Seminar

Measles
William J Moss, Diane E Grin

Measles is a highly contagious disease caused by measles virus and is one of the most devastating infectious diseases of manmeasles was responsible for millions of deaths annually worldwide before the introduction of the measles vaccines. Remarkable progress in reducing the number of people dying from measles has been made through measles vaccination, with an estimated 164 000 deaths attributed to measles in 2008. This achievement attests to the enormous importance of measles vaccination to public health. However, this progress is threatened by failure to maintain high levels of measles vaccine coverage. Recent measles outbreaks in sub-Saharan Africa, Europe, and the USA show the ease with which measles virus can re-enter communities if high levels of population immunity are not sustained. The major challenges for continued measles control and eventual eradication will be logistical, nancial, and the garnering of sucient political will. These challenges need to be met to ensure that future generations of children do not die of measles.

Lancet 2012; 379: 15364 Published Online August 18, 2011 DOI:10.1016/S01406736(10)62352-5 Department of Epidemiology (W J Moss MD) and W Harry Feinstone Department of Molecular Microbiology and Immunology (WJ Moss, D E Grin MD), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA Correspondence to: Dr William J Moss, Departments of Epidemiology, International Health, and W Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD, USA wmoss@jhsph.edu

Introduction
Measles is a highly contagious disease caused by measles virus. Measles is one of the most devastating infectious diseases of man and caused millions of deaths worldwide each year before the introduction of measles vaccines. Measles virus most closely resembles rinderpest virusa recently eradicated pathogen of cattleand probably evolved from an ancestral virus as a zoonotic infection in communities in which cattle and human beings lived in close proximity. Measles virus is believed to have become established in human beings about 500010 000 years ago, when populations achieved sucient size in Middle Eastern river valley civilisations to maintain virus transmission;1 however, phylogenetic analysis suggests a more recent divergence from rinderpest virus in the 11th or 12th century.2 Attenuated and killed measles vaccines were introduced in the 1960s after successful isolation and growth of measles virus in tissue culture by John Enders3 and further attenuation by Maurice Hilleman. Present eorts to control and eliminate measles aim to achieve and sustain high levels of population immunity through measles vaccination to reduce measles mortality and interrupt virus transmission. In light of recent discussions of potential measles eradication and ongoing measles outbreaks in Europe and Africa, we review the epidemiology, pathophysiology, clinical features, management, and prevention of measles and consider the prospects for measles eradication.

born to women with vaccine-induced immunity become susceptible to measles at a younger age than those born to women with naturally acquired immunity.6 The average age at which people contract measles depends on the rate of decline of protective maternal antibodies, the amount of contact with infected people, and the level of measles vaccine coverage. In densely populated urban settings with low vaccination coverage, measles mainly aects infants and young children. As measles vaccine coverage increases, or population density decreases, the age distribution shifts towards older children. As vaccination coverage, and thus population immunity, increases further, the age distribution of cases might shift into adolescence and adulthood. Evidence suggests that measles mortality might be higher in girls than boys. Among people of dierent ages and across dierent regions (primarily in the Americas and Europe), measles mortality in girls was estimated to be 5% higher than in boys.7 Although older historical data and surveillance data from the USA did not identify similar sex dierences,8 if true, the higher mortality in girls contrasts with most other infectious diseases, in which disease severity and mortality is higher in males.9 Supporting the hypothesis of sex dierences in immune responses to measles virus was the nding that girls and not boys were at risk of delayed mortality after receipt of high-titre measles vaccine,10 which led to discontinuation of this vaccine.

Search strategy and selection criteria

Epidemiology and disease burden

Measles virus is one of the most highly contagious, directly transmitted pathogens, and outbreaks can occur in populations in which fewer than 10% of people are susceptible.4 No latent or persistent measles virus infections result in prolonged contagiousness and there are no animal reservoirs that maintain virus transmissionfeatures that make eradication possible. Measles virus can only be maintained in human populations by an unbroken chain of acute infections. Infants become susceptible to measles virus infection when passively acquired maternal antibody is lost.5 Infants
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We searched PubMed from 1999, to May 2010, for publications in English using the terms measles, measles and epidemiology, measles and pathophysiology, measles and diagnosis, measles and therapy, and measles and prevention. Our search focused on, but was not restricted to, publications in the past 5 years. We also searched the Cochrane Database of Systematic Reviews with the term measles and checked through our own database of references as well as those of linked articles in the searched journals. When more than one article showed a specic point, the most representative article was chosen.

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1 000 000

Estimates Projected worst case Projected status quo

800 000

600 000

400 000

200 000

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Year

Figure 1: Estimated number of measles deaths worldwide 200008 and projections of possible resurgence of measles deaths worldwide, 200913 Lines=uncertainty bounds based on Monte Carlo stimulations that account for uncertainty in key input variables (ie, vaccination coverage and case fatality ratios). Reproduced from reference 15 with permission from WHO.

