Measles Vaccines

History of Measles

The written history of measles is often traced to the writings of the Persian physician Rhazes, also known as Abu Becr, who lived during the 10th century ( Fig. 38.1 ). However, the disease was apparently recognized as early as the 7th century by such persons as the Hebrew physician Al Yehudi. Comparative analyses of measles virus genomes suggest an origin as early as the sixth century BCE, ^, and some have speculated an even earlier origin arising from an ancestral morbillivirus in the ancient Near East where human populations achieved sufficient size to sustain measles virus transmission after the agricultural revolution. Rhazes referred to measles as hasbah, which means “eruption” in Arabic. Rubeola and morbilli are descriptive Latin words first used in the Middle Ages. The latter is a diminutive of morbus , meaning “disease,” which was reserved to refer to the bubonic plague; morbilli referred to a minor disease. Measles is probably derived from mesels, the anglicized form of misellus, which, in turn, is a diminutive of the Latin word miser, meaning miserable and referring to the sufferer of various eruptions or sores. The presence of non-specific leprous sores was incorrectly identified with the disease called morbilli in Latin. Thus, mesels came to be equated with the disease and not the sufferer of ill-defined skin lesions.

Rhazes appears to have been the first to make the distinction between measles and smallpox. ^, He considered measles to be a severe disease, “more to be dreaded than smallpox.” Although Rhazes distinguished between the two diseases, he and others probably considered them to be closely related. Furthermore, although he was aware of the seasonal nature of measles, he did not think the disease was contagious.

The distinction between measles and smallpox became clearer by the beginning of the 17th century, when annual Bills of Mortality in London in 1629 listed the two diseases separately. Thomas Sydenham described the clinical characteristics of measles during this period and believed the disease to be contagious. It was, however, Francis Home, a Scottish physician who worked in Edinburgh in the mid-18th century, who recognized the infectious nature of the illness in his attempts to prevent it through cutaneous inoculation, analogous to variolation to prevent smallpox. Understanding of the epidemiology of measles was greatly enhanced by the classic investigation of a measles epidemic on the Faroe Islands in 1846 by the Danish physician Peter Panum. He not only confirmed that measles was contagious but also defined the 14-day interval between exposure and appearance of exanthem, recognized the higher mortality at the extremes of age, and observed that infection provided lifelong immunity.

In 1911, using infected material from acute cases, Goldberger and Anderson transmitted measles virus to monkeys, clearly demonstrating the existence of a filterable agent responsible for measles. This finding antedated knowledge of the nature of viruses and technologies to isolate and culture measles virus. In 1954, John F. Enders and Thomas C. Peebles successfully isolated measles virus in human and monkey kidney tissue cultures. Adaptation of the virus to chicken embryos and cultivation in chicken embryo tissue culture paved the road to vaccine development and licensure in 1963.

Clinical Description

The first symptoms of measles occur after a 10–14-day incubation period following exposure to measles virus from an infectious person. A systematic review estimated the median incubation period to be 12.5 days (95% confidence interval [CI], 11.8–13.2) based on 55 observations from eight observational studies. Measles incubation periods vary by setting depending on population dynamics, measles virus transmission patterns, and the nature of infectious events. For example, if infection occurs after parenteral exposure, the incubation period is shortened by 2–4 days. Individual case reports have suggested potential exposure events occurring at least 21 days prior to rash onset, ^{, , ,} with one report of an incubation period of 23 days. To ensure high sensitivity for disease surveillance, an incubation period of 7–23 days is recommended by the World Health Organization (WHO) for epidemiological investigations and identify contacts and potential transmission events to guide control activities ^, although evidence for a 23- rather than 21-day upper limit on the incubation period (as used by the Centers for Disease Control and Prevention) is very limited. Immunosuppressed persons may have a prolonged incubation period because host immune responses, which are responsible for most of the signs and symptoms of measles, may be absent or delayed in persons with cellular immune deficiencies. ^,

