SUPPLEMENT ARTICLE

The Theory of Measles Elimination: Implications

for the Design of Elimination Strategies

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Nigel J. Gay
Health Protection Agency, Modelling and Economics Unit, Communicable Disease Surveillance Centre, London, United Kingdom

The theory of disease transmission provides a consistent framework within which to design, evaluate, and
monitor measles elimination programs. Elimination of measles requires maintaining the effective reproduction
number R at !1, by achieving and maintaining low levels of susceptibility. The essential features of different
vaccination strategies (e.g., routine versus campaigns, number of doses) can be compared within this frame-
work. Designing an elimination program for a particular population involves setting target levels of suscep-
tibility, establishing the current susceptibility profile, selecting an approach to reduce susceptibility below the
target, and selecting an approach to maintain susceptibility below the target. A key indicator of the sustainability
of an elimination program is the residual level of susceptibility of a cohort after it has completed its scheduled
vaccination opportunities. This can be estimated from vaccination coverage data. The high transmissibility of
measles poses a significant challenge to any attempt to eliminate it.

Measles elimination goals have been adopted in a range duced by a typical infective person in a totally suscep-
of countries, subregions, and regions adopting a variety tible population. It depends on the characteristics of
of vaccination strategies. Here I present the theoretical the infectious agent (e.g., infectivity and duration of
concepts relevant to measles elimination, such as the infectiousness) and of the population (e.g., population
reproduction number and susceptibility threshold; in- density and social mixing patterns). R0 therefore differs
vestigate and compare the essential features of routine between infections in the same population but also for
and campaign vaccination strategies within this frame- the same infection in different populations. For ex-
work; present the stages of designing a measles elimi- ample, within any given population, the R0 for measles
nation strategy; and discuss implications for surveil- is greater than the R0 for rubella, and, all else being
lance of measles elimination programs. equal, the R0 for measles is greater in a dense, urban
population than a sparse, rural population.
BASIC CONCEPTS Because R0 is defined on the basis of the potential
for transmission in a totally susceptible population, it
Measles is transmitted from person to person. The cru- does not depend on the level of susceptibility in the
cial factor determining the spread of infection is there- population and is unaffected by vaccination. It repre-
fore the number of secondary cases caused by each sents the maximum transmission potential of the in-
infectious person. fection—the average number of persons with whom an
Basic reproduction number, R0. The basic repro-
infected person makes effective contact during the in-
duction number, R0, is a summary measure of the trans-
fectious period.
missibility of an infection within a population, defined
Effective reproduction number, R. The effective
as the average number of secondary infections pro-
reproduction number, R, is a summary measure of the
potential for transmission of an infection within a pop-
ulation, defined as the average number of secondary
Reprints or correspondence: Nigel J. Gay, Health Protection Agency, Modelling
and Economics Unit, Communicable Disease Surveillance Centre, 61 Colindale infections produced by a typical infective person. The
Ave., London NW9 5EQ, United Kingdom (nigel.gay@hpa.org.uk). value of R depends on the levels of susceptibility in the
The Journal of Infectious Diseases 2004; 189(Suppl 1):S27–35
population and on the basic reproduction number R0.
 2004 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2004/18909S1-0005$15.00 In a completely susceptible population R p R 0.

Theory of Measles Elimination • JID 2004:189 (Suppl 1) • S27

 When R is 11, each case produces on average 11 secondary will be sufficient to attain elimination. Two important points
case, so the number of cases increases from one generation of are often overlooked. First, the formula assumes that vacci-
cases to the next; when R is !1, the number of cases decreases. nation is given at birth, or as soon as infants become suscep-
Thus, the value R p 1 is an important threshold [1]. tible—if vaccination is delayed until the second or third year
Elimination criterion. If R is maintained constantly at !1, of life, a higher proportion immune will be required [2]. Sec-
the number of cases will decrease (on average) with each gen- ond, this formula refers to the level of immunity that must be
eration, and all endemic chains of transmission will eventually achieved, not the vaccination coverage—the efficacy of the vac-
die out. Imported cases introduced into the population will cine must be taken into account when calculating the coverage
not be able reestablish endemic transmission. Elimination of required. The duration of protection afforded by successful