Panel 1: Denitions of measles transmission and elimination terms Measles eradication Worldwide interruption of measles virus transmission in the presence of a surveillance system that has been veried to be performing well. Measles elimination The absence of endemic measles transmission in a dened 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 dened 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 dened geographical area where measles had previously been eliminated. Measles outbreak in countries with an elimination goal When two or more conrmed cases are temporally related (with dates of rash onset occurring between 7 and 21 days apart) and are epidemiologically or virologically linked, or both.
Reproduced from reference 17 with permission from WHO.

When endemic, measles incidence has a typical temporal pattern characterised by yearly seasonal epidemics superimposed on longer epidemic cycles of 25 years. These cycles result from the accumulation of
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susceptible people over successive birth cohorts and the subsequent decline in the number of susceptible people after an outbreak. In temperate climates, yearly measles outbreaks typically occur in the late winter and early spring. These seasonal outbreaks result in part from facilitation of transmission through social networks (eg, congregation of children at school)11 and environmental factors that favour the viability and transmission of measles virus. In the tropics, measles outbreaks have variable associations with rainy seasons, which, combined with high birth rates, result in highly irregular, large measles outbreaks.12 In 2003, the World Health Assembly endorsed a resolution that urged member countries to reduce the number of deaths attributed to measles by 50% compared with 1999 estimates by the end of 2005.13 This global public health target was met, with estimated measles mortality reduced by 60% from an estimated 873 000 deaths in 1999 (uncertainty bounds 634 0001 140 000) to 345 000 deaths in 2005 (247 000458 000).14 Further reductions in global measles mortality were achieved by 2008, during which there were an estimated 164 000 deaths attributable to measles (uncertainty bounds 115 000222 000; gure 1).15 These achievements attest to the enormous public-health signicance of measles vaccination. The revised global goal, as stated in the Global Immunization Vision and Strategy 20062015 by WHO and the United Nations Childrens Fund,16 is to reduce global measles deaths by 90% by 2015 compared with the estimated 733 000 deaths in 2000 (uncertainty bounds 530 000959 000). One challenge to documenting this achievement is the validity of the natural history model used to derive global measles mortality estimates. Modelled mortality estimates are mostly calculated by the estimated size of the birth cohort, measles vaccination coverage, and the case fatality ratio,15 and probably become increasingly inaccurate as measles mortality decreases. Comprehensive surveillance for measles incidence, mortality, and vaccine coverage will be needed to obtain valid estimates and to document progress in achieving measles mortality reduction and elimination goals.17 Panel 1 denes measles transmission and elimination terms. The WHO region of the Americas has eliminated measles and four of the ve remaining WHO regions have set measles elimination targets of 2020 or earlier (southeast Asia being the exception). In the Americas, intensive vaccination and surveillance eorts interrupted endemic measles virus transmission.18 More recently, progress in reducing measles incidence and mortality was made in sub-Saharan Africa as a consequence of increased routine measles vaccine coverage and provision of a second dose of measles vaccine through mass measles vaccination campaigns (called supplementary immunisation activities).19 This progress led to the proposal to eliminate measles in the WHO African region by 2020.20 However, measles remains a public-health problem in
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Europe, which did not meet its goal of regional measles elimination by 2010.21 Measles outbreaks are occurring throughout Europe.22 During the rst 19 weeks of 2011, 118 cases of measles were reported in the USAthe highest number reported for this period since 1996.23 Even if achieved, numerous outbreaks highlight the challenges of sustaining measles elimination. Despite very high levels of measles vaccine coverage and population immunity, clustering of susceptible people can lead to measles outbreaks.24 An outbreak of 94 measles cases in Quebec, Canada, in 2007 resulted in transmission within several unrelated networks of unvaccinated people, despite an estimated population immunity of 95%.25 Of great concern are recent large measles outbreaks in countries of southern and eastern Africa, including South Africa, Zimbabwe, Zambia, and Malawi (gure 2),26 which shows the ease with which measles virus can re-enter communities and cause large outbreaks if high levels of population immunity are not sustained. In 2009, 36 000 cases of measles were reported from 46 countries in Africa. The number of measles cases increased to 172 824 in 2010, including large outbreaks in several countries with a history of successful measles control.26 WHO projected that the number of measles deaths could reach 17 million between 2009 and 2013 if high-risk countries are unable to maintain present recommended strategies for measles control (gure 1).15

2008 Ethiopia 3100 cases

Nigeria 9415 cases

Malawi 19 cases

Zambia 111 cases

South Africa 36 cases

Zimbabwe 2 cases

2009

Mali 3086 cases

Ethiopia 4470 cases Kenya 1374 cases

Senegal 1429 cases Benin 1001 cases Nigeria 4800 cases Cameroon 1305 cases South Africa 2510 cases Angola 2657 cases Namibia 2222 cases

