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Seminar

Measles
William J Moss

Lancet 2017; 390: 2490–502 Measles is a highly contagious disease that results from infection with measles virus and is still responsible for more
Published Online than 100 000 deaths every year, down from more than 2 million deaths annually before the introduction and
June 30, 2017 widespread use of measles vaccine. Measles virus is transmitted by the respiratory route and illness begins with fever,
http://dx.doi.org/10.1016/
S0140-6736(17)31463-0
cough, coryza, and conjunctivitis followed by a characteristic rash. Complications of measles affect most organ
systems, with pneumonia accounting for most measles-associated morbidity and mortality. The management of
Department of Epidemiology
(Prof W J Moss MD), patients with measles includes provision of vitamin A. Measles is best prevented through vaccination, and the major
Department of International reductions in measles incidence and mortality have renewed interest in regional elimination and global eradication.
Health (Prof W J Moss), However, urgent efforts are needed to increase stagnating global coverage with two doses of measles vaccine through
W Harry Feinstone Department
advocacy, education, and the strengthening of routine immunisation systems. Use of combined measles-rubella
of Molecular Microbiology and
Immunology (Prof W J Moss), vaccines provides an opportunity to eliminate rubella and congenital rubella syndrome. Ongoing research efforts,
and International Vaccine including the development of point-of-care diagnostics and microneedle patches, will facilitate progress towards
Access Center (Prof W J Moss), measles elimination and eradication.
Bloomberg School of Public
Health, Johns Hopkins
University, Baltimore, MD, USA Introduction 100 000 deaths each year, and serves as an indicator of the
Correspondence to: Measles is a highly contagious, acute febrile illness that quality of immunisation programmes. The reduction in
Prof William J Moss, Department results from infection with measles virus. Measles virus measles incidence and mortality, along with progress
of Epidemiology, Bloomberg is most closely related genetically to rinderpest virus, a toward achieving polio eradication, have renewed interest
School of Public Health,
pathogen of cattle that was declared eradicated by the in measles regional elimination and global eradication.4
Johns Hopkins University,
Baltimore, MD 21205, USA World Organization for Animal Health in May, 2011, and However, increased political will, public support, and
wmoss1@jhu.edu probably evolved as a zoonotic infection in communities financial resources, facilitated by new instruments,
in which humans and cattle lived together.1 Although technologies, and strategies, such as point-of-care
historical evidence is lacking, epidemiological evidence diagnostics and microneedle patches, will be needed to
suggests measles likely became a disease of humans achieve regional measles elimination goals and eventual
5000–10 000 years ago when early agrarian civilisations in eradication.5 This primer updates a previous Lancet
the fertile crescent achieved sufficient population size to seminar published in 20126 and summarises current
maintain virus transmission.2,3 Measles was a leading knowledge of the disease burden, epidemiology,
global cause of child morbidity and mortality before the virology, pathophysiology, immune responses, clinical
introduction of measles vaccines in the 1960s, and was manifestations, diagnosis, management, and prevention
responsible for more than 2 million deaths annually of measles, highlighting recent research findings as well
before the increase in global measles vaccine coverage in as the progress and challenges of measles elimination
the 1980s as a result of the Expanded Programme on and eradication (panel 1).
Immunization (figure 1). Measles incidence and
mortality have declined substantially over the past Disease burden
two decades due to the increasingly widespread use of Deaths due to measles have declined substantially over
attenuated measles vaccines administered through the past century, first through improvements in nutrition,
routine immunisation programmes and mass socioeconomic status, and health care and subsequently
vaccination campaigns. Despite this enormous progress, through a major reduction in measles incidence as a
measles remains an important vaccine-preventable cause consequence of increasing measles vaccine coverage.7
of morbidity and mortality, responsible for more than This progress has had the perverse effect of diminishing
the perceived public health importance of measles and
the value of measles vaccination. Nevertheless, there is
Search strategy and selection criteria no doubt that the burden of measles, including
I searched PubMed for publications in English using the terms pneumonia, blindness, chronic neurological conditions,
“measles”, “measles virus”, “measles and epidemiology”, and death, has decreased substantially because of
“measles and pathophysiology”, “measles and diagnosis”, measles vaccination. Precise measurements of measles
“measles and treatment”, and “measles and prevention”. incidence and mortality are lacking, however, because
My search focused on, but was not restricted to, publications most cases and deaths occur in countries with poor
in the past 4 years. I also searched the Cochrane Database of vital registration and disease surveillance systems.
Systematic Reviews using the term “measles” and our own Consequently, estimates are based on imperfect reporting
database of references, as well as those of linked articles in and models. Almost all countries use case-based
the searched journals. When more than one article illustrated surveillance and have access to standardised laboratory
a specific point, the most representative article was chosen. testing through the WHO Global Measles and Rubella
Laboratory Network for diagnostic confirmation and

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Rhazes Francis Home Henry Koplik Joseph Licensure of Start of the Measles and Measles elimination goal
distinguishes transmits describes spots Goldberger and first attenuated Expanded Rubella for European and Eastern
smallpox and measles on the buccal John Anderson measles vaccine Programme on Initiative Mediterranean regions
measles through blood, mucosa with show measles is Immunization launched
Gavi, the Vaccine Alliance
analogous to measles caused by a
commits support for
variolation filterable virus
measles and rubella
vaccines
Certification of measles
elimination in the Americas
September, 2016;
rubella declared eliminated
in 2015

