Seminar

Measles
William J Moss

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
http://dx.doi.org/10.1016/
widespread use of measles vaccine. Measles virus is transmitted by the respiratory route and illness begins with fever, S0140-6736(17)31463-0
cough, coryza, and conjunctivitis followed by a characteristic rash. Complications of measles affect most organ Department of Epidemiology
systems, with pneumonia accounting for most measles-associated morbidity and mortality. The management of (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), W Harry
Feinstone Department of
However, urgent efforts are needed to increase stagnating global coverage with two doses of measles vaccine through Molecular Microbiology and
advocacy, education, and the strengthening of routine immunisation systems. Use of combined measles-rubella 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),
Bloomberg School of Public
measles elimination and eradication. Health, Johns Hopkins
University, Baltimore, MD, USA
Introduction manifestations, diagnosis, management, and prevention Correspondence to:
Measles is a highly contagious, acute febrile illness that of measles, highlighting recent research findings as well Prof William J Moss, Department
of Epidemiology, Bloomberg
results from infection with measles virus. Measles virus as the progress and challenges of measles elimination School of Public Health,
is most closely related genetically to rinderpest virus, a and eradication (panel 1). Johns Hopkins University,
pathogen of cattle that was declared eradicated by the Baltimore, MD 21205, USA
World Organization for Animal Health in May, 2011, and Disease burden wmoss1@jhu.edu

probably evolved as a zoonotic infection in communities
in which humans and cattle lived together.1 Although
historical evidence is lacking, epidemiological evidence
suggests measles likely became a disease of humans
5000–10 000 years ago when early agrarian civilisations in
the fertile crescent achieved sufficient population size to
maintain virus transmission.2,3 Measles was a leading
global cause of child morbidity and mortality before the
introduction of measles vaccines in the 1960s, and was
responsible for more than 2 million deaths annually
before the increase in global measles vaccine coverage in
the 1980s as a result of the Expanded Programme on
Immunization (figure 1). Measles incidence and
mortality have declined substantially over the past
two decades due to the increasingly widespread use of
attenuated measles vaccines administered through
routine immunisation programmes and mass
vaccination campaigns. Despite this enormous progress,
measles remains an important vaccine-preventable cause
of morbidity and mortality, responsible for more than
100 000 deaths each year, and serves as an indicator of the
quality of immunisation programmes. The reduction in
measles incidence and mortality, along with progress
toward achieving polio eradication, have renewed interest
in measles regional elimination and global eradication.4
However, increased political will, public support, and
financial resources, facilitated by new instruments,
technologies, and strategies, such as point-of-care
diagnostics and microneedle patches, will be needed to
achieve regional measles elimination goals and eventual
eradication.5 This primer updates a previous Lancet
seminar published in 20126 and summarises current
knowledge of the disease burden, epidemiology,
virology, pathophysiology, immune responses, clinical
Deaths due to measles have declined substantially over
the past century, first through improvements in nutrition,
socioeconomic status, and health care and subsequently
through a major reduction in measles incidence as a
consequence of increasing measles vaccine coverage.7
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
no doubt that the burden of measles, including
pneumonia, blindness, chronic neurological conditions,
and death, has decreased substantially because of
measles vaccination. Precise measurements of measles
incidence and mortality are lacking, however, because
most cases and deaths occur in countries with poor vital
registration and disease surveillance systems.
Consequently, estimates are based on imperfect reporting
and models. Almost all countries use case-based
surveillance and have access to standardised laboratory
testing through the WHO Global Measles and Rubella
Laboratory Network for diagnostic confirmation and
Search strategy and selection criteria
I searched PubMed for publications in English using the terms
“measles”, “measles virus”, “measles and epidemiology”,
“measles and pathophysiology”, “measles and diagnosis”,
“measles and treatment”, and “measles and prevention”. My
search focused on, but was not restricted to, publications in
the past 4 years. I also searched the Cochrane Database of
Systematic Reviews using the term “measles” and our own
database of references, as well as those of linked articles in
the searched journals. When more than one article illustrated
a specific point, the most representative article was chosen.

www.thelancet.com Published online June 30, 2016 http://dx.doi.org/10.1016/S0140-6736(17)31463-0 1