Uganda 1216 cases Malawi 533 cases Zambia 26 cases Zimbabwe 524 cases

Pathophysiology
Measles control is based on knowledge of the virology, pathophysiology, and immunology of measles. Measles virus is a spherical, enveloped, non-segmented, singlestranded, negative-sense RNA virus and a member of the Morbillivirus genus in the Paramyxoviridae family The measles virus RNA genome consists of about 16 000 nucleotides and encodes eight proteins. The haemagglutinin protein binds to cellular receptors and interacts with the fusion protein to mediate fusion of the viral envelope with the host cell membrane (gure 3).28 The haemagglutinin protein elicits strong immune responses29 and the lifelong immunity after infection is mostly attributed to neutralising antibodies against haemagglutinin. Cellular receptors for measles virus include CD46 and CD150 (signalling lymphocyte activation molecule [SLAM]).30 CD46 is a complement regulatory molecule that is expressed on all nucleated cells in human beings. SLAM is expressed on activated T and B lymphocytes and antigen-presenting cells. The distribution of virus receptors determines the cell types infected by measles virus. Wild-type measles virus enters cells mainly through SLAM, but vaccine strains also bind to CD46.30 CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) has been identied as a measles virus receptor on epithelial cells.31 RNA viruses typically have high mutation rates; estimates of mutation rates in measles virus range from 10 to 10 per nucleotide per year within the
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2010 Mali 1990 cases Mauritania 538 cases Nigeria 14 028 cases Zambia 15 736 cases Namibia 2242 cases Botswana 1412 cases South Africa 24 393 cases Angola 1679 cases Congo 1421 cases Uganda 1313 cases Ethiopia 8261 cases Kenya 1279 cases Tanzania 1086 cases Malawi 73 727 cases Mozambique 2318 cases Zimbabwe 9993 cases Lesotho 2857 cases

Figure 2: Conrmed cases of measles reported to WHO from countries that participated in measles surveillance in Africa in 2008, 2009, and 2010 Countries with more than 1000 cases of measles reported to the WHO from 46 countries that participated in measles surveillance in Africa in 2008, 2009, and 2010 are shown in blue. Reported measles cases include cases conrmed clinically, by laboratory testing, or by epidemiological linkage. Countries with fewer than 1000 conrmed cases of measles reported to the WHO in 2008 and 2009 that had more than 5000 conrmed cases of measles in 2010 are shown in white. Data from reference 26.

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RNA

Lipid bilayer

Fusion

Haemagglutinin

Nucleocapsid

Large protein

Matrix

Phosphoprotein

Figure 3: Measles virus structure Reproduced with permission from Moss and Grin.27

