Seminar
Measles
Lancet 2017; 390: 2490–502
Published Online
June 30, 2017
http://dx.doi.org/10.1016/
S0140-6736(17)31463-0
Department of Epidemiology
(Prof W J Moss MD),
Department of International
Health (Prof W J Moss),
W Harry Feinstone Department
of Molecular Microbiology and
Immunology (Prof W J Moss),
and International Vaccine
Access Center (Prof W J Moss),
Bloomberg School of Public
Health, Johns Hopkins
University, Baltimore, MD, USA
Correspondence to:
Prof William J Moss, Department
of Epidemiology, Bloomberg
School of Public Health,
Johns Hopkins University,
Baltimore, MD 21205, USA
wmoss1@jhu.edu
2490 www.thelancet.com Vol 390 December 2, 2017
William J Moss
Measles is a highly contagious disease that results from infection with measles virus and is still responsible for more
than 100 000 deaths every year, down from more than 2 million deaths annually before the introduction and
widespread use of measles vaccine. Measles virus is transmitted by the respiratory route and illness begins with fever,
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
patients with measles includes provision of vitamin A. Measles is best prevented through vaccination, and the major
reductions in measles incidence and mortality have renewed interest in regional elimination and global eradication.
However, urgent efforts are needed to increase stagnating global coverage with two doses of measles vaccine through
advocacy, education, and the strengthening of routine immunisation systems. Use of combined measles-rubella
vaccines provides an opportunity to eliminate rubella and congenital rubella syndrome. Ongoing research efforts,
including the development of point-of-care diagnostics and microneedle patches, will facilitate progress towards
measles elimination and eradication.
Introduction 100 000 deaths each year, and serves as an indicator of the
Measles is a highly contagious, acute febrile illness that quality of immunisation programmes. The reduction in
results from infection with measles virus. Measles virus measles incidence and mortality, along with progress
is most closely related genetically to rinderpest virus, a toward achieving polio eradication, have renewed interest
pathogen of cattle that was declared eradicated by the in measles regional elimination and global eradication.4
World Organization for Animal Health in May, 2011, and However, increased political will, public support, and
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
 Seminar

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

www.thelancet.com Vol 390 December 2, 2017 2491

 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

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

0·1 0
06

08
09

06

08
09
04

04
00

00
02
03

05

02
03

05
14
07

14
07
01

10

01

10
12
13

15

12
13

15
11

11
20

20
20
20

20

20
20

20
20

20

20

20
20

20

20

20
20
20

20

20
20

20
20

20
20

20
20

20
20

20

20
20

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

2492 www.thelancet.com Vol 390 December 2, 2017

 Seminar

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

80

82

84

86

88

90

92

94

96

98

06

08
00

02

04

10

12

14
20
20

20
20
19

19

20

20
19

19

20

20
19

19
19

19

19

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
patterns facilitating transmission (eg, congregation of
children at school) and environmental factors favouring
the viability and transmission of measles virus.26 Measles
outbreaks in the tropics have more variable seasonal
patterns and, in regions with high birth rates, highly
irregular, large measles outbreaks can occur.27
Passively acquired, maternal anti-measles virus IgG
antibodies protect young infants against measles in the
first months of life but can also interfere with vaccine
responses by neutralising vaccine virus.28 Because
antibody levels are generally higher in women with
naturally acquired immunity, infants born to women
with vaccine-induced immunity become susceptible to
measles at a younger age than those born to women with
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
19
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.
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
cells,36 and nectin-4, a component of epithelial cell
adherens junctions.37 The distribution of these receptors

www.thelancet.com Vol 390 December 2, 2017 2493

 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.