 Seminar

molecular epidemiology,8 consisting of 703 laboratories although these reports vastly underestimate the true
that support surveillance in 191 countries. number of measles cases. Improving measles surveillance
WHO publishes annually the reported number of and reporting will be crucial to achieving regional and
measles cases and estimated number of deaths, as well as global milestones. Most reported measles cases in 2015
estimates of national measles vaccine coverage for both were from the African (40%), Western Pacific (27%), and
the first and second doses (figures 2, 3). The number of South East Asia (12%, with 88% of these from India)
reported measles cases decreased worldwide between Regions.9 Importantly, 11% of reported global measles
2000 to 2015 by 70%, from 853 479 to 254 928 cases,9 cases were from the European region (25 947 cases).
WHO measles mortality estimates are derived from a
model based on the number and age distribution of
Panel 1: Important recent developments in measles reported cases, measles vaccine coverage (routine and
• Disease burden: estimated global measles deaths decreased 79% from 2000 to 2015 supplemental mass vaccination), and age and country
• Epidemiology: measles outbreaks have been reported in populations with immunity specific case fatality ratios.10 Between 2000 and 2015,
gaps despite high overall vaccine coverage, including individuals who received estimated measles deaths decreased by 79% from 651 600
two doses of measles vaccine (95% CI 449 900–1 034 500) to 134 200 (74 400–353 600;
• Virology: only eight of the 24 known measles virus genotypes have been detected figure 2).9 Almost two-thirds (64%) of all measles deaths
since 2009, suggesting many genotypes are no longer circulating were estimated to have occurred in the African Region,
• Pathophysiology: persistence of measles virus RNA for 2–3 months after rash onset although measles mortality declined by 85% in this
could contribute to the life-long immunity and prolonged state of immune region from 2000 to 2015.9 A quarter of global measles
suppression following measles deaths occurred in the South East Asia region, with India
• Immune responses: development of so-called immune amnesia after measles, in which accounting for two-thirds of these deaths.9 Measles
measles virus-specific lymphocytes replace the established memory cell repertoire, is a vaccination was estimated to have prevented 20·3 million
recent hypothesis to explain the immune suppression that follows measles deaths during this period.9 This decline in measles
• Clinical presentation, complications, and outcomes: the incidence of subacute mortality was a key factor in progress toward achieving
sclerosing panencephalitis might be higher than previously estimated, particularly the Millennium Development Goal 4 to reduce child
when measles is acquired in early childhood mortality.11
• Diagnosis: point-of-care diagnostic tests that detect measles virus-specific IgM
antibodies in blood or oral fluid might allow earlier response to outbreaks Epidemiology
• Prevention: Global measles vaccine coverage has stagnated at 85% for almost a The epidemiology of measles is largely determined by
decade but microneedle patches might revolutionise measles vaccine delivery the respiratory mode of transmission, high
• Elimination and eradication: the Region of the Americas was the first WHO region to contagiousness and lifelong immunity that follows
be declared to have eliminated measles in September, 2016, but the 2015 global infection or vaccination. Measles has thus served as a
measles milestones were not met model of an acute, immunising infection for studies of
infectious disease dynamics,12,13 driven by contact

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

2 www.thelancet.com Published online June 30, 2016 http://dx.doi.org/10.1016/S0140-6736(17)31463-0

 Seminar

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

Annual number of measles deaths (millions)

AMR 95% lower confidence limit

100·0
1·0

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

0·1 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.

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

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 Seminar

100
patterns facilitating transmission (eg, congregation of
MCV1 coverage
MCV2 coverage
children at school) and environmental factors favouring
90
the viability and transmission of measles virus.26 Measles
80
outbreaks in the tropics have more variable seasonal
70
patterns and, in regions with high birth rates, highly
MCV coverage* (%)

60
irregular, large measles outbreaks can occur.27
50 Passively acquired, maternal anti-measles virus IgG
40 antibodies protect young infants against measles in the
30 first months of life but can also interfere with vaccine
20 responses by neutralising vaccine virus.28 Because
10 antibody levels are generally higher in women with
0 naturally acquired immunity, infants born to women
with vaccine-induced immunity become susceptible to
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measles at a younger age than those born to women with