variable haemagglutinin and nucleocapsid genes.32 However, measles virus is thought to be an antigenically monotypic virus. Neutralising epitopes on the haemagglutinin protein are highly conserved, as shown by the recent identication of the proteins crystal structure,33 probably because of functional constraints on the aminoacid sequence and tertiary structure of the surface proteins.34 The public-health signicance is that attenuated measles vaccines that were developed decades ago from a single measles virus genotype remain protective worldwide. Measles virus is killed by ultraviolet light and heat and attenuated measles vaccine viruses retain these characteristics; thus a cold chain is needed for transportation and storage of measles vaccines. Measles virus is transmitted mainly by respiratory droplets over short distances and less commonly by smallparticle aerosols that remain suspended in the air for long periods of time.35 The incubation period for measles is about 10 days to the onset of fever and 14 days to the onset of rash. A systematic review estimated the median incubation period from infection to the rst onset of signs
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and symptoms to be 125 days (95% CI 118132) on the basis of 55 observations from eight observational studies.36 People with measles are infectious for several days before and after the onset of rash, when concentrations of measles virus in blood and body uids are presumed to be highest and when the symptoms of cough, coryza, and sneezing are most severe. These symptoms facilitate the spread of the virus, and the fact that measles virus is contagious before the onset of recognisable disease hinders the eectiveness of quarantine measures. Measles virus RNA can be detected in clinical samples for at least 3 months after rash onset,37 and viral shedding can be prolonged in HIV-infected children with impaired cellmediated immunity,38 although whether the infectious period is prolonged is not clear. Respiratory droplets from infected people serve as vehicles of transmission by delivering infectious virus to respiratory-tract mucosa of susceptible hosts. During the incubation period, measles virus replicates and spreads within the infected host. In the standard model of measles virus pathogenesis, viral replication occurs initially in epithelial cells in the upper respiratory tract and the virus spreads to local lymphatic tissue. Replication in local lymph nodes is followed by viraemia and the dissemination of measles virus to many organs, including lymph nodes, skin, kidney, gastrointestinal tract, and liver (gure 4),39 where the virus replicates in epithelial and endothelial cells and lymphocytes, monocytes, and macrophages. In a rhesus macaque model, the predominant cell types infected by measles virus were CD150+ cells and dendritic cells.40 An alternative model of measles virus pathogenesis has been proposed, in which measles virus enters respiratory epithelial cells from infected lymphocytes and monocytes through the basolateral surface.41,42 Virus then buds from the apical surface, which enables respiratory transmission. Host immune responses at sites of virus replication are responsible for the signs and symptoms of measles, which might be absent or delayed in people with cellular immune deciencies.43 Host immune responses to measles virus are essential for viral clearance, clinical recovery, and the establishment of long-term immunity. Early innate immune responses occur during the prodromal phase.44 The adaptive immune responses consist of measles virus-specic humoral and cellular responses (gure 4).39,45 The protective ecacy of antibodies to measles virus is shown by the immunity conferred to infants from passively acquired maternal antibodies and the protection against disease of exposed, susceptible individuals after post-exposure administration of anti-measles-virus immune globulin.46 Evidence for the importance of cellular immunity to measles virus is shown by the ability of children with agammaglobulinaemia to recover from measles, whereas children with severe defects in T-lymphocyte function often develop severe or fatal disease.47 Plasma cytokine proles show increased concentrations of interferon
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during the acute phase of measles, followed by a shift to high concentrations of interleukin (IL)-4 and IL-10 during convalescence.48 The initial predominant T-helper-1 (Th1) response is essential for viral clearance, whereas the later Th2 response promotes the development of protective measles virus-specic antibodies (gure 4). Reports of measles pathogenesis in a rhesus macaque model, in conjunction with reports of prolonged detection of measles virus RNA in children,37,38 suggest that measles virus RNA persists in peripheral blood mononuclear cells for up to 4 months after infection and is associated with a biphasic T-cell response with peaks at 725 days and 90110 days.49 Immune responses induced by measles virus infection are paradoxically associated with depressed responses to non-measles-virus antigensan eect that continues for several weeks to months after resolution of the acute illness.50 After measles virus infection, delayed-type hypersensitivity responses to recall antigens, such as tuberculin, are suppressed,51 and cellular and humoral responses to new antigens are impaired.52 This measlesvirus-induced immune suppression renders individuals more susceptible to secondary bacterial and viral infections, which can cause pneumonia and diarrhoea and is responsible for much measles-related morbidity and mortality.53,54 Historically, reactivation of tuberculosis was reported to follow measles, presumably as a consequence of impaired cellular immunity. Immune suppression after measles was rst described by the Austrian physician Clemens von Pirquet in the early 20th century on the basis of his observation that children lost tuberculin skin test responses after measles.55 Abnormalities of both innate and adaptive immune responses have been described after measles virus infection.39,56 Transient lymphopenia with a reduction in CD4+ and CD8+ T lymphocytes occurs in children with measles, although this reduction might be a result of redistribution of lymphocytes from peripheral blood to lymphatic tissues.57 Functional abnormalities of immune cells have also been detected after measles infection, including decreased lymphocyte proliferative responses58 and impaired dendritic cell function.59 The dominant Th2 response in children recovering from measles can inhibit Th1 responses and increase susceptibility to intracellular pathogens.60,61 Concentrations of IL-10which downregulates the synthesis of cytokines, suppresses macrophage activation and T-cell proliferation, and inhibits delayed-type hypersensitivity responsesare raised for weeks in the plasma of children with measles48 and are associated with increased concentrations of regulatory T cells in adults with measles.62

Virus replication Liver Thymus Lung Lymphatic tissue Spleen Blood Local lymph nodes Respiratory tract Skin

Clinical symptoms

Conjunctivitis Cough Fever Kopliks spots

Rash

Immune responses CD8 T cells IgG

CD4 T cells

IgM

Immune suppression

Cytokine responses IFN- IL-2 IL-8

IL-4 IL-10 IL-13

10 Days after infection

15

20

Clinical presentation
Clinically apparent measles begins with a prodromal illness characterised by fever, cough, coryza, and conjunctivitis (gure 4). Kopliks spotssmall white lesions on the buccal mucosamight be visible during
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Figure 4: Schematic diagram of the pathogenesis of measles from virus infection to recovery (A) Virus infection starts in the respiratory tract and then spreads to infect multiple organs including lymphoid tissue, liver, lungs, and skin. Virus clearance begins with the onset of rash. Clearance of infectious virus is complete 20 days after infection but viral RNA persists at multiple sites. (B) Clinical signs and symptoms begin about 10 days after infection with prodromal symptoms of fever, conjunctivitis and appearance of Kopliks spots followed by the maculopapular rash that lasts 35 days. (C) The rash is a manifestation of the adaptive immune response with inltration of CD4+ and CD8+ T cells into sites of virus replication and initiation of virus clearance. There is a rapid activation, expansion, and then contraction of virus-specic CD8+ T cells. The CD4+ T-cell response appears at the same time, but activation is prolonged. Measles-virus-specic IgM appears with the rash and is commonly used to conrm the diagnosis of measles. This is followed by the sustained synthesis of measles-virus-specic IgG. Immune suppression is evident during acute disease and for many weeks after recovery. (D) Cytokines and chemokines that are produced during infection in sucient quantities to be found in increased concentrations in plasma are of several distinct types. Shortly after infection, the chemokine IL-8 is increased. During rash, IFN- and IL-2 are produced by activated type 1 CD4+ T cells and by CD8+ T cells. After resolution of the rash, type 2 and regulatory CD4+ T cells produce IL-4, IL-10, and IL-13. Dashed line=viral RNA. IFN=interferon. IL=interleukin. Reproduced with permission from Grin.39

the prodrome and allow diagnosis of measles before the onset of rash (gure 5).63 The prodromal symptoms intensify several days before the onset of rash. The
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Figure 5: Kopliks spots on the buccal mucosa of a child with measles Reproduced with permission from reference 63.