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indigenous transmission will therefore be achieved. vaccination is also important—waning of immunity that en-
Susceptibility threshold. To be relevant to vaccination pol- abled persons experiencing secondary vaccine failure to become
icy decisions, the theoretical concepts of R0 and R must be significant transmitters of infection would thwart attempts at
applicable to practical questions regarding available data. Per- elimination.
haps the most important question regards the susceptibility Epidemic cycle. If measles is endemic in a population, it
threshold: What level of susceptibility corresponds to the R p occurs in epidemic cycles (figure 1). During the course of an
1 threshold? The simplest case to consider is that of a homo- epidemic cycle, R oscillates around threshold at R p 1, chang-
geneously mixing population. Although such simple models ig- ing constantly as the level of susceptibility fluctuates. An epi-
nore the complexities of real populations, they are worthy of demic can begin if R 1 1. After the onset of an epidemic, those
discussion to establish the basic principles, many of which carry infected acquire immunity, so the number of susceptible per-
over into more complicated models. sons falls and R begins to decline. When infection has depleted
In a homogeneously mixing population, the basic and ef- the pool of susceptible persons sufficiently, R is reduced to !1
fective reproduction numbers are related simply by R p R 0 x, and the number of cases in the outbreak declines. At the end
where x is the proportion of the population susceptible to of the outbreak, R begins to increase again because of the
infection. The threshold at R p 1 defines the critical proportion addition of new susceptible persons through birth. When R
susceptible, x ∗ p 1/R 0. exceeds 1, a new epidemic can begin. If a population is suffi-
Critical vaccination coverage. Eliminating infection re- ciently large, chains of transmission can be sustained through-
quires maintaining R ! 1 , by keeping the proportion suscepti- out the period when R ! 1; otherwise, an epidemic will not
ble below the critical value x ∗ p 1/R 0 . Equivalently, the propor- occur until the infection is reintroduced to the population.
tion immune must be greater than the critical proportion Critical community size. The concept of a critical com-
immune pc p 1 ⫺ x ∗ p 1 ⫺ 1/R 0. Achieving this level of im- munity size for sustaining endemic measles transmission arose
munity through a vaccination program administered at birth through work in the prevaccination era, studying the persis-

Figure 1. Simple model of measles transmission in a population with 80% routine vaccination coverage (90% efficacy) from year 5. (Two-week
time step: number of cases indicated by bars; number of susceptibles by dots.)

S28 • JID 2004:189 (Suppl 1) • Gay

tence of measles in island and city populations [3, 4]. The issue measles is endemic, R0 can be estimated directly as the recip-
is whether chains of transmission could persist through the rocal of the average proportion susceptible. This provides a
post-epidemic period, when R ! 1 , until the susceptible persons straightforward method for estimating R0 from seroprevalence
build up to the critical level at which R 1 1, when the next data, which can be used after the introduction of vaccination,
epidemic can begin. At such low levels of transmission, sto- even for growing populations.
chastic (chance) effects become paramount. Consider cases as Various formulas have been derived to relate the average
occurring in discrete generations. At each generation there is proportion susceptible before introduction of vaccination to
a finite probability that no secondary infections will be pro- easily observed parameters such as the average age at infection
duced and therefore that transmission will die out. This prob- in the absence of vaccination, A; the life expectancy, L; and the