Year
Figure 3: Global measles vaccine coverage for the first (MCV1) and second (MCV2) doses
Reproduced from WHO, by permission of WHO. MCV=measles-containing vaccine. *Coverage as estimated by
WHO and UNICEF.
The high contagiousness of measles virus is expressed
by the basic reproductive number (R0), which is the
average number of secondary cases resulting from the
introduction of an infectious individual into a completely
susceptible population.22 A function of pathogen
transmission characteristics, population density, and
social contact patterns, the basic reproductive number of
measles virus has been estimated to be 9–18 in different
settings (figure 4).23 Measles has one of the highest basic
reproductive numbers for a directly transmitted pathogen,
significantly higher than that for smallpox (R0=5–7) or
influenza (R0=2–3) viruses. This epidemiological
characteristic of measles is the major obstacle to
elimination as the virus spreads rapidly in susceptible
populations and requires high levels of population
immunity to interrupt transmission. A simple analytical
estimate, assuming random mixing of individuals, is that
levels of population immunity as high as 89–94% are
required to achieve measles elimination. However, these
estimates do not account for spatial heterogeneities in
susceptibility and non-random contact patterns.24
Measles virus can only be maintained in human
populations by unbroken chains of transmission. Measles
does not result in known latent or persistent infectious
states and no animal reservoirs maintain virus
transmission, features that make eradication possible.5
Non-human primates can be infected with measles virus,25
but their population size is well below the critical
community size of up to 300 000 to 500 000 individuals to
sustain virus transmission.2
Endemic measles virus transmission has a typical
temporal pattern characterised by annual seasonal
epidemics superimposed upon longer epidemic cycles of
2–5 years, resulting from the accumulation of susceptible
people over successive birth cohorts and the subsequent
decline in the number of susceptible individuals following
an outbreak (figure 4).26 Annual measles outbreaks
typically occur in the late winter and early spring in
temperate climates, determined in part by social contact
a history of wildtype measles virus infection.29,30 The
average age of measles cases is a function of the rate of
decline of protective maternal antibodies, the age at
which children acquire protective immunity from
vaccination, and the rate of contact between susceptible
and infectious individuals. In densely populated urban
settings with low measles vaccine coverage, the average
age of infection is low and measles is a disease of
infants and young children. As measles vaccine coverage
increases, or the rate of contact between susceptible and
infectious individuals decreases, the age distribution
shifts toward older children. With increasing vaccination
coverage and levels of population immunity, the age
distribution of measles is further shifted into adolescence
and adulthood. Following recent progress in increasing
measles vaccine coverage, many countries now face a
changing epidemiological profile in which a higher
proportion of measles cases occur in adolescents and
adults, albeit with a lower number of measles cases.31
In addition to the changing age distribution of measles
cases, measles outbreaks have been increasingly
recognised within populations with immunity gaps
despite high overall vaccine coverage, including cases in
individuals who received two doses of measles vaccine.32,33
For example, during a measles outbreak at a high school
in Quebec, Canada, in 2011, measles cases were identified
among students who received two doses of measles
vaccine, with those who received the first dose before
15 months of age at greatest risk of infection.34,35
Virology
The measles virus is a non-segmented, negative-sense
RNA virus and a member of the Morbillivirus genus in
the family of Paramyxoviridae. The genome of about
16 000 nucleotides encodes six structural proteins, the
nucleoprotein, phosphoprotein, matrix, fusion, haemag­
glutinin, and large protein, and two non-structural
proteins V and C encoded within the phosphoprotein
gene. The haemagglutinin protein is one of two trans­
membrane glycoproteins on the surface of the virion and
binds to cellular receptors, including the signalling
lymphocyte activation molecule (SLAM or CD150) on
lymphocytes, monocytes, macrophages, and dendritic

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 Seminar

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

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.

cells,36 and nectin-4, a component of epithelial cell membrane, enabling entry of viral ribonucleoproteins
adherens junctions.37 The distribution of these receptors into the cell cytoplasm.39
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