encephalitis and subacute sclerosing panencephalitis (SSPE), which are caused by persistent measles virus infection. Measles inclusion body encephalitis is a rare but fatal complication associated with progressive neurological deterioration that aects individuals with defective cellular immunity and typically occurs months after infection. Measles inclusion body encephalitis has been described in children with renal70 and stem-cell transplants71 and might be an outcome of measles in HIV-infected people. SSPE is a rare delayed complication of measles that occurs in about one in 10 000100 000 patients72 and is characterised by seizures and progressive deterioration of cognitive and motor functions followed by death 515 years after measles virus infection. SSPE most often occurs in people infected with measles virus before 2 years of age. Measles vaccination programmes have led to a dramatic reduction in the incidence of SSPE.73

Massachusetts Medical Society

characteristic erythematous and maculopapular rash appears rst on the face and behind the ears and then spreads in a centrifugal manner to the trunk and extremities. The rash lasts for 35 days and fades in the same manner as it appeared. Malnourished children might develop a deeply pigmented rash that desquamates or peels during recovery.64 In uncomplicated measles, clinical recovery begins soon after appearance of the rash. Complications can occur in up to 40% of patients, and the risk of complication is increased by extremes of age and undernutrition. Case fatality is highest in infants and young children.65 Complications often occur in the respiratory tract; pneumonia accounts for most measles-associated deaths.66 The risk of pneumonia is increased by the immune suppression induced by measles virus as well as local immune dysfunction within the lungs.67 Pneumonia is caused by secondary viral or bacterial infections or, in immunocompromised people, by measles virus itself causing a giant cell pneumonitis. Other respiratory complications include laryngotracheobronchitis (croup) and otitis media. Mouth ulcers, or stomatitis, might hinder children from eating or drinking. Many children with measles develop diarrhoea, which further contributes to undernutrition. Keratoconjunctivitis is common after measles, particularly in children with vitamin A deciency, and is a cause of blindness in these patients.68 Rare but serious complications of measles involve the CNS. Post-measles encephalomyelitis occurs in about one in 1000 patientsmainly in older children and adults. Encephalomyelitis occurs within 2 weeks of the onset of rash and is characterised by fever, seizures, and various neurological abnormalities. Periventricular demyelination, induction of immune responses to myelin basic protein, and absence of measles virus in the brain suggest that post-measles encephalomyelitis is an autoimmune disorder triggered by measles virus infection.69 Other CNS complications that occur months to years after acute infection are measles inclusion body
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Diagnosis
Measles should be considered in people who present with fever and generalised rash, particularly when measles virus is known to be circulating or in individuals with a history of travel to endemic areas. Physical examination should focus on the clinical features of measles, specically Kopliks spots and rash, as well as potential sites of secondary infections such as pneumonia and otitis media. Appropriate precautions need to be taken to prevent transmission within health-care settings.74 Measles is readily diagnosed by clinicians familiar with the disease, particularly during outbreaks. Kopliks spots are especially helpful because they appear before the rash and are pathognomonic. Clinical diagnosis is dicult in regions where the incidence of measles is low because other pathogens are responsible for most illnesses with presenting symptoms of fever and rash, particularly rubella virus in countries that have not introduced rubella vaccination.75 The WHO clinical case denition for measles is a person with fever and maculopapular rash (ie, non-vesicular) and cough, coryza, or conjunctivitis.76 Serology is the most common method of laboratory conrmation.77 The detection of measles virus-specic IgM in a specimen of serum or oral uid is deemed diagnostic of acute infection and is the most commonly used serological test. Alternatively, acute infection can be conrmed with a four-times or greater increase in measles-virus-specic IgG antibody concentrations between acute and convalescent sera. The presence of IgG antibodies to measles virus in a single serum specimen is evidence of previous infection or immunisation, which cannot be distinguished serologically. Measles-virus-specic IgM antibodies might not be detectable until 4 days or more after rash onset and usually fall to undetectable concentrations within 48 weeks of rash onset.78 Oral uid assays have been used to detect both IgM and IgG antibodies to measles virus.79 A point-of-care diagnostic test for measles is
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needed, similar to a rapid diagnostic test for malaria, which ideally could be done with oral uid samples.80 Measles can also be diagnosed by isolating measles virus in cell culture from respiratory secretions, nasopharyngeal and conjunctival swabs, blood, or urine. Detection of measles virus RNA by reverse transcriptasePCR amplication of RNA extracted from clinical specimens can be done with primers targeted to highly conserved regions of measles virus genes. Primers that span a variable region combined with nucleotide sequencing allow the identication and characterisation of measles virus genotypes for molecular epidemiological studies and can distinguish wild-type and vaccine measles virus strains.81 Molecular epidemiology can be used to identify sources of importation in regions that have eliminated measles. For example, the D4 genotype endemic to Romania was responsible for the measles outbreak in Indiana, USA, after importation.24 As global measles surveillance is improved, new genotypes will probably be identied, as recently shown in China (genotype d11).82