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ability depends on the expected number of cases in the next average duration of maternal antibody protection, m [5, 6].
generation (i.e., on the number of cases in the current gen- The simplest case is for a population with no growth in which
eration and the current value of R). In small communities, the no individuals die before acquiring measles. In this scenario,
number of cases in each generation becomes so low in the the average time for which an individual is susceptible to mea-
trough of transmission that the chain almost always breaks at sles is A–m (being susceptible between ages m and A), out of
some point, and transmission fades out before the susceptible a life expectancy L. With no population growth, the average
persons have built up again. In contrast, the probability of fade- proportion of the population susceptible is given simply by
out is very low in sufficiently large communities, because the x ∗ p (A–m)/L. Note that the relationship R 0 p 1/x ∗ can be
number of cases never becomes critically small. The critical used to express R0 in terms of these parameters; R0 p L/
community size is the size of population needed to sustain (A–m) in the above example. This simple formula has been
endemic transmission (i.e., to prevent fade-out). For measles used to estimate R0 for measles at 14–18 in England and Wales
in an unvaccinated population, this is observed to be ∼250,000– and at 12.5 in North America [2].
500,000 [3, 4], possibly lower for sparse populations and higher Thus, assuming homogeneous mixing, the critical level of
for dense populations [4]. The critical community size may be immunity in England and Wales was calculated as 94% (using
better expressed in terms of the average number of cases per the upper estimate of R 0 p 18 ) or 96% if vaccination was de-
generation, or equivalently the average input of susceptible per- layed until the second birthday [2]. Such high levels of im-
sons into the population per generation interval. Routine vac- munity cannot be achieved with a single dose of a vaccine that
cination (at a level insufficient to achieve elimination) would has 90%–95% efficacy.
increase the community size needed to sustain measles trans- Heterogeneity. Although homogeneous mixing models il-
mission, because it reduces the input of new susceptible persons lustrate qualitatively the impact of vaccination, many practical
into the population. applications demand that some of the heterogeneity of the pop-
The concepts of elimination and critical community size ulation is accounted for. In the design of vaccination programs,
should not be confused. In sufficiently small populations, fade- most attention has focused on modeling heterogeneity arising
out can occur after only a short period in which R ! 1. How- from age-related contact patterns [7–12], but spatial and tem-
ever, if susceptible persons are allowed to reaccumulate and R poral heterogeneity can also have implications [6, 11]. Such
is not maintained at !1, widespread transmission may re- models divide the population into subgroups and specify the
commence when the infection is reintroduced. This is not elim- degree of mixing within and between these subgroups [6]. Dif-
ination. Elimination requires the (indefinite) maintenance of ficulties in estimating the contact patterns arise from the ab-
R ! 1 throughout a population. If this is achieved, by achieving sence of information on “who acquired infection from whom”
a sufficiently low proportion of susceptible persons in each [6, 9], but further progress has been made by combining in-
population subgroup, chains of transmission will eventually die formation from several infections with similar transmission
out regardless of the total number of susceptible persons within routes [13].
the population, because each case will, on average, produce !1 Given the different contact rates between the various groups
secondary case. Moreover, elimination achieves a stable situa- in a heterogeneously mixing population, the difficulty in cal-
tion—reintroduction of infection will not lead to widespread culating R0 and R lies in defining a “typical” infective person
transmission. as some suitable average across all subgroups within the pop-
Estimating R0. During the course of an epidemic cycle, R os- ulation. A mathematically rigorous method for calculating R0
cillates around 1 as the proportion susceptible oscillates around and R from the average number of secondary cases in each
the threshold. If disease remains endemic, the average pro- group caused by an infective person in each of the groups (the
portion susceptible to infection remains at the threshold level, “next-generation matrix”) does not yield any simple formu-
even after vaccination is introduced (figure 1). Thus, in any las [14]. In particular, R0 cannot be estimated as the reciprocal
population that is assumed to mix homogeneously in which of the average proportion susceptible. However, the rigorous

Theory of Measles Elimination • JID 2004:189 (Suppl 1) • S29

definition does preserve the most important results from ho- and duration of such outbreaks depends on R; the larger the
mogeneous mixing populations for heterogeneously mixing value of R, the larger and longer the outbreaks [16].
populations. Most notably, R ! 1 remains the criterion for elim-
ination. Also, if a proportion x of every population subgroup
IMPLICATIONS FOR DESIGN OF MEASLES
is susceptible, then R p R 0 x . Thus, elimination can be achieved
ELIMINATION PROGRAMS
by reducing the proportion susceptible in each population sub-
group below 1/R0 (pc p 1 ⫺ 1/R 0 ). However, this is not the most The implications of this theory for elimination strategies are
efficient way of eliminating the disease. There are many dif- clear. The first step is to reduce the levels of susceptibility in
ferent combinations of susceptibility levels in the various sub- the population so that R ! 1; the task thereafter is to ensure

