 12 (Table 2).
the country level, by recommending specific inter-SIA periods to
Also, in the absence of data, we did not account for potential
achieve measles control at the national and sub-national levels,
variations in vaccine effectiveness at the country/region level. Sec-
depending on a range of country-specific routine immunization
ond, due to lack of data, the model does not take into account
coverage rates and demography, and including within country
potential correlation between MCV1 and SIA coverage, and the
heterogeneities. Our analysis highlights country inter-SIA periods
fact that often children with better access to health systems and
hence more likely to have received MCV1 can be easier to reach
through SIA. Neither does it account for changes in immunization
10

SIA effective coverage

and birth rates into the future, as these are largely uncertain to
10%
30% forecast. Finally, though the model captures the conditions neces-
50% sary for measles control, it is not intended to realistically model
8

70%
90% measles elimination (i.e. zero indigenous transmission events).
Elimination goals depend on monitoring measles importations,
vaccine coverage in hard-to-reach groups and stochastic one-off
SIA period (years)

events, none of which are captured by the model (and rarely so

6

by most models published in the literature). One could however

examine the potential of an imported case to invade the popula-
tion.
4

Despite these limitations, the broad conclusions of the model

appear robust, particularly the need for regular SIAs to control
measles in low routine coverage settings as in many high-
2

endemicity countries. Models such as the one presented here

are important tools for vaccination decision making, comple-
menting existing information from surveillance systems. Our
findings generally substantiate the guidance given by WHO, but
0

most importantly can be used by country policymakers to tailor

10 20 30 40 50 60 70 80 90 100
their SIA scheduling and planning to their specific setting, tak-
Routine coverage (%) ing into account local demographics and routine coverage. As a
result, countries with longer estimated inter-SIA periods might
Fig. 3. Inter-SIA period (years) as a function of routine immunization coverage for
consider further investments in routine immunization services,
the first dose of measles vaccine, for different levels of SIA coverage with Indian
demographic inputs and R0 of 16. Note: the dotted vertical line depicts the current whereas those with shorter inter-SIA periods may postpone such
routine immunization coverage for the first dose of measles vaccine in India (74%). investments. Since measles control and elimination strategies are
1296 S. Verguet et al. / Vaccine 33 (2015) 1291–1296

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