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

2494 www.thelancet.com Vol 390 December 2, 2017


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
Measles virus RNA remained detectable in lymphoid
tissue after it was no longer detectable in blood.55
www.thelancet.com Vol 390 December 2, 2017 2495
Seminar
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
 Seminar
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
Complications of measles can affect most organ
systems and are most common in young infants, adults
2496 www.thelancet.com Vol 390 December 2, 2017
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
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
confirmed by detection of viral RNA through RT-PCR
www.thelancet.com Vol 390 December 2, 2017 2497
Seminar
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 ad­
ministered 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.
 Seminar
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
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
2498 www.thelancet.com Vol 390 December 2, 2017
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 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 (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
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
www.thelancet.com Vol 390 December 2, 2017 2499
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
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.
References
1 Nambulli S, Sharp CR, Acciardo AS, Drexler JF, Duprex WP.
Mapping the evolutionary trajectories of morbilliviruses: what,
where and whither. Curr Opin Virol 2016; 16: 95–105.
2 Black FL. Measles endemicity in insular populations: critical
community size and its evolutionary implication. J Theor Biol 1966;
11: 207–11.
3 Keeling MJ, Grenfell BT. Disease extinction and community size:
modeling the persistence of measles. Science 1997; 275: 65–67.
4 Meeting of the International Task Force for Disease Eradication,
November 2015. Weekly Epidemiol Rec 2016; 91: 61–71.
5 Moss WJ, Strebel P. Biological feasibility of measles eradication.
J Infect Dis 2011; 204: S47–53.
6 Moss WJ, Griffin DE. Measles. Lancet 2012; 379: 153–64.
7 Shanks GD, Waller M, Briem H, Gottfredsson M. Age-specific
measles mortality during the late 19th-early 20th centuries.
Epidemiol Infect 2015; 143: 3434–41.
8 Mulders MN, Rota PA, Icenogle JP, et al. Global Measles and
Rubella Laboratory Network Support for Elimination Goals,
2010–2015. MMWR Morb Mortal Wkly Rep 2016; 65: 438–42.
 Seminar
9 Patel MK, Gacic-Dobo M, Strebel PM, et al. Progress toward
regional measles elimination—worldwide, 2000–2015.
MMWR Morb Mortal Wkly Rep 2016; 65: 1228–33.
10 Simons E, Ferrari M, Fricks J, et al. Assessment of the 2010 global
measles mortality reduction goal: results from a model of
surveillance data. Lancet 2012; 379: 2173–78.
11 Liu L, Oza S, Hogan D, et al. Global, regional, and national causes
of child mortality in 2000–13, with projections to inform post-2015
priorities: an updated systematic analysis. Lancet 2015; 385: 430–40.
12 McLean AR, Anderson RM. Measles in developing countries.
Part I. Epidemiological parameters and patterns. Epidemiol Infect
1988; 100: 111–33.
13 McLean AR, Anderson RM. Measles in developing countries.
Part II. The predicted impact of mass vaccination. Epidemiol Infect
1988; 100: 419–42.
14 Ferrari MJ, Grenfell BT, Strebel PM. Think globally, act locally:
the role of local demographics and vaccination coverage in the
dynamic response of measles infection to control.