9th century 1676 1757 1846 1896 1905 1911 1954 1963 1968 1974 1987 2001 2012 2015 2020

Peter Panum
investigates Maurice
measles Hilleman
outbreak on further
Thomas Faroe Islands Ludvig Hektoen attenuates Cuba conducts
Sydenham and describes transmits measles first mass Measles Measles
provides first incubation measles John Enders vaccine; rubella measles elimination elimination
detailed clinical period and experimentally and Thomas vaccine vaccination goal for the goal for Africa
description of lifelong and studies Peebles isolate introduced in catch-up Western Pacific and South East
measles immunity effects measles virus 1969 campaign region Asia Regions

Figure 1: Measles timeline

molecular epidemiology,8 consisting of 703 laboratories


that support surveillance in 191 countries. Panel 1: Important recent developments in measles
WHO publishes annually the reported number of • Disease burden: estimated global measles deaths decreased 79% from 2000 to 2015
measles cases and estimated number of deaths, as well as • Epidemiology: measles outbreaks have been reported in populations with immunity
estimates of national measles vaccine coverage for both gaps despite high overall vaccine coverage, including individuals who received
the first and second doses (figures 2, 3). The number of two doses of measles vaccine
reported measles cases decreased worldwide between • Virology: only eight of the 24 known measles virus genotypes have been detected
2000 to 2015 by 70%, from 853 479 to 254 928 cases,9 since 2009, suggesting many genotypes are no longer circulating
although these reports vastly underestimate the true • Pathophysiology: persistence of measles virus RNA for 2–3 months after rash onset
number of measles cases. Improving measles surveillance could contribute to the life-long immunity and prolonged state of immune
and reporting will be crucial to achieving regional and suppression following measles
global milestones. Most reported measles cases in 2015 • Immune responses: development of so-called immune amnesia after measles, in which
were from the African (40%), Western Pacific (27%), and measles virus-specific lymphocytes replace the established memory cell repertoire, is a
South East Asia (12%, with 88% of these from India) recent hypothesis to explain the immune suppression that follows measles
Regions.9 Importantly, 11% of reported global measles • Clinical presentation, complications, and outcomes: the incidence of subacute
cases were from the European region (25 947 cases). sclerosing panencephalitis might be higher than previously estimated, particularly
WHO measles mortality estimates are derived from a when measles is acquired in early childhood
model based on the number and age distribution of • Diagnosis: point-of-care diagnostic tests that detect measles virus-specific IgM
reported cases, measles vaccine coverage (routine and antibodies in blood or oral fluid might allow earlier response to outbreaks
supplemental mass vaccination), and age and country • Prevention: Global measles vaccine coverage has stagnated at 85% for almost a
specific case fatality ratios.10 Between 2000 and 2015, decade but microneedle patches might revolutionise measles vaccine delivery
estimated measles deaths decreased by 79% from 651 600 • Elimination and eradication: the Region of the Americas was the first WHO region to
(95% CI 449 900–1 034 500) to 134 200 (74 400–353 600; be declared to have eliminated measles in September, 2016, but the 2015 global
figure 2).9 Almost two-thirds (64%) of all measles deaths measles milestones were not met
were estimated to have occurred in the African Region,
although measles mortality declined by 85% in this
region from 2000 to 2015.9 A quarter of global measles Epidemiology
deaths occurred in the South East Asia region, with India The epidemiology of measles is largely determined
accounting for two-thirds of these deaths.9 Measles by the respiratory mode of transmission, high
vaccination was estimated to have prevented 20·3 million contagiousness and lifelong immunity that follows
deaths during this period.9 This decline in measles infection or vaccination. Measles has thus served as a
mortality was a key factor in progress toward achieving model of an acute, immunising infection for studies of
the Millennium Development Goal 4 to reduce child infectious disease dynamics,12,13 driven by contact
mortality.11 patterns between susceptible and infectious individuals

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A MCV1 coverage in infants, 2015

<50% (four countries or 2%) ≥90% (119 countries or 61%)


50–79% (38 countries or 20%) Not available
80–89% (33 countries or 17%)

B Global measles incidence by WHO region, 2000–15 C Estimated annual number of global measles deaths, 2000–15
1000·0 Goal EMR SEAR 1·5 Estimated number of measles deaths
Measles incidence per million population (log scale)

AFR EUR WPR 95% upper confidence limit


AMR Annual number of measles deaths (millions) 95% lower confidence limit

100·0
1·0

10·0
2015 measles incidence goal
5·0
0·5
1·0

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Year Year

Figure 2: Progress toward achieving global measles milestones for measles vaccine coverage (A), measles incidence (B), and measles mortality (C)
(A) Milestone 1: increase routine coverage with the first dose of measles-containing vaccine (MCV1) for children aged 1 year to ≥90% nationally and ≥80% in every
district. Progress: The number of countries with ≥90% MCV1 coverage increased from 84 (44%) in 2000 to 119 (61%) in 2015.9 Among countries with ≥90% MCV1
coverage nationally, the percentage with ≥80% coverage in every district was only 39% of 119 countries in 2015. (B) Milestone 2: reduce global measles incidence to
less than 5 cases per 1 million population. Progress: reported global annual measles incidence decreased 75% from 2000 to 2015, but only the Region of the Americas
achieved the milestone of less than 5 cases per 1 million population.9 (C) Milestone 3: reduce global measles mortality by 95% from the 2000 estimate. Progress: the
number of estimated global annual measles deaths decreased 79% from 2000 to 2015.9 EMR=Eastern Mediterranean Region. SEAR=South-East Asia Region.
AFR=African Region. EUR=European Region. WPR=Western Pacific Region. AMR=Region of the Americas. Reproduced from WHO,9 with permission from the WHO
and the US Centers for Disease Control and Prevention.