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 Seminar
verifying measles elimination by demonstrating the
absence of endemic viral strains.41 Genotyping can also
differentiate vaccine from wildtype measles virus, which is
important in assessing vaccine-associated adverse events.42
Only 13 of the 24 known genotypes were detected between
2005 and 2014 and only eight since 2009, suggesting that
many genotypes are no longer circulating.43 Recent
evidence suggests detailed measles virus transmission
networks can be identified by sequencing larger segments
of the measles virus genome, such as the haemagglutinin
and phosphoprotein genes, or sequencing the whole viral
genome through Sanger or next generation sequencing
techniques.44,45
An important characteristic of measles virus is that it
is an antigenically monotypic virus, despite its genotypic
diversity and the fact that RNA viruses have high
mutation rates.46 Consequently, attenuated measles
vaccines derived from a single measles virus genotype
isolated in the 1950s,47 including the Schwarz and
Moraten measles vaccine strains, remain protective
worldwide. Thus, new measles vaccines do not need to
be developed to counter evolving measles virus strains
because the neutralising epitopes on the haemagglutinin
protein that confer protection are highly conserved,
probably because of functional constraints on the amino
acid sequence and tertiary structure of the surface
proteins.48
Pathophysiology
Measles virus acquired through respiratory droplets
or aerosolised particles initially infects lymphocytes,
dendritic cells, and alveolar macrophages in the respiratory
tract.49,50 The virus replicates and spreads during the
incubation period, first to local lymphoid tissue and is
then disseminated throughout the blood stream by
infected lymphocytes, infecting epithelial and endothelial
cells primarily through direct transmission across cells51
in almost all organ systems.52 Infected dendritic cells and
lymphocytes transfer measles virus to epithelial cells of
the respiratory tract using the nectin-4 receptor.53 Measles
virus buds from the apical surface of respiratory epithelial
cells or is shed through damaged epithelium, enabling
respiratory transmission to susceptible hosts.54
Although the infectious period for measles extends
from several days before to several days after start of the
rash, measles virus RNA can be detected in clinical
samples for at least 3 months after rash onset.20 Recent
studies of measles pathogenesis further challenge the
traditional view that measles is an acute infection of
2–3 weeks duration. For instance, measles virus
nucleoprotein RNA was detected in peripheral blood
mononuclear cells for up to 67 days in an experimental
macaque model, with clearance of measles virus RNA
occurring in three phases.55 Measles virus RNA declined
rapidly as infectious virus was cleared, followed by a
rebound in measles virus RNA by as much as ten-fold
that slowly declined to undetectable levels over 10 weeks.55
6 www.thelancet.com Published online June 30, 2016 http://dx.doi.org/10.1016/S0140-6736(17)31463-0
Measles virus RNA remained detectable in lymphoid
tissue after it was no longer detectable in blood.55
Immune responses
Immune responses to measles virus are crucial for viral
clearance and the establishment of protective immunity
but also are the pathological basis of the clinical signs
and symptoms that contribute to measles morbidity
and mortality. The rash of measles, for example, is
characterised histologically by perivascular, lymphocytic
infiltrates.56 The earliest, innate immune responses occur
during the prodromal phase before the onset of rash. Two
non-structural viral proteins (V and C) suppress host
interferon production, facilitating virus replication.57 The
adaptive immune response follows and consists of cellular
and humoral responses, which are essential for recovery
and the establishment of long-term, protective immunity,
respectively. The initial humoral response consists of IgM
antibodies that arise at the time of the rash and persist for
6–8 weeks. Detection of IgM antibodies by enzyme
immunoassay is the most commonly used laboratory
method of confirming measles virus infection, but IgM
antibodies might not be detectable early in the disease
course shortly after rash onset.58 Subsequently, IgG
antibodies are produced, the most abundant of which are
against the nucleoprotein. The efficacy of antibodies alone
in preventing measles is shown by the protection
conferred by passively acquired maternal antibodies and
post-exposure administration of antimeasles virus
immune globulin.59 Cellular immune responses to
measles virus are important for viral clearance and
recovery, as shown by the fact that children with agamma­
globulinaemia recover from measles, but children with
T-cell deficiencies develop severe or fatal disease.60 The
importance of cellular immune responses for viral
clearance were further shown in macaque models.61,62
Plasma interferon-γ levels, consistent with a predominant
Th1 immune response, are increased during the
acute phase of infection.63 During convalescence, a Th2
response promotes the development of protective measles
virus-specific antibodies and is characterised by high
concentrations of interleukin 4, interleukin 10, and
interleukin 13.64
Measles was the first immunosuppressive infection to
be described.65 Deficiencies of both innate and adaptive
immune responses can render individuals with measles
more susceptible to secondary bacterial and viral
infections.66 Transient lymphopenia occurs in the blood
during measles67 but is likely due to the redistribution of
lymphocytes from peripheral blood to lymphatic tissues.68
Functional abnormalities of immune cells have been
described, including decreased lymphocyte proliferative
responses and impaired dendritic cell function ex vivo,69
but it is not clear that these mechanisms are responsible
for immune suppression in vivo.70 The Th2 response
during convalescence might inhibit Th1 responses,
increasing susceptibility to intracellular pathogens.