Phill Trans Royal Soc London B 2013; 368: 20120141.
15 Remington PL, Hall WN, Davis IH, Herald A, Gunn RA.
Airborne transmission of measles in a physician’s office. JAMA
1985; 253: 1574–77.
16 Hope K, Boyd R, Conaty S, Maywood P. Measles transmission in
health care waiting rooms: implications for public health
response. West Pacific Surv Resp J 2012; 3: 33–38.
17 Sartwell PE. The incubation period and the dynamics of infectious
disease. Am J Epidemiol 1966; 83: 204–06.
18 Lessler J, Reich NG, Brookmeyer R, Perl TM, Nelson KE,
Cummings DA. Incubation periods of acute respiratory viral
infections: a systematic review. Lancet Infect Dis 2009; 9: 291–300.
19 Fitzgerald TL, Durrheim DN, Merritt TD, Birch C, Tran T.
Measles with a possible 23 day incubation period.
Commun Dis Intel Quart Report 2012; 36: E277–80.
20 Riddell MA, Moss WJ, Hauer D, Monze M, Griffin DE.
Slow clearance of measles virus RNA after acute infection.
J Clin Virol 2007; 39: 312–17.
21 Fill MM, Sweat D, Morrow H, et al. Notes from the field: measles
outbreak of unknown source - Shelby County, Tennessee,
April–May 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 1039–40.
22 Dietz K. The estimation of the basic reproduction number for
infectious diseases. Stat Method Med Res 1993; 2: 23–41.
23 Anderson R MR. Infectious Diseases of Humans. Oxford:
Oxford University Press, 1991.
24 Wallinga J, Heijne JC, Kretzschmar M. A measles epidemic
threshold in a highly vaccinated population. PLoS Med 2005;
2: e316.
25 Jones-Engel L, Engel GA, Schillaci MA, et al.
Considering human-primate transmission of measles virus
through the prism of risk analysis. Am J Primatol 2006; 68: 868–79.
26 Fine PE, Clarkson JA. Measles in England and Wales—I:
An analysis of factors underlying seasonal patterns. Int J Epidemiol
1982; 11: 5–14.
27 Ferrari MJ, Grais RF, Bharti N, et al. The dynamics of measles in
sub-Saharan Africa. Nature 2008; 451: 679–84.
28 Albrecht P, Ennis FA, Saltzman EJ, Krugman S. Persistence of
maternal antibody in infants beyond 12 months: mechanism of
measles vaccine failure. J Pediatr 1977; 91: 715–18.
29 Leuridan E, Hens N, Hutse V, Ieven M, Aerts M, Van Damme P.
Early waning of maternal measles antibodies in era of measles
elimination: longitudinal study. BMJ 2010; 340: 1626.
30 Waaijenborg S, Hahne SJ, Mollema L, et al. Waning of maternal
antibodies against measles, mumps, rubella, and varicella in
communities with contrasting vaccination coverage. J Infect Dis
2013; 208: 10–16.
31 Durrheim DN, Crowcroft NS, Strebel PM. Measles—the epidemiology
of elimination. Vaccine 2014; 32: 6880–83.
32 Sugerman DE, Barskey AE, Delea MG, et al. Measles outbreak in a
highly vaccinated population, San Diego, 2008: role of the
intentionally undervaccinated. Pediatrics 2010; 125: 747–55.
33 Phadke VK, Bednarczyk RA, Salmon DA, Omer SB.
Association between vaccine refusal and vaccine-preventable
diseases in the United States: A review of measles and pertussis.
JAMA 2016; 315: 1149–58.
2500 www.thelancet.com Vol 390 December 2, 2017
34 De Serres G, Boulianne N, Defay F, et al. Higher risk of measles
when the first dose of a 2-dose schedule of measles vaccine is given
at 12-14 months versus 15 months of age. Clin Infect Dis 2012;
55: 394–402.
35 Defay F, De Serres G, Skowronski DM, et al. Measles in children
vaccinated with 2 doses of MMR. Pediatrics 2013; 132: e1126–33.
36 Tatsuo H, Ono N, Tanaka K, Yanagi Y. SLAM (CDw150) is a cellular
receptor for measles virus. Nature 2000; 406: 893–97.
37 Muhlebach MD, Mateo M, Sinn PL, et al. Adherens junction protein