and affected by birth rates (introducing new susceptible incubation period for measles was 23 days.19 The
individuals), heterogeneities in vaccine coverage, and infectious period begins several days before and lasts for
human mobility.14 Measles virus is most often several days after the onset of rash, coinciding with peak
transmitted by respiratory droplets over short distances, levels of viraemia and when cough and coryza are most
but also by small particle aerosols that remain suspended intense, facilitating transmission. However, precise
in the air for up to 2 h (figure 4).15,16 The incubation measurements of the duration of infectiousness are
period for measles is about 10 days from the time of difficult and require detailed contact histories. Measles
infection to the onset of fever and 14 days to the onset of virus RNA can be detected for several months in blood,
rash, although these frequently cited estimates represent urine, and nasopharyngeal specimens after rash onset.20
a log-normal distribution of incubation periods.17 A Although the infectious period is unlikely to be this
systematic review based on 55 observations from long, measles cases are reported with no known source
eight observational studies estimated the median despite intense contact investigation,21 raising the
incubation period from infection to the onset of signs possibility of rare, prolonged infectious periods.
and symptoms to be 12·5 days, with a 95% CI extending The high contagiousness of measles virus is expressed
from 11·8 days to 13·2 days.18 The longest reported by the basic reproductive number (R0), which is the

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average number of secondary cases resulting from the 100


MCV1 coverage
introduction of an infectious individual into a completely MCV2 coverage
90
susceptible population.22 A function of pathogen
80
transmission characteristics, population density, and
70
social contact patterns, the basic reproductive number of

MCV coverage* (%)


60
measles virus has been estimated to be 9–18 in different
settings (figure 4).23 Measles has one of the highest basic 50

reproductive numbers for a directly transmitted pathogen, 40


significantly higher than that for smallpox (R0=5–7) or 30
influenza (R0=2–3) viruses. This epidemiological 20
characteristic of measles is the major obstacle to 10
elimination as the virus spreads rapidly in susceptible 0
populations and requires high levels of population

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immunity to interrupt transmission. A simple analytical
Year
estimate, assuming random mixing of individuals, is that
levels of population immunity as high as 89–94% are Figure 3: Global measles vaccine coverage for the first (MCV1) and second (MCV2) doses
required to achieve measles elimination. However, these Reproduced from WHO, by permission of WHO. MCV=measles-containing vaccine. *Coverage as estimated by
WHO and UNICEF.
estimates do not account for spatial heterogeneities in
susceptibility and non-random contact patterns.24 settings with low measles vaccine coverage, the average
Measles virus can only be maintained in human age of infection is low and measles is a disease of
populations by unbroken chains of transmission. Measles infants and young children. As measles vaccine coverage
does not result in known latent or persistent infectious increases, or the rate of contact between susceptible and
states and no animal reservoirs maintain virus infectious individuals decreases, the age distribution
transmission, features that make eradication possible.5 shifts toward older children. With increasing vaccination
Non-human primates can be infected with measles virus,25 coverage and levels of population immunity, the age
but their population size is well below the critical distribution of measles is further shifted into adolescence
community size of up to 300 000 to 500 000 individuals to and adulthood. Following recent progress in increasing
sustain virus transmission.2 measles vaccine coverage, many countries now face a
Endemic measles virus transmission has a typical changing epidemiological profile in which a higher
temporal pattern characterised by annual seasonal proportion of measles cases occur in adolescents and
epidemics superimposed upon longer epidemic cycles of adults, albeit with a lower number of measles cases.31
2–5 years, resulting from the accumulation of susceptible In addition to the changing age distribution of measles
people over successive birth cohorts and the subsequent cases, measles outbreaks have been increasingly
decline in the number of susceptible individuals following recognised within populations with immunity gaps
an outbreak (figure 4).26 Annual measles outbreaks despite high overall vaccine coverage, including cases in
typically occur in the late winter and early spring in individuals who received two doses of measles vaccine.32,33
temperate climates, determined in part by social contact For example, during a measles outbreak at a high school
patterns facilitating transmission (eg, congregation of in Quebec, Canada, in 2011, measles cases were identified
children at school) and environmental factors favouring among students who received two doses of measles
the viability and transmission of measles virus.26 Measles vaccine, with those who received the first dose before
outbreaks in the tropics have more variable seasonal 15 months of age at greatest risk of infection.34,35
patterns and, in regions with high birth rates, highly
irregular, large measles outbreaks can occur.27 Virology
Passively acquired, maternal anti-measles virus IgG The measles virus is a non-segmented, negative-sense
antibodies protect young infants against measles in the RNA virus and a member of the Morbillivirus genus in
first months of life but can also interfere with vaccine the family of Paramyxoviridae. The genome of about
responses by neutralising vaccine virus.28 Because 16 000 nucleotides encodes six structural proteins, the
antibody levels are generally higher in women with nucleoprotein, phosphoprotein, matrix, fusion, haemag­
naturally acquired immunity, infants born to women glutinin, and large protein, and two non-structural
with vaccine-induced immunity become susceptible to proteins V and C encoded within the phosphoprotein
measles at a younger age than those born to women with gene. The haemagglutinin protein is one of two trans­
a history of wildtype measles virus infection.29,30 The membrane glycoproteins on the surface of the virion and
average age of measles cases is a function of the rate of binds to cellular receptors, including the signalling
decline of protective maternal antibodies, the age at lymphocyte activation molecule (SLAM or CD150) on
which children acquire protective immunity from lymphocytes, monocytes, macrophages, and dendritic
vaccination, and the rate of contact between susceptible cells,36 and nectin-4, a component of epithelial cell
and infectious individuals. In densely populated urban adherens junctions.37 The distribution of these receptors