Plasma interleukin 10 concentrations are increased for
weeks in children with measles and also might contribute
to immune suppression.64 A more recent hypothesis is
that measles virus infection results in a proliferation of
measles virus-specific lymphocytes that replace the
established memory cell repertoire, resulting in so-called
immune amnesia and susceptibility to previously
encountered antigens, including vaccine antigens.70
Immune suppression and the associated increased risk
of secondary infections are thought to last several weeks
to months following measles.71,72 However, a recent
intriguing study suggested this state of increased risk
could extend for as long as 2–3 years after measles.73
Stimulated by research on immune amnesia and the
potential loss of immunological memory to previously
encountered antigens, this study using population-level
data from high-income countries found that non-measles
infectious disease mortality lagged measles incidence by
2–3 years, a finding that is consistent with, but does not
in itself prove, the immune amnesia hypothesis.73
Another intriguing but controversial observation is the
potential for non-specific beneficial effects of measles
vaccination, such as reduced mortality from other
infectious diseases.74,75 This phenomenon is part of a larger
debate on potential non-specific clinical and immunological
effects of vaccines, both positive and negative.76,77
Clinical presentation, complications,
and outcomes
Measles is an acute febrile illness associated with a
characteristic erythematous, maculopapular rash
(figure 4). The illness begins with fever and typically at
least one of the three “Cs”: cough, coryza, and
conjunctivitis. Koplik’s spots appear on the buccal mucosa
as small white papules and provide an opportunity to
clinically diagnose measles a day or two before the rash.
The rash appears 3–4 days after the onset of fever, first on
the face and behind the ears, and then spreads to the
trunk and extremities, coinciding with development of the
adaptive immune response. The fever and catarrhal
symptoms typically peak with the rash, which persists for
3–4 days. The rash might be minimal in children with
vaccine-modified measles who have previous immunity
following vaccination, and these children might not have
cough, coryza, or conjunctivitis.78 Malnourished children
can develop a deeply pigmented rash that desquamates
during recovery.79 As the rash represents a perivascular
lymphocytic infiltration, children with impaired cellular
immunity, such as those infected with HIV, might not
develop the characteristic rash or the rash might be
delayed.80 Recovery typically occurs within 1 week of rash
onset in people with uncomplicated measles. The measles
case definition, consisting of a generalised maculopapular
rash, fever (≥38·3oC) and either cough, coryza, or
conjunctivitis, has high sensitivity (75–90%) but a low
positive predictive value when measles incidence is low,
highlighting the need for serological confirmation.81
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Seminar
Complications of measles can affect most organ
systems and are most common in young infants, adults
older than 20 years, pregnant women, and those who are
immunocompromised or undernourished, particularly
children with vitamin A deficiency (figure 4).82 The
respiratory tract is a frequent site of complication, with
pneumonia accounting for most measles-associated
morbidity and mortality.83 Pneumonia is most often
caused by secondary viral or bacterial pathogens but can
be due to measles virus itself resulting in Hecht’s giant
cell pneumonia.84 Bacterial and viral pathogens associated
with pneumonia in children with measles are not well
characterised, particularly in children vaccinated against
pneumococcus and Haemophilus influenzae type b. Other
complications of the respiratory tract include laryngo­
tracheobronchitis (croup) and otitis media. Diarrhoea
can result in considerable morbidity and mortality, and
is often due to secondary infections with bacteria
or protozoa. Keratoconjunctivitis, another serious
complication of measles, was a frequent cause of
blindness before the widespread use of measles vaccine
and vitamin A supplementation.85 Measles in pregnancy
is associated with an increased risk of low birthweight,
spontaneous abortion, intrauterine fetal death, and
maternal death.86
Three rare but serious CNS complications of measles
were a major motivating factor to prevent infection
through vaccination in countries where case fatality was
low (figure 4). First, acute disseminated encephalomyelitis
(ADEM) is a demyelinating autoimmune disease that is
triggered by measles virus and occurs within days to weeks
in approximately one in 1000 cases. ADEM is characterised
by fever, seizures, and other neurological deficits.87 Second,
measles inclusion body encephalitis (MIBE) is a
progressive measles virus infection of the brain that results
in neurological deterioration and death in individuals with
impaired cellular immunity within months of the acute
illness.87 MIBE has been described in children who are
immunosuppressed following organ transplants and in
HIV-infected persons.88 Third, subacute sclerosing
panencephalitis (SSPE) is a delayed complication of
measles that occurs in about 1:10 000 to 1:100 000 cases
5–10 years after the acute illness, caused by the host
response to production of mutated virions with defective
assembly and budding.87 SSPE most often occurs in people
infected with measles virus before 2 years of age and is
characterised by seizures, progressive deterioration of
cognitive and motor function, and death.87 A recent report
of SSPE in the USA identified a much higher incidence
than previously described, including an incidence of
1:1367 cases in children who acquired measles younger
than 5 years of age and 1:609 cases in children with measles
before 1 year of age.89 Measles vaccination reduces the
incidence of SSPE.90
Measles case fatality ratios range from less than one in
