Download Biological Feasibility of Measles Eradication

SUPPLEMENT ARTICLE
Biological Feasibility of Measles Eradication
William J. Moss1 and Peter Strebel2
1Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and 2World Health Organization,
Geneva, Switzerland
Recent progress in reducing global measles mortality has renewed interest in measles eradication. Three
biological criteria are deemed important for disease eradication: (1) humans are the sole pathogen reservoir;
(2) accurate diagnostic tests exist; and (3) an effective, practical intervention is available at reasonable cost.
Interruption of transmission in large geographical areas for prolonged periods further supports the feasibility
of eradication. Measles is thought by many experts to meet these criteria: no nonhuman reservoir is known to
exist, accurate diagnostic tests are available, and attenuated measles vaccines are effective and immunogenic.
Measles has been eliminated in large geographical areas, including the Americas. Measles eradication is
biologically feasible. The challenges for measles eradication will be logistical, political, and financial.
Measles elimination refers to the interruption of measles
virus transmission within a defined geographic area,
such as country, continent, or World Health Organization region, whereas measles eradication is the global
interruption of measles virus transmission such that
control efforts could be stopped. The feasibility of
measles eradication has been discussed for more than 30
years, beginning in the late 1960s when the long-term
protective immunity induced by measles vaccines was
becoming evident [1]. Three biological criteria are
deemed important for disease eradication: (1) humans
are the sole pathogen reservoir; (2) accurate diagnostic
tests exist; and (3) an effective, practical intervention is
available at reasonable cost [2]. Interruption of transmission in large geographical areas for prolonged periods further supports the feasibility of eradication.
Measles is thought by many experts to meet these criteria [3]. In this article, we review the biological feasibility of measles eradication and consider potential
biological obstacles to eradication.
Potential conflicts of interest: none reported.
Supplement sponsorship: This article is part of a supplement entitled ''Global
Progress Toward Measles Eradication and Prevention of Rubella and Congenital Rubella
Syndrome,'' which was sponsored by the Centers for Disease Control and Prevention.
Correspondence: William J. Moss, MD, MPH, Department of Epidemiology,
Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street,
Baltimore, MD 21205 ([email protected]).
The Journal of Infectious Diseases 2011;204:S47–S53
Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected]
0022-1899 (print)/1537-6613 (online)/2011/204S1-0008$14.00
DOI: 10.1093/infdis/jir065
ARE HUMANS THE ONLY RESERVOIR
FOR MEASLES VIRUS?
Measles virus infection is presumed to be sustained
through an unbroken chain of human-to-human
transmission, and no animal or environmental reservoir is known to exist. However, nonhuman primates can be infected with measles virus and can
develop an illness similar to measles in humans with
rash, coryza, and conjunctivitis. Many primate species are susceptible to measles virus infection, including Macaca mulatta, M. fascicularis, M. radiata,
M. cyclopis, Papio cristatus, Cercopithecus aethiops,
Saimiri sciureus, Colobus quereza, Pan troglodytes,
Callithrix jacchus, Saguinus oedipus, S. fuscicollis, and
Aotus trivirgatus [4]. Much of the evidence for the
susceptibility of these nonhuman primates comes
from laboratory colonies and the use of nonhuman
primates as animal models for the study of measles
virus pathogenesis.
Interestingly, serological studies have demonstrated
evidence of prior measles virus infection in free-ranging
populations of nonhuman primates, outside of laboratory colonies. One-fourth of 47 Rhesus macaques in
southern India [5] and one-third of 15 wild macaques in
Indonesia had serological evidence of measles virus infection [6]. Presumably, measles virus infection resulted
from human-to-animal transmission, perhaps followed
by limited spread within the primate population. Justification for the conclusion that wild primate populations do not serve as natural reservoirs is based on the
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critical population size necessary to sustain transmission of
highly infectious measles virus. To provide a sufficient number
of new susceptibles through births to maintain measles virus
transmission in humans, a population size of several hundred
thousand persons with 5000–10,000 births per year is required
[7]. If measles virus is as infectious in primates, wild populations
of up to several hundred individuals [8] are not of sufficient size.
ARE THERE ACCURATE DIAGNOSTIC TESTS
FOR MEASLES?
Several diagnostic tests for measles exist, although some are
limited by low positive predictive value in low transmission
settings [9]. Measles is readily diagnosed by clinicians familiar
with the disease in endemic areas or during outbreaks, but
clinical diagnosis is more difficult when incidence is low. In
low-transmission settings, other pathogens or inflammatory
reactions are responsible for the majority of illnesses with fever
and rash. Koplik spots are especially helpful because they appear
early and are pathognomonic, but with the declining incidence
of measles fewer clinicians can recognize them. The rash of
measles may be absent or delayed in immunocompromised or
severely malnourished children with impaired cellular immunity, also impeding clinical diagnosis.