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A Epidemiology
40 Measles can have regular temporal patterns, driven by
35 the accumulation and decline of susceptible individuals,
Number of measles cases
notified (in thousands)

and cluster spatially among susceptible populations


30
25
20
15
10
5
0
1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978

B Transmission
Measles virus is transmitted A single person with Measles virus spreads first
by respiratory droplets and measles infects 9–18 to local lymphoid tissue
aerosolised particles other people on average and is then disseminated
throughout the blood
stream through infected
lymphocytes, infecting cells
F protein in almost all organ systems
H protein

The incubation period for


measles is 12·5 days on
average (95% CI 11·8–13·2
days), with a range up to
23 days

C Disease course D Complications


Fever
Temperature (°C)

40
39 Neurological:
Keratoconjunctivitis
ADEM, MIBE, SSPE
38 (blindness)
37 Otitis media
Stomatitis
Laryngitis (croup)
Rash
Pneumonia

Koplik’s spots

Conjunctivitis Adverse pregnancy


outcomes Diarrhoea

Coryza

Death

Cough

1 2 3 4 5 6 7 8 9 10

Incubation Prodromal Rash phase Convalescent


phase phase phase

Figure 4: Measles epidemiology (A), transmission (B),disease course (C), and complications (D)
Part A adapted from Fine PE and Clarkson JA.26 ADEM=acute demyelinating encephalomyelitis. MIBE=measles inclusion body encephalitis. SSPE=subacute sclerosing
panencephalitis.

determines the broad cell types and tissues infected with Measles virus can be genetically characterised by
measles virus. The lifelong immunity that follows sequencing a stretch of 450 basepairs that code for a
measles is due to neutralising IgG antibodies to the variable region of the nucleoprotein gene. 24 genotype
haemagglutinin protein that block binding to host cell reference strains are recognised by WHO.40 Genetic
receptors.38 The fusion protein, the second viral characterisation of circulating wildtype measles virus is
glycoprotein exposed on the viral surface, is responsible important in documenting transmission pathways,
for fusion of the viral envelope with the host cell distinguishing endemic from imported strains, and
membrane, enabling entry of viral ribonucleoproteins verifying measles elimination by demonstrating the
into the cell cytoplasm.39 absence of endemic viral strains.41 Genotyping can also

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differentiate vaccine from wildtype measles virus, which is Immune responses