1000 cases to 5% in endemic areas in sub-Saharan Africa
and Asia, to as high as 20–30% in refugees and internally
 Seminar
displaced populations.91 This variation is determined by
the average age of infection, nutritional and immunological
status of the population, measles vaccine coverage, and
access to health care.
Diagnosis
Measles is readily recognised by clinicians familiar
with the disease in people presenting with fever and
generalised rash, particularly during outbreaks or in
patients with a history of travel to endemic areas. Other
acute viral infections that might be confused with
measles include infection with rubella virus, human
herpes virus type 6, parvovirus B19, and dengue viruses.
The medical history and physical examination should
focus on the clinical features of measles as well as
potential complications, including pneumonia, otitis
media, keratoconjunctivitis, and diarrhoea. Assessment
of nutritional and immune status, most importantly
vitamin A deficiency and HIV infection, will identify
individuals at highest risk of mortality. Health-care
personnel should take appropriate measures, including
prompt isolation of infectious cases using airborne
precautions, to prevent transmission within health-care
settings.92 The clinical diagnosis of measles is more
challenging to clinicians unfamiliar with the disease,
before the onset of rash, in immunocompromised and
undernourished children in whom the rash might be
absent or altered, and in individuals with pre-existing
antibodies from maternal immunity, immune globulin,
or previous vaccination who can have a longer incubation
period, milder prodromal illness, and a less apparent
rash than typical cases.
The most common laboratory method for confirming
measles virus infection is detection of measles virus-
specific IgM antibodies in serum or plasma. However,
measles virus-specific IgM antibodies might be low or
undetectable until 4 days or more after rash onset,
resulting in false negative results if samples are collected
early.58 About 75% of people with measles will have
detectable measles virus-specific IgM antibodies within
the first 72 h after rash and almost all people with measles
will have detectable measles virus-specific IgM antibodies
after 4 days.93 Measles virus-specific IgM antibodies peak
within 1–3 weeks after the onset of rash and decline to
undetectable levels within 4–8 weeks. Acute infection
also can be confirmed serologically by measuring a four-
fold or greater increase in measles virus-specific IgG
antibody levels between acute and convalescent sera.
Commercially available enzyme immunoassays are most
often used to detect antibodies to measles virus, although
the gold standard test with the highest sensitivity is the
plaque reduction neutralisation assay.94 Individuals who
are seronegative by enzyme immunoassay might have
detectable antibodies to measles virus by neutralisation
assay. The presence of IgG antibodies to measles virus in
a single serum specimen is evidence of previous infection
or immunisation. Measles virus infection also can be
8 www.thelancet.com Published online June 30, 2016 http://dx.doi.org/10.1016/S0140-6736(17)31463-0
confirmed by detection of viral RNA through RT-PCR
using throat, nasal, nasopharyngeal, and urine samples
before measles virus-specific IgM antibodies are
detectable.
Recent advances in diagnostic technologies could
facilitate rapid outbreak detection and response. IgM and
IgG antibodies to measles virus, as well as measles virus
RNA, can be detected in oral fluid or in serum eluted
from dried blood spots. The use of oral fluid samples
might increase participation in serological surveys in
some communities, although this approach comes with
loss of sensitivity.95 Dried blood spots facilitate
uncomplicated specimen transport and storage.96 Point-
of-care diagnostic tests that detect measles virus-specific
IgM and IgG antibodies in blood and oral fluid have been
developed and validated, but are not yet widely
available.97,98
Management
The management of patients with measles consists of
supportive therapy to correct or prevent dehydration
and nutritional deficiencies, prompt recognition and
treatment of secondary bacterial infections, and provision
of vitamin A. WHO recommends administration of once
daily doses of 200 000 IU of vitamin A for 2 consecutive
days to all children with measles older than 1 year of age.99
In younger children, lower doses are recommended,
specifically 100 000 IU per day for children 6–12 months
of age and 50  000 IU per day for children younger
than 6 months.99 For children with clinical evidence of
vitamin A deficiency, a third dose is recommended
2–4 weeks later.99 Two doses of vitamin A, but not a single
dose, has been associated with a reduction in the risk of
mortality in children younger than 2 years (risk ratio 0·18
[95% CI 0·03–0·61]) and a reduction in the risk of
pneumonia-specific mortality (0·33 [0·08–0·92]).100 No
specific antiviral therapies exist for measles, although
ribavirin, interferon alfa, and other antiviral drugs have
been used to treat severe measles.101 Evidence supporting
the use of prophylactic antibiotics for children with
measles is limited and such use is not recommended,102
but antibiotics are indicated for people with measles who
have clinical evidence of bacterial infection, including
pneumonia and otitis media.
Prevention
Measles is best prevented through measles vaccination.
Currently licensed measles vaccines are attenuated viral
vaccines that replicate within the host to induce
protective immunity.99 Measles vaccines can be
administered as combined vaccines with those for
rubella (MR), mumps (MMR), or varicella (MMR-V).
Use of combined measles–rubella vaccines provides an
opportunity to eliminate rubella and congenital rubella
syndrome, and are increasingly used throughout the
world through the support of Gavi, the Vaccine Alliance.
Attenuation is achieved by passaging wildtype measles