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groups that produce the threshold R p 1. Achieving levels of that these low levels of susceptibility are maintained. To design
susceptibility below 1/R0 in the core groups that contribute an elimination program for a particular population following
most to transmission allows higher levels of susceptibility else- this general approach requires setting target levels of suscep-
where and consequently more susceptible persons overall [15]. tibility, establishing the current susceptibility profile, selecting
The importance of schools in the transmission of measles in an approach to reduce susceptibility below the target, and se-
developed countries was confirmed by a model that incorpo- lecting an approach to maintain susceptibility below the target.
rated variable contact rates among school-aged children (higher
during school terms than during school holidays) [8], which
reproduced the seasonal pattern of measles within the biannual Setting Susceptibility Targets
epidemic cycle. Incorporating age-dependent contact rates re- Setting target levels of susceptibility first requires Rmax, the max-
duced estimates of pc for measles to 84%–92% [7] (from 94%, imum permissible value of R, to be selected. Clearly, for elim-
using a homogeneous model). However, these early models ination, R max ! 1, but the choice of a particular value is a policy
focused on primary school children and underestimated the decision that takes into account the safety margin desired, the
potential for measles transmission among older children. Re- degree of secondary spread from imported cases that can be
fining the contact rates used for these age groups on the basis tolerated, and the resources available—lower values of Rmax pro-
of more recent data precludes values of pc !90% [9]. vide more security but require a greater vaccination effort. At
Epidemiology after elimination. After the elimination of the simplest level, all that is then required is an estimate of R0.
endemic measles transmission from a population, all cases of For example, if R 0 p 16 and Rmax is chosen to be 0.8, the target
measles must be linked to infections imported from outside level below which the proportion susceptible in all age groups
the population [16]. As long as R is maintained at !1, impor- and other subgroups must be reduced is 0.8/16 p 5%.
tations will not reestablish endemic transmission but may cause More flexibility can be introduced into susceptibility targets
limited secondary spread. The expected distribution of the size by balancing higher levels in some age groups against lower

Figure 2. World Health Organization target levels of susceptibility for measles elimination in Europe

S30 • JID 2004:189 (Suppl 1) • Gay

levels in others, to give the same overall R. The effects of age- The proportion of each birth cohort not protected by vac-
specific transmission rates can be accounted for in these cal- cination can be calculated from vaccination status—the pro-
culations. For example, the target levels of susceptibility in the portions that have received no dose, 1 dose only, or 2 doses—
World Health Organization (WHO) strategy for the elimination and the efficacy of 1 and 2 doses: proportion not protected by
of measles from the European region were designed for vaccination p proportion unvaccinated + [proportion receiv-
R max p 0.7 by use of a heterogeneous mixing model for which ing 1 dose only ⫻ (1 ⫺ efficacy of 1 dose)] + [proportion re-
R 0 p 11 (figure 2). A crude calculation suggests a 6.4% sus- ceiving 2 doses ⫻ (1 ⫺ efficacy of 2 doses)]. Vaccination status
ceptibility target for all age groups, but achieving a lower level may be measured directly (e.g., in surveys) or inferred from
(5%) in age groups with the highest transmission rates, namely coverage data. Because this calculation does not attempt to

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secondary school children and young adults, allows higher lev- account for naturally acquired immunity, it is most useful in
els of susceptibility in preschool (15%) and primary school cohorts with high vaccine coverage. It will significantly over-
(10%) children. estimate the proportion susceptible in cohorts with low vaccine
coverage and a high exposure to natural infection.
Establishing Susceptibility Profile Case notifications are best used by calculating the age-specific
The susceptibility profile describes the distribution of suscep- incidence during the most recent epidemic by means of the
tibility to measles within a population. Most important is the finest possible age stratification. This provides only a qualitative
variation in the proportion susceptible to measles by age, but indication of the relative susceptibility at different ages, because
other relevant variables include vaccination status and, in some the attack rate among susceptible persons may be age-depen-
cases, population subgroup. Three sources of data are useful dent—it is often higher in school-aged children than in pre-
in assessing the susceptibility profile: measles case notifications, school children. It should also be noted that cases may provide
vaccination coverage reports, and seroprevalence surveys. a better reflection of the susceptibility before the epidemic than
The most direct way to estimate the susceptibility profile is after it.
via a suitably stratified serological survey, interpreting samples More complex methods that combine information from sev-
negative for measles antibody as indicating susceptibility to eral types of data are also available, including susceptible recon-
measles. It is essential to ensure that the assay used is adequately struction methods [18] and dynamic transmission models [19].
sensitive and specific, especially in highly vaccinated popula-
tions in which many persons protected by vaccination may Reducing Susceptibility below Targets
have low antibody levels. Use of quantitative assays allows stan- Campaigns. Mass vaccination campaigns aim to immunize
dardization of results between different surveys through panels a high proportion of the susceptible persons in the population
of reference serum samples [17] and against international by achieving a high level of coverage across a wide age range,
standards. often over a short period of time. The age range for a campaign

Figure 3. Simple model of measles transmission in a population with an vaccination campaign in year 5 that immunizes 80% of all susceptible
persons and 80% routine vaccination coverage from year 5.