important in assessing vaccine-associated adverse events.42 Immune responses to measles virus are crucial for viral
Only 13 of the 24 known genotypes were detected between clearance and the establishment of protective immunity
2005 and 2014 and only eight since 2009, suggesting that but also are the pathological basis of the clinical signs
many genotypes are no longer circulating.43 Recent and symptoms that contribute to measles morbidity
evidence suggests detailed measles virus transmission and mortality. The rash of measles, for example, is
networks can be identified by sequencing larger segments characterised histologically by perivascular, lymphocytic
of the measles virus genome, such as the haemagglutinin infiltrates.56 The earliest, innate immune responses occur
and phosphoprotein genes, or sequencing the whole viral during the prodromal phase before the onset of rash. Two
genome through Sanger or next generation sequencing non-structural viral proteins (V and C) suppress host
techniques.44,45 interferon production, facilitating virus replication.57 The
An important characteristic of measles virus is that it adaptive immune response follows and consists of cellular
is an antigenically monotypic virus, despite its genotypic and humoral responses, which are essential for recovery
diversity and the fact that RNA viruses have high and the establishment of long-term, protective immunity,
mutation rates.46 Consequently, attenuated measles respectively. The initial humoral response consists of IgM
vaccines derived from a single measles virus genotype antibodies that arise at the time of the rash and persist for
isolated in the 1950s,47 including the Schwarz and 6–8 weeks. Detection of IgM antibodies by enzyme
Moraten measles vaccine strains, remain protective immunoassay is the most commonly used laboratory
worldwide. Thus, new measles vaccines do not need to method of confirming measles virus infection, but IgM
be developed to counter evolving measles virus strains antibodies might not be detectable early in the disease
because the neutralising epitopes on the haemagglutinin course shortly after rash onset.58 Subsequently, IgG
protein that confer protection are highly conserved, antibodies are produced, the most abundant of which are
probably because of functional constraints on the amino against the nucleoprotein. The efficacy of antibodies alone
acid sequence and tertiary structure of the surface in preventing measles is shown by the protection
proteins.48 conferred by passively acquired maternal antibodies
and post-exposure administration of antimeasles virus
Pathophysiology immune globulin.59 Cellular immune responses to
Measles virus acquired through respiratory droplets measles virus are important for viral clearance and
or aerosolised particles initially infects lymphocytes, recovery, as shown by the fact that children with agamma­
dendritic cells, and alveolar macrophages in the respiratory globulinaemia recover from measles, but children with
tract.49,50 The virus replicates and spreads during the T-cell deficiencies develop severe or fatal disease.60 The
incubation period, first to local lymphoid tissue and is importance of cellular immune responses for viral
then disseminated throughout the blood stream by clearance were further shown in macaque models.61,62
infected lymphocytes, infecting epithelial and endothelial Plasma interferon-γ levels, consistent with a predominant
cells primarily through direct transmission across cells51 Th1 immune response, are increased during the
in almost all organ systems.52 Infected dendritic cells and acute phase of infection.63 During convalescence, a Th2
lymphocytes transfer measles virus to epithelial cells of response promotes the development of protective measles
the respiratory tract using the nectin-4 receptor.53 Measles virus-specific antibodies and is characterised by high
virus buds from the apical surface of respiratory epithelial concentrations of interleukin 4, interleukin 10, and
cells or is shed through damaged epithelium, enabling interleukin 13.64
respiratory transmission to susceptible hosts.54 Measles was the first immunosuppressive infection to
Although the infectious period for measles extends be described.65 Deficiencies of both innate and adaptive
from several days before to several days after start of the immune responses can render individuals with measles
rash, measles virus RNA can be detected in clinical more susceptible to secondary bacterial and viral
samples for at least 3 months after rash onset.20 Recent infections.66 Transient lymphopenia occurs in the blood
studies of measles pathogenesis further challenge the during measles67 but is likely due to the redistribution of
traditional view that measles is an acute infection of lymphocytes from peripheral blood to lymphatic tissues.68
2–3 weeks duration. For instance, measles virus Functional abnormalities of immune cells have been
nucleoprotein RNA was detected in peripheral blood described, including decreased lymphocyte proliferative
mononuclear cells for up to 67 days in an experimental responses and impaired dendritic cell function ex vivo,69
macaque model, with clearance of measles virus RNA but it is not clear that these mechanisms are responsible
occurring in three phases.55 Measles virus RNA declined for immune suppression in vivo.70 The Th2 response
rapidly as infectious virus was cleared, followed by a during convalescence might inhibit Th1 responses,
rebound in measles virus RNA by as much as ten-fold increasing susceptibility to intracellular pathogens.
that slowly declined to undetectable levels over 10 weeks.55 Plasma interleukin 10 concentrations are increased for
Measles virus RNA remained detectable in lymphoid weeks in children with measles and also might contribute
tissue after it was no longer detectable in blood.55 to immune suppression.64 A more recent hypothesis is