Serology is the most commonly used method of laboratory
diagnosis. The detection of measles virus-specific immunoglobulin M (IgM) antibodies in a single specimen of serum
or oral fluid is considered diagnostic of acute infection, as is
a 4-fold or greater increase in measles virus-specific immunoglobulin G (IgG) antibodies between acute and convalescent
serum samples. Measles virus-specific IgM antibodies may not
be detectable until 4 days after rash onset and usually fall to
undetectable concentrations within 4–8 weeks.
Measles also can be confirmed by isolating measles virus in
cell culture from respiratory secretions, nasopharyngeal and
conjunctival swabs, blood, or urine. Although Vero cells are
commonly used for neutralization tests using laboratory-adapted measles virus strains, a derivative (B95-a) of the Epstein-Barr
virus-transformed marmoset B lymphocyte cell line B95-8 has
greater sensitivity than Vero cells for the isolation of wild-type
strains of measles virus. Expression of the measles virus receptor
CD150 (SLAM) on Vero cells enhances the ability to isolate
wild-type measles virus strains in tissue culture.
Detection of measles virus RNA by reverse transcriptase-PCR
(RT-PCR) amplification of RNA extracted from clinical specimens can be accomplished using primers targeted to highly
conserved regions of measles virus genes. When combined with
nucleotide sequencing, these assays permit the precise identification and characterization of measles virus genotypes for molecular epidemiological studies and can distinguish wild-type
and vaccine measles virus strains. However, measles virus
RNA may persist for several months in both healthy and
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immunocompromised children [10] and under experimental
conditions in macaques [11]. Consequently, detection of measles virus RNA does not necessarily indicate acute infection.
Limitations of current diagnostic tests for measles, specifically
IgM enzyme immunoassays (EIAs), are the potential for both
false negative and false positive results. Concentrations of IgM
antibodies may be low during the first three days of the rash,
resulting in false negative test results [12]. False positive results
may occur in the presence of rheumatoid factor and certain viral
coinfections, including rubella, parvovirus B19, and human
herpes virus 6. In addition, laboratory testing is usually only
performed on suspected cases; thus, persons with uncharacteristic or minimal signs or symptoms may be missed.
Although these limitations may pose challenges to the diagnosis
of measles in certain individuals, available diagnostic tests are
unlikely to miss measles outbreaks or sustained measles virus
transmission.
ARE THERE EFFECTIVE INTERVENTIONS FOR
MEASLES?
Two broad approaches have been used to measure the effectiveness of measles vaccines: the effectiveness of measles vaccines
in preventing clinical measles and measurement of vaccine immunogenicity. Measles vaccine effectiveness has been evaluated
in numerous studies. A review of 69 published studies of measles
vaccine effectiveness from 1969 to 2006 found an overall estimate of measles vaccine effectiveness of 90% [13]. Median
measles vaccine effectiveness was estimated to be 77% when
administered between 9 and 11 months of age, and 92% when
administered at 12 months or older. These findings are consistent with immunogenicity studies.
Measles vaccine immunogenicity is commonly assessed by
measuring IgG antibodies to measles virus. Antibodies first appear between 12 and 15 days after vaccination and typically peak
at 21–28 days. The protective efficacy of antibodies to measles
virus is illustrated by protection conferred to infants from passively acquired maternal antibodies and the protection of
exposed, susceptible individuals following administration of
anti-measles virus immunoglobulin. Consequently, antibody
concentrations serve as useful surrogate markers of protection
[14], despite the fact that cell-mediated immunity is important
for viral clearance [15].
The proportion of children who develop protective antibody
concentrations following measles vaccination depends on the
presence of inhibitory maternal antibodies and the immunologic
maturity of the vaccine recipient, as well as the dose and strain of
vaccine virus. Frequently cited figures are that 85% of children
develop protective antibody concentrations when given 1 dose
of measles vaccine at 9 months of age, and 90%–95% respond
when vaccinated at 12 months of age [16]. In a review of measles
vaccine immunogenicity (Figure 1) [17], the median proportion
Figure 1. Box plots showing the proportion of children who respond to
standard-titer measles vaccine by age at vaccination. Source: Moss WJ,
Scott S. WHO Immunological Basis for Immunization Series: Measles.