Management
Vitamin A is eective for the treatment of measles and can result in a reduction in morbidity and mortality.83 WHO recommends administration of once daily doses of 200 000 IU of vitamin A for 2 consecutive days to all children aged 12 months or older who have measles.84 Lower doses are recommended for younger children: 100 000 IU per day for children aged 612 months and 50 000 IU per day for children younger than 6 months. In children with clinical evidence of vitamin A deciency, a third dose is recommended 24 weeks later. There is no specic antiviral therapy for people with measles, although ribavirin, interferon , and other antiviral drugs have been used to treat severe measles, particularly measles virus infections of the CNS.85 Secondary bacterial infections are a major cause of morbidity and mortality after measles and eective case management involves prompt treatment with antibiotics.86 Antibiotics are indicated for people with measles who have clinical evidence of bacterial infection, including pneumonia and otitis media. Streptococcus pneumoniae and Haemophilus inuenzae type b are common causes of bacterial pneumonia after measles, and vaccines against these pathogens will probably lower the incidence of secondary bacterial infections after measles.

Prevention
The best means of preventing measles is active immunisation with measles vaccine.87 The rst attenuated measles vaccine was developed by passage of the Edmonston strain of measles virus, isolated by John Enders, in chick embryo broblasts to produce the Edmonston B virus.88 Licensed in 1963 in the USA, this vaccine was protective but also induced fever and rash in many vaccinated children. Further passage of the
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Edmonston B virus produced the more attenuated Schwarz vaccine, which was licensed in 1965 and is at present the standard measles vaccine in much of the world. The Moraten strain (meaning more attenuated Enders and licensed in 1968) was developed by Maurice Hilleman and is used in the USA. Attenuated measles vaccine strains have mutations that distinguish them from wild-type viruses89 and exhibit decreased tropism for lymphocytes.90 The recommended age of rst vaccination varies from 6 to 15 months and is a balance between the optimum age for seroconversion and the probability of acquiring measles before that age.91 The proportion of children who develop protective concentrations of antibody after measles vaccination are about 85% at age 9 months and 95% at 12 months.92 Two doses of measles vaccine are needed to achieve suciently high levels of population immunity to interrupt transmission.4 The rst dose is typically administered through the primary health-care system. WHO recommends that the rst dose of measles vaccine be administered at age 9 months,87 although countries in which the risk of measles is low often provide the rst dose at age 1215 months. Two strategies to administer the second dose of measles vaccine are through the primary health-care system or mass immunisation campaigns, called supplementary immunisation activitiesan approach rst developed by the Pan American Health Organization for South and Central America and modelled after polio eradication strategies.93 These campaigns are used to deliver other health interventions, including insecticide-treated bednets, vitamin A, anthelmintic drugs, and other vaccines, such as rubella vaccine. The duration of vaccine-induced immunity is at least several decades if not longer.94 Secondary vaccine failure rates are estimated to be about 5% at 1015 years after immunisation, but are probably lower when vaccination is given after 12 months of age.95 Decreasing antibody concentrations do not necessarily imply a complete loss of protective immunity, because a secondary immune response usually develops after re-exposure to measles virus, with a rapid rise in antibody titres without overt clinical disease. Standard doses of licensed measles vaccines are safe in children and adults who are immunocompetent. Fever to 394C (103F) occurs in about 5% of seronegative vaccine recipients and 2% of vaccine recipients develop a transient rash. Transient thrombocytopenia has been reported with a median incidence of 26 cases per 100 000 doses of measles-mumps-rubella (MMR) vaccine.96 Much public attention has focused on a purported association between MMR vaccine and autism after a case series in 1998 suggested that the MMR vaccine might cause a syndrome of autism and intestinal inammation.97 The events that followed, and the public concern over the safety of the MMR vaccine, led to diminished vaccine coverage in the UK and increased
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incidence of measles,98 and provide important lessons in the misinterpretation of epidemiological evidence and the communication of scientic results to the public.99 Several comprehensive reviews and epidemiological studies found no evidence of a causal relation between MMR vaccination and autism,100,101 and the paper was formally retracted by The Lancet.102 The ideal measles vaccine would be inexpensive, safe, heat stable, immunogenic in neonates and very young infants, and administered as a single dose without a needle or syringe.103 The age at vaccination would ideally coincide with other vaccines in the Expanded Programme on Immunization schedule to maximise compliance and share resources. Finally, a new vaccine should not prime individuals for atypical measles on exposure of immunised individuals to wild-type measles virus (a complication of formalin-inactivated measles vaccines),104 and should not be associated with prolonged immunosuppression, which adversely aects immune responses to subsequent infections (a complication of high-titre measles vaccines).105 Several candidate vaccines with some of these characteristics are in development and testing. Naked cDNA vaccines are thermostable, inexpensive, and could