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that measles virus infection results in a proliferation of older than 20 years, pregnant women, and those who are
measles virus-specific lymphocytes that replace the immunocompromised or undernourished, particularly
established memory cell repertoire, resulting in so-called children with vitamin A deficiency (figure 4).82 The
immune amnesia and susceptibility to previously respiratory tract is a frequent site of complication, with
encountered antigens, including vaccine antigens.70 pneumonia accounting for most measles-associated
Immune suppression and the associated increased risk morbidity and mortality.83 Pneumonia is most often
of secondary infections are thought to last several weeks caused by secondary viral or bacterial pathogens but can
to months following measles.71,72 However, a recent be due to measles virus itself resulting in Hecht’s giant
intriguing study suggested this state of increased risk cell pneumonia.84 Bacterial and viral pathogens associated
could extend for as long as 2–3 years after measles.73 with pneumonia in children with measles are not well
Stimulated by research on immune amnesia and the characterised, particularly in children vaccinated against
potential loss of immunological memory to previously pneumococcus and Haemophilus influenzae type b. Other
encountered antigens, this study using population-level complications of the respiratory tract include laryngo­
data from high-income countries found that non-measles tracheobronchitis (croup) and otitis media. Diarrhoea
infectious disease mortality lagged measles incidence by can result in considerable morbidity and mortality, and
2–3 years, a finding that is consistent with, but does not is often due to secondary infections with bacteria
in itself prove, the immune amnesia hypothesis.73 or protozoa. Keratoconjunctivitis, another serious
Another intriguing but controversial observation is the complication of measles, was a frequent cause of
potential for non-specific beneficial effects of measles blindness before the widespread use of measles vaccine
vaccination, such as reduced mortality from other and vitamin A supplementation.85 Measles in pregnancy
infectious diseases.74,75 This phenomenon is part of a larger is associated with an increased risk of low birthweight,
debate on potential non-specific clinical and immunological spontaneous abortion, intrauterine fetal death, and
effects of vaccines, both positive and negative.76,77 maternal death.86
Three rare but serious CNS complications of measles
Clinical presentation, complications, were a major motivating factor to prevent infection
and outcomes through vaccination in countries where case fatality was
Measles is an acute febrile illness associated with low (figure 4). First, acute disseminated encephalomyelitis
a characteristic erythematous, maculopapular rash (ADEM) is a demyelinating autoimmune disease that is
(figure 4). The illness begins with fever and typically triggered by measles virus and occurs within days to weeks
at least one of the three “Cs”: cough, coryza, and in approximately one in 1000 cases. ADEM is characterised
conjunctivitis. Koplik’s spots appear on the buccal by fever, seizures, and other neurological deficits.87 Second,
mucosa as small white papules and provide an measles inclusion body encephalitis (MIBE) is a
opportunity to clinically diagnose measles a day or two progressive measles virus infection of the brain that results
before the rash. The rash appears 3–4 days after the onset in neurological deterioration and death in individuals with
of fever, first on the face and behind the ears, and then impaired cellular immunity within months of the acute
spreads to the trunk and extremities, coinciding with illness.87 MIBE has been described in children who are
development of the adaptive immune response. The immunosuppressed following organ transplants and in
fever and catarrhal symptoms typically peak with the HIV-infected persons.88 Third, subacute sclerosing
rash, which persists for 3–4 days. The rash might be panencephalitis (SSPE) is a delayed complication of
minimal in children with vaccine-modified measles who measles that occurs in about 1:10 000 to 1:100 000 cases
have previous immunity following vaccination, and these 5–10 years after the acute illness, caused by the host
children might not have cough, coryza, or conjunctivitis.78 response to production of mutated virions with defective
Malnourished children can develop a deeply pigmented assembly and budding.87 SSPE most often occurs in people
rash that desquamates during recovery.79 As the rash infected with measles virus before 2 years of age and is
represents a perivascular lymphocytic infiltration, characterised by seizures, progressive deterioration of
children with impaired cellular immunity, such as those cognitive and motor function, and death.87 A recent report
infected with HIV, might not develop the characteristic of SSPE in the USA identified a much higher incidence
rash or the rash might be delayed.80 Recovery typically than previously described, including an incidence of
occurs within 1 week of rash onset in people with 1:1367 cases in children who acquired measles younger
uncomplicated measles. The measles case definition, than 5 years of age and 1:609 cases in children with measles
consisting of a generalised maculopapular rash, fever before 1 year of age.89 Measles vaccination reduces the
(≥38·3oC) and either cough, coryza, or conjunctivitis, has incidence of SSPE.90
high sensitivity (75–90%) but a low positive predictive Measles case fatality ratios range from less than one in
value when measles incidence is low, highlighting the 1000 cases to 5% in endemic areas in sub-Saharan Africa
need for serological confirmation.81 and Asia, to as high as 20–30% in refugees and internally
Complications of measles can affect most organ displaced populations.91 This variation is determined by
systems and are most common in young infants, adults the average age of infection, nutritional and immunological

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status of the population, measles vaccine coverage, and using throat, nasal, nasopharyngeal, and urine samples
access to health care. before measles virus-specific IgM antibodies are
detectable.
Diagnosis Recent advances in diagnostic technologies could
Measles is readily recognised by clinicians familiar facilitate rapid outbreak detection and response. IgM and
with the disease in people presenting with fever and IgG antibodies to measles virus, as well as measles virus
generalised rash, particularly during outbreaks or in RNA, can be detected in oral fluid or in serum eluted
patients with a history of travel to endemic areas. Other from dried blood spots. The use of oral fluid samples
acute viral infections that might be confused with might increase participation in serological surveys in
measles include infection with rubella virus, human some communities, although this approach comes with
herpes virus type 6, parvovirus B19, and dengue viruses. loss of sensitivity.95 Dried blood spots facilitate
The medical history and physical examination should uncomplicated specimen transport and storage.96 Point-
focus on the clinical features of measles as well as of-care diagnostic tests that detect measles virus-specific
potential complications, including pneumonia, otitis IgM and IgG antibodies in blood and oral fluid have been
media, keratoconjunctivitis, and diarrhoea. Assessment developed and validated, but are not yet widely
of nutritional and immune status, most importantly available.97,98
vitamin A deficiency and HIV infection, will identify
individuals at highest risk of mortality. Health-care Management
personnel should take appropriate measures, including The management of patients with measles consists of
prompt isolation of infectious cases using airborne supportive therapy to correct or prevent dehydration
precautions, to prevent transmission within health-care and nutritional deficiencies, prompt recognition and
settings.92 The clinical diagnosis of measles is more treatment of secondary bacterial infections, and provision
challenging to clinicians unfamiliar with the disease, of vitamin A. WHO recommends administration of once
before the onset of rash, in immunocompromised and daily doses of 200 000 IU of vitamin A for 2 consecutive
undernourished children in whom the rash might be days to all children with measles older than 1 year of
absent or altered, and in individuals with pre-existing age.99 In younger children, lower doses are recommended,
antibodies from maternal immunity, immune globulin, specifically 100 000 IU per day for children 6–12 months
or previous vaccination who can have a longer incubation of age and 50 000 IU per day for children younger
period, milder prodromal illness, and a less apparent than 6 months.99 For children with clinical evidence of
rash than typical cases. vitamin A deficiency, a third dose is recommended
The most common laboratory method for confirming 2–4 weeks later.99 Two doses of vitamin A, but not a single
measles virus infection is detection of measles virus- dose, has been associated with a reduction in the risk of
specific IgM antibodies in serum or plasma. However, mortality in children younger than 2 years (risk ratio
measles virus-specific IgM antibodies might be low or 0·18 [95% CI 0·03–0·61]) and a reduction in the risk of
undetectable until 4 days or more after rash onset, pneumonia-specific mortality (0·33 [0·08–0·92]).100 No
resulting in false negative results if samples are specific antiviral therapies exist for measles, although
collected early.58 About 75% of people with measles will ribavirin, interferon alfa, and other antiviral drugs have
have detectable measles virus-specific IgM antibodies been used to treat severe measles.101 Evidence supporting
within the first 72 h after rash and almost all people with the use of prophylactic antibiotics for children with
measles will have detectable measles virus-specific IgM measles is limited and such use is not recommended,102
antibodies after 4 days.93 Measles virus-specific IgM but antibiotics are indicated for people with measles who
antibodies peak within 1–3 weeks after the onset of rash have clinical evidence of bacterial infection, including
and decline to undetectable levels within 4–8 weeks. pneumonia and otitis media.
Acute infection also can be confirmed serologically by
measuring a four-fold or greater increase in measles Prevention
virus-specific IgG antibody levels between acute and Measles is best prevented through measles vaccination.
convalescent sera. Commercially available enzyme Currently licensed measles vaccines are attenuated
immunoassays are most often used to detect antibodies viral vaccines that replicate within the host to induce
to measles virus, although the gold standard test with protective immunity.99 Measles vaccines can be ad­
the highest sensitivity is the plaque reduction ministered as combined vaccines with those for rubella
neutralisation assay.94 Individuals who are seronegative (MR), mumps (MMR), or varicella (MMR-V). Use
by enzyme immunoassay might have detectable of combined measles–rubella vaccines provides an
antibodies to measles virus by neutralisation assay. The opportunity to eliminate rubella and congenital rubella
presence of IgG antibodies to measles virus in a single syndrome, and are increasingly used throughout the
serum specimen is evidence of previous infection or world through the support of Gavi, the Vaccine Alliance.
immunisation. Measles virus infection also can be Attenuation is achieved by passaging wildtype measles
confirmed by detection of viral RNA through RT-PCR viruses through repeated culture in non-human cells.