viruses through repeated culture in non-human cells.
The first measles vaccine (Edmonston B strain) was
licensed in the USA in 1963, but caused mild measles
with fever and rash, and was administered with gamma
globulin (figure 1). Further attenuated measles vaccine
strains were licensed in the late 1960s, including the
Schwarz and Moraten vaccine viruses that are still widely
used. Two previously licensed measles vaccines were
subsequently withdrawn after they were shown to have
serious adverse effects. The first was a formalin-
inactivated measles vaccine, also licensed in the early
1960s, that led to the formation of immune complexes103
and atypical measles, including pneumonitis and a
maculopapular or petechial rash that started on the
wrists and ankles, upon exposure to wildtype virus.104
The second was a high-titre measles vaccine
recommended for use by WHO in 1989 that contained a
higher concentration of measles virus to overcome the
inhibitory effect of maternal antibodies but resulted in
unexplained delayed mortality in girls.105
WHO recommends that the first dose of measles-
containing vaccine (MCV1) be administered at 9 months
of age in settings with endemic measles but as early as
6 months of age in some circumstances, including
during outbreaks, for internally displaced populations
and refugees, for HIV-infected and exposed children,
and children at high risk of contracting measles, but
allows flexibility based on local epidemiology.99 The
proportions of children who develop protective levels of
antibody after measles vaccination are about 85% at
9 months of age and 95% at 12 months of age.106 When
measles vaccine is given to children younger than
9 months of age, a lower proportion develop protective
immunity because of the inhibitory effect of maternal
antibodies and immaturity of the immune system.107
Administering the first dose of measles vaccine at
12–15 months results in a higher proportion of protected
children, but can only be done in settings where the risk
of measles is low. Children who are infected with HIV
should be revaccinated against measles following
immune reconstitution with highly active antiretroviral
therapy because of failure to maintain protective
antibody levels.108
The high levels of population immunity necessary to
interrupt measles virus transmission cannot be achieved
with a single dose schedule. A second dose of measles
vaccine should be provided to immunise those children
who failed to respond to the first dose. MCV1 is usually
given through routine immunisation services but two
strategies have been used to administer additional doses
of measles vaccine, the first through routine
immunisation services (MCV2) and the second
through mass vaccination campaigns (sometimes
called supplemental immunisation activities [SIAs]) that
typically target children from 9 months to 5 years or
15 years of age. In countries where MCV1 is administered
at 9 months of age, MCV2 can be administered through
www.thelancet.com Published online June 30, 2016 http://dx.doi.org/10.1016/S0140-6736(17)31463-0 9
Seminar
the routine immunisation system at 15–18 months of
age with a minimum of 4 weeks between doses. In
countries with low level measles virus transmission
where MCV1 is administered at 12 months of age or
older, MCV2 can be administered at 15–18 months of age
or at school entry.
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
remaining 15% of children to raise global MCV1
coverage above 85% should be the primary goal of
measles control and elimination programmes. Among
the 20·8 million children who did not receive MCV1 in
2015, 53% lived in six countries: India, Nigeria, Pakistan,
Indonesia, Ethiopia, and the Democratic Republic of
Congo.9 An increasing number of countries provide
MCV2 through routine immunisation services but
estimated global MCV2 coverage remains suboptimal, at
only 61% in 2015.9 Measles SIAs continue to be used to
achieve high levels of population immunity and
184 million people received MCV through SIAs in 2015.9
However, SIAs are expensive and resource-intensive,
require careful planning, monitoring, and evaluation,
and coverage is often lower than planned.
Measles elimination and eradication
The World Health Assembly established three global
milestones for measles control to be achieved by 2015
(figure 2).43 The first addressed routine measles
vaccination coverage, with the goal of 90% or higher
coverage nationally and 80% or higher in every district
Panel 2: Definitions109
• Measles eradication: worldwide interruption of measles
virus transmission in the presence of a surveillance system
that has been verified to be performing well
• Measles elimination: the absence of endemic measles
virus transmission in a defined geographical area for more
than 12 months in the presence of a well performing
surveillance system
• Endemic measles transmission: the existence of
continuous transmission of indigenous or imported
measles virus that persists for more than 12 months in
any defined geographical area
• Re-establishment of endemic transmission: occurs when
epidemiological and laboratory evidence indicates the
presence of a chain of transmission of a virus strain that
continues uninterrupted for more than 12 months in a
defined geographical area where measles had previously
been eliminated
• Measles outbreak in countries with an elimination goal:
when two or more confirmed cases are temporally related
(with dates of rash onset occurring between 7 and 21 days
apart) and are epidemiologically or virologically linked,
or both