Panel 2: Research needs Continued research on biological, operational, and programmatic aspects of measles epidemiology, pathogenesis, diagnosis, and prevention will be crucial for furthering the goal of measles eradication. Research needs include: Development of rapid, point-of-care tests for measles and rubella that would enable laboratory conrmation of the outbreak in the eld and timely and targeted outbreak response measures Development of more accurate and comprehensive surveillance systems to track progress in measles control and mortality reduction, without relying on existing natural history models Better understanding of the pathogenesis of measles, particularly the target cells, process of virus clearance, mechanism of immune suppression, mechanism of protection by vitamin A, and development of lifelong immunity Better understanding of the eect of heterogeneities in population immunity and clustering of susceptible people in sustaining measles virus transmission120 Assessment of existing methods and strategies in the most challenging settings, including settings with very high birth rates, large-scale migration, and weak primary health-care infrastructure Continued progress towards development of the ideal measles vaccine, which would be inexpensive, safe, heat-stable, immunogenic in neonates or very young infants, and administered as a single dose without needle or syringe103

theoretically elicit antibody responses in the presence of passively acquired maternal antibody. DNA vaccines that encode either or both the measles haemagglutinin and fusion proteins are safe, immunogenic, and protective against measles challenge in naive, juvenile rhesus macaques.106 A dierent construct, containing haemagglutinin, fusion, and nucleocapsid genes and an IL-2 molecular adjuvant, provided protection to infant macaques in the presence of neutralising antibody.107,108 Alternative techniques for administration of measles virus genes, such as alphavirus,49 parainuenza virus,109 or enteric bacterial110 vectors, are also under investigation. Oral immunisation strategies have been developed by means of plant-based expression of the measles virus haemagglutinin protein in tobacco,111 and dry powder attenuated measles vaccine delivered by inhalation induced protective immunity in rhesus macaques.112 Aerosol administration of liquid attenuated measles vaccine was rst assessed in the early 1960s in several countries, including the former Soviet Union and the USA. More recent studies in South Africa113 and Mexico114 have shown that aerosol administration of measles vaccine is eective in boosting antibody concentrations, although the primary humoral and cellular immune responses to aerosolised measles vaccines are lower than after subcutaneous administration at age 9 months115 and 12 months.116 A systematic review and meta-analysis in children aged 1036 months concluded that the seroconversion rate with aerosolised measles vaccine was 94% compared with 97% for subcutaneously administered vaccine.117 Administration of measles vaccine by aerosol has the potential to facilitate measles vaccination during mass campaigns and eliminate the medical waste problems associated with needles and syringes.

Measles eradication
The feasibility of measles eradication has been discussed for more than 30 years, beginning in the late 1960s when the long-term protective immunity induced by measles vaccines was becoming evident.118 Three biological criteria are deemed important for disease eradication: (1) human beings as the sole pathogen reservoir; (2) existence of accurate diagnostic tests; and (3) availability of an eective, practical intervention at reasonable cost.119 Interruption of transmission in large geographical areas for prolonged periods further supports the feasibility of eradication. Measles is thought by many experts to meet these criteria (panel 2).121 Several potential biological obstacles to measles eradication should be considered. Persistent infection with transmissible measles virus would pose a biological barrier to eradication. Measles virus establishes persistent infection in people with SSPE; however, virion assembly and budding is defective and multiple mutations occur throughout the measles virus genome.122 As a consequence, infectious measles virus is not present. Theoretically, selective pressure on measles viruses to
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mutate neutralising epitopes and escape protective immune responses induced by vaccines could be a biological obstacle to measles eradication. However, despite the high degree of genetic variation expected of an RNA virus, mutations in the measles virus genome have not reduced the protective immunity induced by measles vaccines.123 Subclinical infection that results in sustained measles virus transmission could also pose a barrier to eradication,124 as it has for polioviruses. However, sustained measles virus transmission among partly immune individuals that does not result in clinical disease is unlikely.125 In regions of high HIV prevalence, HIV-infected children might play a part in sustaining measles virus transmission. Children with defective cell-mediated immunity can develop measles without the characteristic rash,43 hampering clinical diagnosis. Children born to HIV-infected mothers have lower concentrations of passively acquired maternal antibodies, and thus have increased susceptibility to measles at a younger age than children born to uninfected mothers.126,127 Also, protective antibody concentrations after vaccination might wane within 23 years in many HIV-infected children who are not receiving antiretroviral therapy,128 creating a potential pool of susceptible children.129 A study in South Africa reported lower levels of vaccine eectiveness among HIV-infected compared with uninfected children, although few HIV-infected children were studied.130 Thus, population immunity could be reduced in regions of high HIV prevalence despite high levels of measles vaccine coverage. Counteracting the increased susceptibility of HIVinfected children is their high mortality rate, particularly in sub-Saharan Africa, such that these children do not live long enough for a sizeable pool of susceptible children to build up.131 Successful control of measles in southern Africa suggests that the HIV epidemic has not been a major barrier to measles control.132 However, with increased access to antiretroviral therapy, survival might be prolonged without enhancement of protective immunity in the absence of revaccination.133,134 HIVinfected children who achieve immune reconstitution after initiation of antiretroviral therapy would probably benet from revaccination.135