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The first measles vaccine (Edmonston B strain) was 9 months of age, a lower proportion develop protective
licensed in the USA in 1963, but caused mild measles immunity because of the inhibitory effect of maternal
with fever and rash, and was administered with gamma antibodies and immaturity of the immune system.107
globulin (figure 1). Further attenuated measles vaccine Administering the first dose of measles vaccine at
strains were licensed in the late 1960s, including the 12–15 months results in a higher proportion of protected
Schwarz and Moraten vaccine viruses that are still widely children, but can only be done in settings where the risk
used. Two previously licensed measles vaccines were of measles is low. Children who are infected with HIV
subsequently withdrawn after they were shown to have should be revaccinated against measles following
serious adverse effects. The first was a formalin- immune reconstitution with highly active antiretroviral
inactivated measles vaccine, also licensed in the early therapy because of failure to maintain protective
1960s, that led to the formation of immune complexes103 antibody levels.108
and atypical measles, including pneumonitis and a The high levels of population immunity necessary to
maculopapular or petechial rash that started on the interrupt measles virus transmission cannot be achieved
wrists and ankles, upon exposure to wildtype virus.104 with a single dose schedule. A second dose of measles
The second was a high-titre measles vaccine vaccine should be provided to immunise those children
recommended for use by WHO in 1989 that contained a who failed to respond to the first dose. MCV1 is usually
higher concentration of measles virus to overcome the given through routine immunisation services but two
inhibitory effect of maternal antibodies but resulted in strategies have been used to administer additional doses of
unexplained delayed mortality in girls.105 measles vaccine, the first through routine immunisation
WHO recommends that the first dose of measles- services (MCV2) and the second through mass vaccination
containing vaccine (MCV1) be administered at 9 months campaigns (sometimes called supplemental immunisation
of age in settings with endemic measles but as early as activities [SIAs]) that typically target children from 9 months
6 months of age in some circumstances, including to 5 years or 15 years of age. In countries where MCV1
during outbreaks, for internally displaced populations is administered at 9 months of age, MCV2 can be
and refugees, for HIV-infected and exposed children, administered through the routine immunisation system
and children at high risk of contracting measles, but at 15–18 months of age with a minimum of 4 weeks
allows flexibility based on local epidemiology.99 The between doses. In countries with low level measles virus
proportions of children who develop protective levels of transmission where MCV1 is administered at 12 months
antibody after measles vaccination are about 85% at of age or older, MCV2 can be administered at 15–18 months
9 months of age and 95% at 12 months of age.106 When of age or at school entry.
measles vaccine is given to children younger than Estimated global coverage with the first dose of MCV1
increased from 72% to 85% from 2000 to 2010 but
plateaued at 85% in 2015 (figure 3).9 Vaccinating these
Panel 2: Definitions109 remaining 15% of children to raise global MCV1
• Measles eradication: worldwide interruption of measles coverage above 85% should be the primary goal of
virus transmission in the presence of a surveillance system measles control and elimination programmes. Among
that has been verified to be performing well the 20·8 million children who did not receive MCV1 in
• Measles elimination: the absence of endemic measles 2015, 53% lived in six countries: India, Nigeria, Pakistan,
virus transmission in a defined geographical area for more Indonesia, Ethiopia, and the Democratic Republic of
than 12 months in the presence of a well performing Congo.9 An increasing number of countries provide
surveillance system MCV2 through routine immunisation services but
• Endemic measles transmission: the existence of estimated global MCV2 coverage remains suboptimal,
continuous transmission of indigenous or imported at only 61% in 2015.9 Measles SIAs continue to be used
measles virus that persists for more than 12 months in to achieve high levels of population immunity and
any defined geographical area 184 million people received MCV through SIAs in 2015.9
• Re-establishment of endemic transmission: occurs when However, SIAs are expensive and resource-intensive,
epidemiological and laboratory evidence indicates the require careful planning, monitoring, and evaluation,
presence of a chain of transmission of a virus strain that and coverage is often lower than planned.
continues uninterrupted for more than 12 months in a
defined geographical area where measles had previously Measles elimination and eradication
been eliminated The World Health Assembly established three global
• Measles outbreak in countries with an elimination goal: milestones for measles control to be achieved by 2015
when two or more confirmed cases are temporally related (figure 2).43 The first addressed routine measles vaccination
(with dates of rash onset occurring between 7 and 21 days coverage, with the goal of 90% or higher coverage
apart) and are epidemiologically or virologically linked, nationally and 80% or higher in every district (although
or both this coverage level is insufficient for elimination). The
second addressed measles incidence, with the goal of