Geneva, Switzerland: World Health Organzation, 2009.
of children responding was 89.6% (mean, 86.7; minimum, 56;
maximum, 100; interquartile range [IQR], 82–95) in 44 studies
in which children were vaccinated between 8 and 9 months
of age; 92.2% (mean, 88.2; minimum, 59; maximum, 100; IQR
84–96) in 24 studies in which children were vaccinated between
9 and 10 months of age; and 99% (mean, 95.7; minimum, 80;
maximum, 100; IQR, 93–100) in 21 studies in which children
were vaccinated between 11 and 12 months of age.
Several biological factors determine measles vaccine effectiveness and immunogenicity. Age at vaccination is the most
important determinant. Antibody responses to measles vaccine
increase with age up to 15 months, due to the presence of
inhibitory maternal antibodies and immaturity of the immune
system. This immaturity of the immune system in neonates and
young infants includes a limited B cell repertoire and inefficient
mechanisms of antigen presentation and T cell help [18]. Although protective, maternally acquired antibodies interfere with
the immune responses to the attenuated measles vaccine by
inhibiting replication of vaccine virus necessary for an effective
immune response. In general, maternally acquired antibodies
are no longer present in the majority of children by 6–9 months
of age [19].
A few studies suggest that concurrent acute infections may
interfere with the immune response to measles vaccine [20],
although many studies reported no effect and mild illnesses are
not a contraindication to measles vaccination. Most published
studies found that malnourished children have equivalent seroconversion rates after measles vaccination compared with
children who are well nourished. Host genetic background affects the likelihood of developing protective immune responses
following measles vaccination. Polymorphisms in human immune response genes influence immune responses to measles
vaccine, including class I and class II human leukocyte antigen
(HLA) types and non-HLA alleles [21]. Single-nucleotide
polymorphisms (SNPs) in cytokine and cytokine receptor genes,
as well as SNPs in the measles virus receptors (SLAM and
CD46), also were associated with differences in antibody and
cellular immune responses to measles vaccine. However, in
general, most people develop protective antibody concentrations after a second dose of measles vaccine, regardless of
genetic background.
Measles virus transmission can be interrupted by achieving
high levels of population immunity with measles vaccines, such
that the probability of an infected case coming in contact with
a susceptible individual is low [22]. However, a 2-dose measles
immunization schedule is necessary to achieve the 95% population immunity necessary to interrupt measles virus transmission. This can be readily understood by the fact that 95%
vaccine coverage with a vaccine providing protection to 95% of
recipients only achieves 90% population immunity. Two strategies to administer the second dose of measles vaccine are
through routine immunization services or mass immunization
campaigns (called supplementary immunization activities), an
approach first developed by the Pan American Health Organization (PAHO) for South and Central America and modeled
after polio eradication strategies.
Attenuated measles vaccines have some characteristics that
limit their effectiveness or increase their risk-benefit ratio in
some populations. First, these vaccines are not immunogenic in
young infants, necessitating vaccine administration at 9 months
of age or older. Second, measles vaccines are relatively heatstable in the lyophilized form but rapidly lose potency when
exposed to heat after reconstitution, potentially reducing effectiveness if improperly stored. Third, live viral vaccines are potentially harmful to immunocompromised persons and may
cause disease as a result of vaccine virus replication [23].
A recent systematic review concluded that measles vaccines
appear to be safe in children infected with human immunodeficiency virus (HIV), but there is an absence of studies reporting
relevant information [24]. Despite these limitations, the attenuated measles vaccines currently used have a history of proven
safety and effectiveness over the past 40 years and have resulted
in dramatic reductions in measles incidence, morbidity, and
mortality (Figure 2).
IS THERE EVIDENCE OF SUSTAINED
INTERRUPTION OF MEASLES VIRUS
TRANSMISSION IN LARGE GEOGRAPHIC
AREAS?
Measles elimination was achieved in the United States in 2000
and in the Americas by November 2002 [25]. Small outbreaks of
primary and secondary cases may occur following importation
from outside the region but sustained transmission does not
occur, as exemplified by recent measles outbreaks in the United
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described. Thus, there is no evidence for persistent shedding of
infectious measles virus.
Sustained Transmission Through Subclinical Infection
Figure 2. Estimated number of measles deaths worldwide, 2000–2008.
Adapted from Weekly Epidemiological Record 2009;85:513.
States [26]. Four other World Health Organization (WHO)
regions have set measles elimination goals: African, Eastern
Mediterranean, Europe, and Western Pacific. The remaining
WHO region, South-East Asia, has a goal to reduce measles
mortality by 90% by 2010 compared with 2000 levels. These
ambitious goals have resulted in part from successful implementation of the WHO/UNICEF strategy of providing the
second dose of measles vaccine through supplementary immunization activities, resulting in dramatic declines in incidence
and mortality (Figure 1). The largest recent decrease in measles
mortality was in Africa, where measles mortality decreased 91%
from 2000–2006, accounting for 70% of the global reduction in
measles mortality [27].