eventual eradication will be logistical, nancial, and the garnering of sucient political will. Meeting these challenges will be necessary to ensure that future generations of children do not die of measles.
Contributors WJM and DEG wrote the manuscript. Conicts of interest We declare that we have no conicts of interest. Acknowledgments WJM was supported by a grant from the National Institute of Allergy and Infectious Diseases (AI070018). DEG was supported by grants from the National Institute of Allergy and Infectious Diseases (AI023047) and the Bill & Melinda Gates Foundation. These funding agencies had no role in the writing of this manuscript. References 1 Black FL. Measles endemicity in insular populations: critical community size and its evolutionary implication. J Theor Biol 1966; 11: 20711. 2 Furuse Y, Suzuki A, Oshitani H. Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries. Virol J 2010; 7: 52. 3 Enders JF, Peebles TC. Propagation in tissue cultures of cytopathic agents from patients with measles. Proc Soc Exp Biol Med 1954; 86: 27786. 4 Gay NJ. The theory of measles elimination: implications for the design of elimination strategies. J Infect Dis 2004; 189 (suppl 1): S2735. 5 Caceres VM, Strebel PM, Sutter RW. Factors determining prevalence of maternal antibody to measles virus throughout infancy: a review. Clin Infect Dis 2000; 31: 11019. 6 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: c1626. 7 Garenne M. Sex dierences in measles mortality: a world review. Int J Epidemiol 1994; 23: 63242. 8 Perry RT, Halsey NA. The clinical signicance of measles: a review. J Infect Dis 2004; 189 (suppl 1): S416. 9 Brown AC, Moss WJ. Sex, pregnancy and measles. In: Klein SL, Roberts C, eds. Sex hormones and immunity to infection. Berlin and Heidelberg, Germany: Springer-Verlag, 2010: 281302. 10 Halsey NA. Increased mortality after high-titre measles vaccines: too much of a good thing. Pediatr Infect Dis J 1993; 12: 46265. 11 Fine PE, Clarkson JA. Measles in England and WalesI: an analysis of factors underlying seasonal patterns. Int J Epidemiol 1982; 11: 514. 12 Ferrari MJ, Grais RF, Bharti N, et al. The dynamics of measles in sub-Saharan Africa. Nature 2008; 451: 67984. 13 WHO. World Health Assembly Resolution WHA 52.20. Reducing global measles mortality. Geneva: World Health Organization, 2003. 14 Wolfson LJ, Strebel PM, Gacic-Dobo M, Hoekstra EJ, McFarland JW, Hersh BS. Has the 2005 measles mortality reduction goal been achieved? A natural history modelling study. Lancet 2007; 369: 191200. 15 WHO. Global reductions in measles mortality 20002008 and the risk of measles resurgence. Weekly Epidemiol Rec 2009; 84: 50916. 16 WHO, United Nations Childrens Fund. Global immunization vision and strategy 20062015. 2005. Geneva, Switzerland: World Health Organization. 17 WHO. Monitoring progress towards measles elimination. Wkly Epidemiol Rec 2010; 85: 49095. 18 de Quadros CA, Andrus JK, Danovaro-Holliday MC, Castillo-Solorzano C. Feasibility of global measles eradication after interruption of transmission in the Americas. Expert Rev Vaccines 2008; 7: 35562. 19 Centers for Disease Control and Prevention. Progress toward measles controlAfrican region, 20012008. MMWR Morb Mortal Wkly Rep 2009; 58: 103641. 20 World Health Organization Regional Committee for Africa. Towards the elimination of measles in the African region by 2020. Report of the Regional Director. 2009.

Conclusions
Remarkable progress has been made in reducing global measles incidence and mortality. Measles, once a leading cause of child mortality worldwide, ranked tenth in a systematic analysis of deaths in children aged 159 months in 2008.136 The global public health community faces a stark choice: continue to make progress in measles mortality reduction, with the ultimate goal of measles eradication, or have the recent successes in measles mortality reduction led to a loss in public interest, donor support, and political motivation. The major challenges for continued measles control and
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