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Seminar

fewer than five cases per 1 million people. And the


third addressed measles deaths, with the goal to reduce Panel 3: Research needs
measles mortality by 95% or higher from 2000 estimates. Research will be crucial to achieving regional measles elimination goals and global
Subsequently, the Global Vaccine Action Plan for 2012–20 eradication. Research is needed on how best to strengthen routine immunisation services
established targets to eliminate measles and rubella in to improve access and increase demand for vaccination; how best to increase measles
five WHO regions by 2020 and, as of September, 2013, all vaccine coverage and identify immunity gaps to achieve high, equitable coverage; and
six WHO regions adopted measles elimination goals by how best to improve measles surveillance to rapidly identify and respond to outbreaks
2020 or earlier (figure 1; panel 2).43 The Region of the and better measure progress towards elimination.
Americas was the first WHO region to be declared to have
eliminated measles after a rigorous verification process by Strengthening routine immunisation services110
the International Expert Committee for Documenting and • Develop better methods to collect valid and timely vaccine coverage data111
Verifying Measles, Rubella, and Congenital Rubella • Develop strategies to address vaccine hesitancy112,113
Syndrome in September, 2016.9 However, in view of the • Build upon lessons learned from the Global Polio Eradication Initiative114
slow progress, the WHO Strategic Advisory Group of Achieving and sustaining high measles vaccine coverage
Experts on Immunization concluded that neither the 2015 • Develop and evaluate better measles vaccines that do not require a cold chain and can
global measles milestones nor the measles elimination be delivered without needles, such as microneedle patches115,116
goals were achieved.108 Identifying, prioritising, funding, • Evaluate the optimal use of serological surveys to guide immunisation programmes117
and answering critical research questions will be necessary
to achieve these goals (panel 3). Improve measles surveillance
Countries or regions that have eliminated measles are • Develop more accurate and comprehensive surveillance systems to track progress
at continual risk of imported measles as long as measles toward measles mortality reduction and elimination31
virus is circulating in other parts of the world, a risk that • Develop and evaluate point-of-care measles and rubella IgM antibody tests, with the
is increased by global travel. Outbreaks result in high capacity to perform viral genotyping97
costs related to case-based investigations, outbreak • Develop better analytical approaches to predicting measles outbreaks through human
responses, and provision of health care.120 This risk will mobility patterns and spatial heterogeneities in susceptibility118,119
only be mitigated if measles is eradicated. Measles virus
meets many of the biological criteria for disease
eradication, including the absence of a non-human global coverage with two doses of measles vaccine through
reservoir, accurate diagnosis, and the availability of a advocacy, education, and the strengthening of routine
highly effective vaccine.5 immunisation systems. Building on the polio legacy, the
political will and financial resources must be garnered to
The future of measles achieve the regional elimination goals and eventual global
Great progress has been made in reducing measles measles eradication.
incidence, morbidity, and mortality through the widespread Declaration of interests
use of measles vaccines (figure 2). Mortality has been WJM is a member of WHO’s Strategic Advisory Group of Experts on
reduced from more than 2 million deaths year before the Immunization Working Group on Measles and Rubella. However, the
views expressed in this Seminar reflect those of the author and are not
widespread use of measles vaccines to slightly more than necessarily those of WHO or the Strategic Advisory Group of Experts on
100 000 in 2015. Global measles vaccine coverage is high Immunization Working Group on Measles and Rubella.
and more countries are introducing a second dose of Acknowledgments
measles vaccine through routine immunisation services. The author is grateful to the anonymous reviewers for their thoughtful
With the support of Gavi, many countries are introducing comments and suggestions.
combined measles–rubella vaccines, providing the References
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