nectin-4 is the epithelial receptor for measles virus. Nature 2011;
480: 530–53.
38 Tahara M, Ohno S, Sakai K, et al. The receptor-binding site of the
measles virus hemagglutinin protein itself constitutes a conserved
neutralizing epitope. J Virol 2013; 87: 3583–86.
39 Plattet P, Alves L, Herren M, Aguilar HC. Measles virus fusion
protein: structure, function and inhibition. Viruses 2016; 8: 112.
40 WHO. Measles virus nomenclature update: 2012.
Wkly Epidemiol Rec 2012; 87: 73–81.
41 Mulders MN, Truong AT, Muller CP. Monitoring of measles
elimination using molecular epidemiology. Vaccine 2001; 19: 2245–49.
42 Moss WJ, Scott S, Ndhlovu Z, et al. Suppression of human
immunodeficiency virus type 1 viral load during acute measles.
Pediatr Infect Dis J 2009; 28: 63–65.
43 Perry RT, Murray JS, Gacic-Dobo M, et al. Progress toward regional
measles elimination—worldwide, 2000–2014.
MMWR Morb Mortal Wkly Rep 2015; 64: 1246–51.
44 Penedos AR, Myers R, Hadef B, Aladin F, Brown KE.
Assessment of the utility of whole genome sequencing of measles
virus in the characterisation of outbreaks. PLoS One 2015;
10: e0143081.
45 Gardy JL, Naus M, Amlani A, et al. Whole-genome sequencing of
measles virus genotypes H1 and D8 during outbreaks of infection
following the 2010 Olympic Winter Games reveals viral
transmission routes. J Infect Dis 2015; 212: 1574–78.
46 Beaty SM, Lee B. Constraints on the genetic and antigenic
variability of measles virus. Viruses 2016; 8: 109.
47 Enders JF, Peebles TC. Propagation in tissue cultures of
cytopathogenic agents from patients with measles.
Proc Soc Exp Biol Med 1954; 86: 277–86.
48 Fulton BO, Sachs D, Beaty SM, et al. Mutational analysis of measles
virus suggests constraints on antigenic variation of the
glycoproteins. Cell Reports 2015; 11: 1331–38.
49 de Swart RL, Ludlow M, de Witte L, et al. Predominant infection of
CD150+ lymphocytes and dendritic cells during measles virus
infection of macaques. PLoS Pathog 2007; 3: e178.
50 Ludlow M, de Vries RD, Lemon K, et al. Infection of lymphoid tissues
in the macaque upper respiratory tract contributes to the emergence
of transmissible measles virus. J Gen Virol 2013; 94: 1933–44.
51 Singh BK, Li N, Mark AC, Mateo M, Cattaneo R, Sinn PL.
Cell-to-cell contact and nectin-4 govern spread of measles virus
from primary human myeloid cells to primary human airway
epithelial cells. J Virol 2016; 90: 6808–17.
52 Ludlow M, McQuaid S, Milner D, de Swart RL, Duprex WP.
Pathological consequences of systemic measles virus infection.
J Pathol 2015; 235: 253–65.
53 Leonard VH, Sinn PL, Hodge G, et al. Measles virus blind to its
epithelial cell receptor remains virulent in rhesus monkeys but
cannot cross the airway epithelium and is not shed. J Clin Invest
2008; 118: 2448–58.
54 de Vries RD, Mesman AW, Geijtenbeek TB, Duprex WP, de Swart RL.
The pathogenesis of measles. Curr Opin Virol 2012; 2: 248–55.
55 Lin WH, Kouyos RD, Adams RJ, Grenfell BT, Griffin DE.
Prolonged persistence of measles virus RNA is characteristic of
primary infection dynamics. Proc Natl Acad Sci USA 2012;
109: 14989–94.
56 Kimura A, Tosaka K, Nakao T. Measles rash. I. Light and electron
microscopic study of skin eruptions. Arch Virol 1975; 47: 295–307.
57 Nakatsu Y, Takeda M, Ohno S, Shirogane Y, Iwasaki M, Yanagi Y.
Measles virus circumvents the host interferon response by different
actions of the C and V proteins. J Virol 2008; 82: 8296–306.
58 Bellini WJ, Helfand RF. The challenges and strategies for laboratory
diagnosis of measles in an international setting. J Infect Dis 2003;
187: S283–90.