POTENTIAL BIOLOGICAL BARRIERS TO
MEASLES ERADICATION
Persistent Human Reservoirs
Persistent infection with transmissible measles virus would pose
a biological barrier to eradication. Measles virus is known to
establish persistent infection in persons with subacute sclerosing
panenephalitis (SSPE). SSPE is a rare delayed complication of
measles that occurs in 1:100,000 to 1:10,000 cases [28], typically 6–8 years after acute measles in the first 2 years of life.
Neurons and glial cells contain typical measles virus nuclear and
cytoplasmic inclusion bodies. However, virion assembly and
budding is defective, and multiple mutations occur throughout
the measles virus genome, especially hypermutations within the
M gene and alterations in the H and F genes. As a consequence,
infectious measles virus is not present. Prolonged shedding of
measles virus RNA for several months has been described in
HIV-infected children [29], although it is not clear if this represents infectious virions and a prolongation of the period of
infectivity. Transmission of measles vaccine virus has not been
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As diagnostic tests for acute measles virus infection are most
often performed on clinically suspected cases, subclinical infection resulting in sustained measles virus transmission would
pose a barrier to eradication. Subclinical measles is defined as
a 4-fold rise in measles virus-specific IgG antibodies following
exposure to wild-type measles virus in an asymptomatic individual, presumably with some prior measles immunity. Subclinical infection may be important in boosting protective
antibody concentrations in children with waning immunity [30]
but raises a concern that persons with incomplete immunity and
subclinical infection may be capable of transmitting measles
virus [31]. In an investigation of potential measles virus shedding from persons with subclinical infection, measles virus was
not detected by culture or reverse transcriptase-polymerase
chain reaction from any of 133 contacts of 6 subclinical cases
with laboratory-confirmed measles [32]. Whether partially immune individuals with subclinical infection can sustain measles
virus transmission in the absence of clinical cases is unlikely.
Waning Vaccine Immunity
If vaccine induced immunity is short-lived, revaccination efforts
would need to be enhanced to maintain the high levels of
population immunity required for measles eradication. Although the duration of immunity following measles vaccination
is more variable and shorter than following wild-type measles
virus infection, protective immunity persists for decades even in
countries where measles is no longer endemic and immunological boosting from wild-type measles virus infection does not
occur [33]. The purpose of a 2-dose schedule for measles vaccination is to immunize children with primary vaccine failure
(as well as those previously unvaccinated) and not to serve as
a booster dose for persons with waning immunity. Furthermore,
although antibody concentrations induced by vaccination may
decline over time and become undetectable, immunological
memory persists and vaccinated persons produce an anamnestic
measles virus-specific immune response following exposure to
wild-type measles virus. Thus, waning immunity is unlikely to
be a biological barrier to measles eradication.
Measles Virus Genetic Diversity
Theoretically, selective pressure on measles viruses to mutate
neutralizing epitopes and escape the protective immune responses induced by vaccines could be a biological obstacle to
measles eradication. Estimates of mutation rates in measles virus
range from 1024 to 1023 per nucleotide per year [34]. However,
despite the high degree of genetic variation expected of a singlestranded RNA virus, mutations in the measles virus genome
have not reduced the protective immunity induced by measles
vaccines. Serum specimens from vaccinated persons and from
persons naturally infected during the 1950s and 1960s had
comparable neutralization titers to vaccine viruses and to more
recently isolated wild-type measles viruses, although serum
samples from persons infected in the 1990s had higher neutralization titers to the homologous wild-type virus [35].
As an example of how genetic changes have not significantly
altered important antigenic epitopes, measles virus isolates from
a genotype circulating in the Peoples Republic of China during
1993 and 1994 differed from other wild type viruses by as much
as 6.9% in the hemagglutinin (H) gene and 7.0% in the nucleocapsid (N) gene, but did not differ significantly from other
wild-type viruses in their anti-H monoclonal antibody binding
patterns and were neutralized by human post-vaccination antiserum [36]. Thus, neutralizing epitopes on the H protein are
highly conserved among measles virus strains, likely because of
functional constraints on the amino acid sequence and tertiary
structure of the surface proteins [37]. Measles virus remains
a monotypic virus for which protective immunity is induced by
vaccine strains first isolated in the 1950’s.