 Seminar
Panel 3: Research needs
Research will be crucial to achieving regional measles elimination goals and global
eradication. Research is needed on how best to strengthen routine immunisation services
to improve access and increase demand for vaccination; how best to increase measles
vaccine coverage and identify immunity gaps to achieve high, equitable coverage; and
how best to improve measles surveillance to rapidly identify and respond to outbreaks
and better measure progress towards elimination.
Strengthening routine immunisation services110
• Develop better methods to collect valid and timely vaccine coverage data111
• Develop strategies to address vaccine hesitancy112,113
• Build upon lessons learned from the Global Polio Eradication Initiative114
Achieving and sustaining high measles vaccine coverage
• Develop and evaluate better measles vaccines that do not require a cold chain and can
be delivered without needles, such as microneedle patches115,116
• Evaluate the optimal use of serological surveys to guide immunisation programmes117
Improve measles surveillance
• Develop more accurate and comprehensive surveillance systems to track progress
toward measles mortality reduction and elimination31
• Develop and evaluate point-of-care measles and rubella IgM antibody tests, with the
capacity to perform viral genotyping97
• Develop better analytical approaches to predicting measles outbreaks through human
mobility patterns and spatial heterogeneities in susceptibility118,119
(although this coverage level is insufficient for
elimination). The second addressed measles incidence,
with the goal of fewer than five cases per 1 million
people. And the third addressed measles deaths, with
the goal to reduce measles mortality by 95% or higher
from 2000 estimates. Subsequently, the Global Vaccine
Action Plan for 2012–20 established targets to eliminate
measles and rubella in five WHO regions by 2020 and,
as of September, 2013, all six WHO regions adopted
measles elimination goals by 2020 or earlier
(figure 1; panel 2).43 The Region of the Americas was the
first WHO region to be declared to have eliminated
measles after a rigorous verification process by the
International Expert Committee for Documenting and
Verifying Measles, Rubella, and Congenital Rubella
Syndrome in September, 2016.9 However, in view of the
slow progress, the WHO Strategic Advisory Group of
Experts on Immunization concluded that neither the
2015 global measles milestones nor the measles
elimination goals were achieved.108 Identifying,
prioritising, funding, and answering critical research
questions will be necessary to achieve these goals
(panel 3).
Countries or regions that have eliminated measles are
at continual risk of imported measles as long as measles
virus is circulating in other parts of the world, a risk that
is increased by global travel. Outbreaks result in high
costs related to case-based investigations, outbreak
responses, and provision of health care.120 This risk will
only be mitigated if measles is eradicated. Measles virus
10 www.thelancet.com Published online June 30, 2016 http://dx.doi.org/10.1016/S0140-6736(17)31463-0
meets many of the biological criteria for disease
eradication, including the absence of a non-human
reservoir, accurate diagnosis, and the availability of a
highly effective vaccine.5
The future of measles
Great progress has been made in reducing measles
incidence, morbidity, and mortality through the
widespread use of measles vaccines (figure 2). Mortality
has been reduced from more than 2 million deaths year
before the widespread use of measles vaccines to slightly
more than 100 000 in 2015. Global measles vaccine
coverage is high and more countries are introducing
a second dose of measles vaccine through routine
immunisation services. With the support of Gavi, many
countries are introducing combined measles–rubella
vaccines, providing the opportunity to eliminate rubella
and congenital rubella syndrome. New technologies,
such as microneedle patches, could revolutionise
measles vaccination strategies. Yet all is not well. MCV1
coverage has stagnated at about 85% for almost a decade.
Anti-vaccine sentiments are increasingly voiced, in part
because of successful measles control. Estimates of
measles incidence, deaths, and vaccine coverage are
often based on poor quality data, hindering the ability to
track progress and target interventions. The Measles and
Rubella Global Strategic Plan 2012–2020 Mid-Term
Review identified deficiencies in implementing current
strategies, largely because of inadequate country
ownership, global political will, and resources.121 Urgent
efforts are needed to improve measles surveillance and
vaccine coverage estimates and increase global coverage
with two doses of measles vaccine through advocacy,
education, and the strengthening of routine
immunisation systems. Building on the polio legacy, the
political will and financial resources must be garnered to
achieve the regional elimination goals and eventual
global measles eradication.
Declaration of interests
WJM is a member of WHO’s Strategic Advisory Group of Experts on
Immunization Working Group on Measles and Rubella. However, the
views expressed in this Seminar reflect those of the author and are not
necessarily those of WHO or the Strategic Advisory Group of Experts on
Immunization Working Group on Measles and Rubella.
Acknowledgments
The author is grateful to the anonymous reviewers for their thoughtful
comments and suggestions.
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