59 Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure
passive immunisation for preventing measles.
Cochrane Database Syst Rev 2014: 4: Cd010056.
60 Good RA, Zak SJ. Disturbances in gamma globulin synthesis as
experiments of nature. Pediatrics 1956; 18: 109–49.
61 Permar SR, Klumpp SA, Mansfield KG, et al. Role of CD8(+)
lymphocytes in control and clearance of measles virus infection of
rhesus monkeys. J Virol 2003; 77: 4396–400.
62 Permar SR, Klumpp SA, Mansfield KG, et al. Limited contribution
of humoral immunity to the clearance of measles viremia in rhesus
monkeys. J Infect Dis 2004; 190: 998–1005.
63 Griffin DE, Ward BJ, Jauregui E, Johnson RT, Vaisberg A.
Immune activation during measles: interferon-gamma and
neopterin in plasma and cerebrospinal fluid in complicated and
uncomplicated disease. J Infect Dis 1990; 161: 449–53.
64 Moss WJ, Ryon JJ, Monze M, Griffin DE. Differential regulation of
interleukin (IL)-4, IL-5, and IL-10 during measles in Zambian
children. J Infect Dis 2002; 186: 879–87.
65 von Pirquet C. Das Verhalten der kutanen Tuberkulin-reaktion
während der Masern. Dtsch Med Wochenschr 1908; 34: 1297–300.
66 Griffin DE. Measles virus-induced suppression of immune
responses. Immunol Rev 2010; 236: 176–89.
67 Ryon JJ, Moss WJ, Monze M, Griffin DE. Functional and
phenotypic changes in circulating lymphocytes from hospitalized
Zambian children with measles. Clin Diagn Lab Immunol 2002;
9: 994–1003.
68 de Vries RD, McQuaid S, van Amerongen G, et al. Measles immune
suppression: lessons from the macaque model. PLoS Pathog 2012;
8: e1002885.
69 Abt M, Gassert E, Schneider-Schaulies S. Measles virus modulates
chemokine release and chemotactic responses of dendritic cells.
J Gen Virol 2009; 90: 909–14.
70 de Vries RD, de Swart RL. Measles immune suppression:
functional impairment or numbers game? PLoS Pathog 2014;
10: e1004482.
71 Tamashiro VG, Perez HH, Griffin DE. Prospective study of the
magnitude and duration of changes in tuberculin reactivity during
uncomplicated and complicated measles. Pediatr Infect Dis J 1987;
6: 451–54.
72 Akramuzzaman SM, Cutts FT, Wheeler JG, Hossain MJ.
Increased childhood morbidity after measles is short-term in urban
Bangladesh. Am J Epidemiol 2000; 151: 723–35.
73 Mina MJ, Metcalf CJ, de Swart RL, Osterhaus AD, Grenfell BT.
Long-term measles-induced immunomodulation increases overall
childhood infectious disease mortality. Science 2015; 348: 694–99.
74 Aaby P. Assumptions and contradictions in measles and measles
immunization research: is measles good for something?
Soc Sci Med 1995; 41: 673–86.
75 Do VA, Biering-Sorensen S, Fisker AB, et al. Effect of an early dose
of measles vaccine on morbidity between 18 weeks and 9 months
of age: a randomized, controlled trial in Guinea-Bissau. J Infect Dis
2017; published online Jan 10. DOI:10.1093/infdis/jiw512.
76 Higgins JP, Soares-Weiser K, Lopez-Lopez JA, et al. Association of
BCG, DTP, and measles containing vaccines with childhood
mortality: systematic review. BMJ 2016; 355: i5170.
77 Kandasamy R, Voysey M, McQuaid F, et al. Non-specific
immunological effects of selected routine childhood
immunisations: systematic review. BMJ 2016; 355: i5225.
78 Choe YJ, Hu JK, Song KM, et al. Evaluation of an expanded case
definition for vaccine-modified measles in a school outbreak in
South Korea in 2010. Jpn J Infect Dis 2012; 65: 371–75.
79 Morley D. Severe measles in the tropics. I. BMJ 1969; 1: 297–300.
80 Moss WJ, Cutts F, Griffin DE. Implications of the human