Measles Outbreaks in Populations With High Levels of
Population Immunity
Numerous outbreak investigations highlight the challenges of
sustaining measles elimination. Despite very high levels of
measles vaccine coverage and population immunity overall,
clustering of susceptible persons can lead to outbreaks. In 2005,
a 17-year-old girl with measles returned to the United States
from Romania and attended a church gathering of over 500
people [38]. Despite 98% measles vaccination coverage in the
state of Indiana (among 6th graders), 34 cases of measles resulted, of whom 94% were unvaccinated. Of greater concern is
the potential for more sustained transmission of measles virus. A
measles outbreak of 94 cases occurred in Quebec, Canada, in
2007 and led to transmission within several unrelated networks
of unvaccinated persons, despite an estimated level of population immunity of 95% [39]. No epidemiological link was
identified for approximately one-third of laboratory confirmed
cases and no source was found for the index case. The ease of
global travel allows for measles virus importation and this risk
will only be abolished by measles eradication.
Impact of the HIV-1 Pandemic
In regions of high HIV prevalence, HIV-infected children may
play a role in the sustaining measles virus transmission. Children
with defective cell-mediated immunity can develop measles
without the characteristic rash [40], hampering clinical diagnosis. Children born to HIV-infected mothers have lower
concentrations of passively acquired maternal antibodies, increasing susceptibility to measles at an earlier age than children
born to uninfected mothers [41, 42], and protective antibody
concentrations following vaccination may wane within 2–3 years
in many HIV-infected children not receiving antiretroviral
therapy [43], creating a potential pool of susceptible children.
A study in South Africa found lower levels of vaccine effectiveness among HIV-infected compared with uninfected children, although the number of HIV-infected children studied was
small [44]. Thus, population immunity could be reduced in
regions of high HIV-1 prevalence despite high levels of measles
vaccine coverage.
Counteracting the increased susceptibility of HIV-infected
children is their high mortality rate, particularly in sub-Saharan
Africa, such that these children do not live long enough to build up
a sizeable pool of susceptible children [45]. Successful control of
measles in the countries of southern Africa suggests that the HIV1 epidemic is not a major barrier to measles control [46], although coinfection with HIV may have exacerbated the large
measles outbreaks that occurred in countries of southern and
eastern Africa in 2010. This may change with increased access to
antiretroviral therapy, which may prolong survival without enhancing protective immunity in the absence of revaccination.
Using a dynamic, age-structured mathematical model, the prevalence of measles increased almost one-third after introduction
of antiretroviral therapy into a hypothetical population of
children with a high prevalence of HIV-1 infection [47].
Potential Use of Measles Virus as an Agent of Bioterrorism
The high infectivity of measles virus is a characteristic suitable to
a bioterrorist agent, but high levels of measles vaccination coverage throughout the world would protect many persons from
the deliberate release of measles virus. Genetic engineering of
a measles virus strain that was not neutralized by antibodies
induced by the current measles vaccines would likely have reduced infectivity, as suggested by the fact that wild-type measles
virus has not mutated to alter neutralizing epitopes. Whether the
threat from bioterrorism precludes stopping measles vaccination after eradication is unclear but, at the least, a single-dose
rather than a 2-dose measles vaccination strategy could be
adopted [48].
RESEARCH NEEDS
Much is known about the biological feasibility of measles
eradication, specifically the absence of nonhuman reservoirs, the
positive predictive value of IgM assays for diagnosis, and the
effectiveness and immunogenicity of measles vaccines. However,
continued research on biological factors (as well as operational
and programmatic research) will be useful to furthering the goal
of measles eradication, including the (1) development of a rapid,
point-of-care test for measles and rubella that would enable
laboratory confirmation of the outbreak in the field and more
timely and targeted outbreak response measures; (2) progress
towards developing the ideal measles vaccine, which would be
inexpensive, safe, heat-stable, immunogenic in neonates or very
young infants, and administered as a single dose without needle
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or syringe [49]; (3) deeper understanding of the impact of
heterogeneities and clustering of susceptibles in sustaining
measles virus transmission [50]; and (4) evaluation of existing
tools and strategies in the most challenging settings (eg, settings
with very high birth rates, large-scale migration, and weak
infrastructure).
CONCLUSIONS
Measles eradication is biologically feasible with available diagnostic assays and vaccines, and elimination has been achieved
in large geographical areas. While the major challenges for
measles eradication will be logistical, financial, and the garnering
of sufficient political will, an active research agenda is needed to
refine current tools and strategies.
Funding
Immunization, Vaccines and Biologicals, World Health Organization
(to W. J. M.) and the National Institute of Allergy and Infectious Diseases
(grant number AI070018 to W. J. M.).
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