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Figure 4. A, Vaccination status in the year 2000 of children in England born during 1990–1998. These cohorts were too young to be vaccinated
in the 1994 national measles vaccination campaign (which targeted 5- to 16-year-olds) and have been vaccinated with measles-mumps-rubella vaccine
according to the routine schedule (at 12–15 months and 4 years). B, Estimated susceptibility in 2000 of children in England born during 1990–1998.
Incidence of measles virus infection in England was very low during 1990–2000, so all immunity is assumed to be vaccine-derived (10% of children
assumed to remain susceptible after 1 dose of vaccine and 1% after 2 doses of vaccine). The second dose (at age 4 years) reduces the susceptibility
of the cohort from 20% to 10% within the WHO European region target for the 5- to 9-year age group. However, the 10% residual susceptibility at
age 5 years is above the 5% target for older age groups, suggesting that this limit will be exceeded as these cohorts age. Targeting of 0-dose children
is needed to reduce susceptibility in these cohorts. Susceptibility in older cohorts targeted by the 1994 campaign, and in adults, is low (!5%).
 that a susceptible person will contact an infectious person and
thereby become infected. Both the direct protection of new
cohorts and the reduction in the risk of infection cause the age
distribution of susceptible persons to shift toward older age
groups [18]. However, unless sufficiently high levels of im-
munity are achieved in the vaccinated cohorts, the infection
will remain endemic and establish a new epidemic cycle oscil-
lating around R p 1 (figure 1). These direct and indirect effects
can be investigated by use of dynamic models of the trans-

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mission of infection.
Use of a single dose of measles vaccine cannot achieve a high
enough level of immunity to achieve elimination. A routine 2-
dose schedule can achieve high levels of immunity (198% ef-
ficacy), but it takes many years to feed through all age groups.
Outbreaks often occur in the cohorts just too old to have re-
ceived 2 doses. Most countries that have achieved elimina-
tion through high coverage with a routine 2-dose schedule have
also conducted specially targeted supplementary vaccination of
older age groups who were born before or missed by the 2-
Figure 5. Estimated proportion of children susceptible to measles in dose schedule.
England in 2000 by district health authority (DHA). Each point represents
1 DHA and shows the proportion susceptible among children born dur-
ing 1990–1994 and 1995–1997. Contour lines indicate the values of R Maintaining Susceptibility below Targets
associated with the susceptibility levels. There is considerable variation
in vaccination coverage between districts: The 20 districts in which To maintain R at !1 requires a strategy for preventing the reac-
R 1 0.85 were provided with some extra resources to conduct additional cumulation of susceptible persons in the population. This entails
vaccinations. achieving high levels of immunity in children too young to be
vaccinated during the campaign and those born after it. Two
can be selected by comparing the susceptibility profile of the alternative approaches are available: a routine 2-dose schedule
population against the susceptibility targets—including in the or 1 routine dose plus regular follow-up campaigns [21].
campaign all cohorts in which susceptibility exceeds the targets. Whatever vaccination strategy is adopted, a crucial factor
By immunizing a high proportion of the susceptible persons determining success or failure in the long run is the residual
in the population, successful campaigns reduce R well below level of susceptibility of a cohort after it has completed its
1. This has a dramatic impact on the incidence of measles, scheduled vaccination opportunities. The choice of strategy
causing chains of transmission to die out rapidly (figure 3). should largely be determined by the need to minimize this
For example, if R is reduced to 0.5, the number of cases will, residual proportion susceptible. If the residual susceptibility of
on average, halve with each new generation of cases (every ∼2 each cohort is not reduced below the critical level, the accu-
weeks). The potential for endemic transmission will not re- mulation of susceptible persons will eventually increase R to
emerge until the input of new susceptible persons into the 11. Vaccination status of each cohort should be assessed once
population has restored susceptibility to the R p 1 threshold. it has completed its scheduled vaccination opportunities to
The time taken to do this will depend principally on the number enable the proportion susceptible to be calculated directly (co-
of susceptible persons immunized by the campaign and the rate horts born after a catch-up campaign will have had little ex-
at which new susceptible persons are added [20]. The duration posure to natural infection). As above, the proportion suscep-
of impact of campaigns in heterogeneously mixing populations tible is most sensitive to the proportion remaining completely
can be estimated in a similar fashion as the time taken for R unvaccinated, and it is crucial that the second opportunity
to exceed 1 [19]. minimizes the number of “0-dose” children.
Routine programs. Introduction of a routine vaccination The other consideration is the age at which this low level of
program does not have the same rapid impact on the propor- susceptibility is achieved: the later the age, the more susceptible
tion of the population susceptible to infection as does a vac- persons in the population, the greater the value of R, and the
cination campaign. Rather, programs that vaccinate early in life greater the risk that R will exceed 1. In this respect, it would
reduce the rate at which susceptible persons are added into the be ideal to give the second dose of a 2-dose schedule as soon
population (figure 1). Protecting some individuals from infec- as possible after the first, for example, at 15–18 months of age.
tion reduces the number of infectious cases, lessening the risk However, the age at vaccination may also affect the coverage