immunodeficiency virus epidemic for control and eradication of
measles. Clin Infect Dis 1999; 29: 106–12.
81 Hutchins SS, Papania MJ, Amler R, et al. Evaluation of the measles
clinical case definition. J Infect Dis 2004; 189: S153–59.
82 Stevens GA, Bennett JE, Hennocq Q, et al. Trends and mortality
effects of vitamin A deficiency in children in 138 low-income and
middle-income countries between 1991 and 2013: a pooled analysis
of population-based surveys. Lancet Glob Health 2015; 3: e528–36.
83 Perry RT, Halsey NA. The clinical significance of measles: a review.
J Infect Dis 2004; 189: S4–16.
www.thelancet.com Vol 390 December 2, 2017 2501
Seminar
84 Enders JF, Mc CK, Mitus A, Cheatham WJ. Isolation of measles
virus at autopsy in cases of giant-cell pneumonia without rash.
N Engl J Med 1959; 261: 875–81.
85 Foster A, Sommer A. Childhood blindness from corneal ulceration
in Africa: causes, prevention, and treatment.
Bull World Health Organ 1986; 64: 619–23.
86 Ogbuanu IU, Zeko S, Chu SY, et al. Maternal, fetal, and neonatal
outcomes associated with measles during pregnancy: Namibia,
2009–2010. Clin Infect Dis 2014; 58: 1086–92.
87 Griffin DE. Measles virus and the nervous system. Handb Clin Neurol
2014; 123: 577–90.
88 Hardie DR, Albertyn C, Heckmann JM, Smuts HE.
Molecular characterisation of virus in the brains of patients with
measles inclusion body encephalitis (MIBE). Virol J 2013; 10: 283.
89 Wendorf KA, Winter, K, Zipprich J, et al. Subacute sclerosing
panencephalitis: the devastating measles complication is more
common than we think. Clin Infect Dis 2017; published online
April 6. DOI:10.1093/cid/cix302.
90 Campbell H, Andrews N, Brown KE, Miller E. Review of the effect
of measles vaccination on the epidemiology of SSPE. Int J Epidemiol
2007; 36: 1334–48.
91 Wolfson LJ, Grais RF, Luquero FJ, Birmingham ME, Strebel PM.
Estimates of measles case fatality ratios: a comprehensive review of
community-based studies. Int J Epidemiol 2009; 38: 192–205.
92 Maltezou HC, Wicker S. Measles in health-care settings.
Am J Infect Cont 2013; 41: 661–63.
93 Helfand RF, Heath JL, Anderson LJ, Maes EF, Guris D, Bellini WJ.
Diagnosis of measles with an IgM capture EIA: the optimal timing of
specimen collection after rash onset. J Infect Dis 1997; 175: 195–99.
94 Cohen BJ, Doblas D, Andrews N. Comparison of plaque reduction
neutralisation test (PRNT) and measles virus-specific IgG ELISA for
assessing immunogenicity of measles vaccination. Vaccine 2008;
26: 6392–97.
95 Hayford KT, Al-Emran HM, Moss WJ, Shomik MS, Bishai D,
Levine OS. Validation of an anti-measles virus-specific IgG assay
with oral fluid samples for immunization surveillance in
Bangladesh. J Virol Meth 2013; 193: 512–18.
96 Uzicanin A, Lubega I, Nanuynja M, et al. Dried blood spots on filter
paper as an alternative specimen for measles diagnostics: detection
of measles immunoglobulin M antibody by a commercial enzyme
immunoassay. J Infect Dis 2011; 204: S564–69.
97 Warrener L, Slibinskas R, Chua KB, et al. A point-of-care test for
measles diagnosis: detection of measles-specific IgM antibodies and
viral nucleic acid. Bull World Health Organ 2011; 89: 675–82.
98 Shonhai A, Warrener L, Mangwanya D, et al. Investigation of a
measles outbreak in Zimbabwe, 2010: potential of a point of care
test to replace laboratory confirmation of suspected cases.
Epidemiol Infect 2015; 143: 3442–50.
99 WHO. Measles vaccines: WHO position paper—April 2017. Wkly
Epidemiol Rec 2017; 92: 205–27.
100 Huiming Y, Chaomin W, Meng M. Vitamin A for treating measles
in children. Cochrane Database Syst Rev 2005; 4: Cd001479.
101 Barnard DL. Inhibitors of measles virus. Antiv Chem Chemother
2004; 15: 111–19.
102 Kabra SK, Lodha R. Antibiotics for preventing complications in
children with measles. Cochrane Database Syst Rev 2013;
8: Cd001477.
103 Polack FP, Hoffman SJ, Crujeiras G, Griffin DE. A role for
nonprotective complement-fixing antibodies with low avidity for
measles virus in atypical measles. Nat Med 2003; 9: 1209–13.
104 Fulginiti VA, Eller JJ, Downie AW, Kempe CH. Altered reactivity
to measles virus. Atypical measles in children previously
immunized with inactivated measles virus vaccines. JAMA 1967;
202: 1075–80.
105 WHO. Expanded programme on immunization (EPI). Safety of
high titre measles vaccines. Wkly Epidemiol Rev 1992; 67: 357–61.
106 Moss WJ, Scott S. The immunological basis for immunization
serie. Module 7: Measles—Update 2009. Geneva: World Health
Organization, 2009.
107 Gans HA, Arvin AM, Galinus J, Logan L, DeHovitz R,
Maldonado Y. Deficiency of the humoral immune response to
measles vaccine in infants immunized at age 6 months. JAMA
1998; 280: 527–32.
 Seminar
108 WHO. Meeting of the Strategic Advisory Group of Experts on
immunization, October 2016—conclusions and recommendations.
Wkly Epidemiol Rec 2016; 91: 561–68.
109 WHO. Framework for verifying elimination of measles and rubella.
Wkly Epidemiol Rev 2013; 88: 89–99.
110 Orenstein WA, Seib K. Beyond vertical and horizontal programs:
a diagonal approach to building national immunization programs
through measles elimination. Expert Rev Vaccine 2016; 15: 791–93.
111 Cutts FT, Izurieta HS, Rhoda DA. Measuring coverage in MNCH:
design, implementation, and interpretation challenges associated
with tracking vaccination coverage using household surveys.
PLoS Med 2013; 10: e1001404.
112 Schuster M, Eskola J, Duclos P. Review of vaccine hesitancy:
Rationale, remit and methods. Vaccine 2015; 33: 4157–60.
113 Jarrett C, Wilson R, O’Leary M, Eckersberger E, Larson HJ.
Strategies for addressing vaccine hesitancy—a systematic review.
Vaccine 2015; 33: 4180–90.
114 Cochi SL, Freeman A, Guirguis S, Jafari H, Aylward B. Global polio
eradication initiative: lessons learned and legacy. J Infect Dis 2014;
210: S540–46.
2502 www.thelancet.com Vol 390 December 2, 2017
115 Edens C, Collins ML, Ayers J, Rota PA, Prausnitz MR.
Measles vaccination using a microneedle patch. Vaccine 2013;
31: 3403–09.
116 Edens C, Collins ML, Goodson JL, Rota PA, Prausnitz MR.
A microneedle patch containing measles vaccine is immunogenic
in non-human primates. Vaccine 2015; 33: 4712–18.
117 Metcalf CJ, Farrar J, Cutts FT, et al. Use of serological surveys to
generate key insights into the changing global landscape of
infectious disease. Lancet 2016; 388: 728–30
118 Bogoch, II, Brady OJ, Kraemer MU, et al. Anticipating the
international spread of Zika virus from Brazil. Lancet 2016;
387: 335–36.
119 Takahashi S, Metcalf CJ, Ferrari MJ, et al. Reduced vaccination and
the risk of measles and other childhood infections post-Ebola.
Science 2015; 347: 1240–42.
120 Ortega-Sanchez IR, Vijayaraghavan M, Barskey AE, Wallace GS.
The economic burden of sixteen measles outbreaks on United States
public health departments in 2011. Vaccine 2014; 32: 1311–17.
121 Orenstein WA HA, Nkowane B, Olive JM, Reingold A. Measles and
Rubella Global Strategic Plan 2012–2020. Mid-term review, 2016.