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Figure 6. R for measles in England, 1995–2002, estimated from distribution of outbreak size. R has increased with the reaccumulation of susceptible
children after the 1994 campaign, because of the failure to maintain sufficiently high vaccination coverage. Elimination of measles, achieved between
1995 and 2001 [23], appears unlikely to be sustained.

achieved; many developed countries find that school entry (at cination program. When necessary, districts can then imple-
age 4–6 years) provides a good opportunity to achieve high ment supplementary measures (e.g., identifying and vaccinating
coverage, particularly among previously unvaccinated children. “0-dose” children) to bring susceptibility below the target level
In such settings, the advantage of achieving lower residual sus- (figure 5).
ceptibility in a cohort must be balanced against the disadvan- Surveillance of measles cases can also be used to monitor
tage of allowing those with failure of first-dose vaccination to the value of R. After the elimination of endemic measles trans-
remain susceptible until school entry. Heterogeneity plays a key mission from a population, all cases of measles must be linked
role in this decision: Contact rates among school-aged children to infections imported from outside the population [16]. The
are considerably higher than among preschool children. Pro- expected distribution of the size of outbreaks depends on R;
vided that first-dose coverage is high, a lower value of R may the larger the value of R, the larger and longer the outbreaks
be achieved by ensuring minimal levels of susceptibility in the [16]. Monitoring the proportion of imported cases and the size
age groups with highest contact rates than by providing an and duration of outbreaks enables R to be estimated [16, 22]
early opportunity to protect those with failure of first-dose (figure 6). A successful elimination program should maintain
vaccination. Delaying the second dose further, for example until R below the target (Rmax).
secondary school entry at 11–12 years, has no such justification,
as it is unlikely to result in further improvement in coverage
Obstacles to Elimination
but allows those experiencing vaccination failure to remain
Clearly, the success of measles elimination strategies depends
susceptible throughout primary school.
on the ability to implement them fully in practice. Potential
problems range from the initial difficulty of identifying suffi-
Surveillance cient resources to the challenge of sustaining high vaccination
Having selected a strategy for maintaining R at !1, monitoring coverage after the disappearance of endemic disease.
its implementation is largely a question of ensuring accurate Measles transmission in groups who refuse vaccination is
and timely vaccination data. To calculate susceptibility of a birth emerging as a problem in many developed countries with elim-
cohort once it has completed its vaccination opportunities re- ination programs and merits discussion here. Such groups do
quires that the vaccination status of the cohort is known (par- not present the potential for sustaining endemic transmission
ticularly the proportion of “0-dose” children) (figure 4), and unless they reach the critical community size. However, little
not just the coverage at each vaccination opportunity inde- can be done to prevent large outbreaks when measles is intro-
pendently. This calculation may be best performed at the local duced into them. Strictly then, measles is not eliminated from
(e.g., district) level as a key performance indicator for the vac- such groups because R is not maintained at !1. However, they

S34 • JID 2004:189 (Suppl 1) • Gay

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