The prodromal stage is heralded by the onset of fever, malaise, conjunctivitis, coryza, and tracheobronchitis (manifesting as cough) and lasts 2–4 days. This symptom complex is similar to that seen with many upper respiratory infections. The temperature rises during the ensuing 4 days and may reach as high as 40.6°C. Koplik spots, the enanthema pathognomonic of measles, appear as multiple 2–4-mm bluish-white plaques on the buccal mucosa, usually on the inside of the cheek opposite the first or second molar, 1–2 days before the onset of a rash and may be noted for an additional 1–2 days after rash onset. Koplik spots are believed to occur in greater than 70% of measles patients and, because they usually first appear prior to rash onset, their early finding by a clinician during physical examination can prompt laboratory testing for rapid confirmation of measles, early treatment, implementation of infection-control practices, and postexposure prophylaxis of close contacts. The rash associated with measles is an erythematous maculopapular eruption that usually appears 14 days after exposure and spreads from the head (face, forehead, hairline, ears, and upper neck) over the trunk to the extremities during a 3–4-day period. The exanthem is usually most confluent on the face and upper body and initially blanches on pressure. During the next 3–4 days, the rash fades in the order of its appearance and assumes a nonblanching brownish appearance. Desquamation may follow, particularly in children who are severely undernourished or immunocompromised such as with HIV infection.

The typical course of measles can be modified by the presence of previously acquired immunity. ^{, ,} This situation usually arises in the infant with residual maternal transplacental IgG antibodies, in a person given immunoglobulin (Ig) or vaccination after exposure in an attempt to prevent or attenuate disease, or in previously vaccinated persons exhibiting an anamnestic immune response following measles virus exposure. ^, In these persons, subclinical infection or a mild abbreviated illness may occur that confers lasting immunity. ^, However, if immunity is incomplete, clinical measles may occur. ^,

Virology

Measles virus is a pleomorphic, nonsegmented, single-stranded, negative-sense RNA virus with a diameter of 120–250 nm. ^, It is a member of the genus Morbillivirus in the family Paramyxoviridae. There are seven known species in this genus and family: measles virus in humans, rinderpest virus in cattle, peste-des-petits-ruminants virus in goats and sheep, canine distemper virus in domestic dogs, feline morbillivirus in wild and domestic cats, phocine distemper virus in seals, and cetacean morbillivirus in cetaceans (whales, dolphins, porpoises). These viruses are all lymphotropic, induce highly contagious and devastating diseases with marked immunosuppression, and have high host specificity. ^, The only natural host for measles virus is humans but non-human primates can be infected with measles virus and are used as experimental models to study measles pathogenesis. Measles virus is inactivated rapidly in the presence of sunlight, heat, and extremes of pH, but can be stored for long periods at −70°C.

The 16-kb virus genome encodes for eight proteins, including replication factors [polymerase (L) and phosphoprotein (P)], structural proteins [hemagglutinin (H), fusion (F), nucleoprotein (N), and matrix (M)], and two accessory proteins involved in subverting host interferon immune responses (C and V). ^{, ,} The H protein is involved in the attachment and entry of measles virus into host cells via interaction with cell surface receptors, including CD150/SLAMF1 on immune cells and nectin-4 expressed by epithelial cells. The F protein is involved in the viral/host-cell membrane fusion and viral entry into the host cell. The N protein forms a helical ribonucleoprotein complex with the RNA genome that is associated with a viral RNA-dependent RNA polymerase (L protein) and polymerase cofactor (P). The M protein interacts with the ribonucleoprotein complex and surface glycoproteins (H and F) to promote virion assembly.

Although measles virus is considered a monotypic virus, sequence analysis of the N, H, P, and M genes has shown that there are multiple, distinct lineages of wild-type viruses. Measles viruses are classified into eight clades containing 24 genotypes based on the nucleotide sequences of their H and N genes, the most variable genes in the genome. This sequence variability has made it possible to use molecular techniques to help monitor transmission pathways. ^, Molecular epidemiologic data, when analyzed in conjunction with standard epidemiologic information, can confirm or suggest the source of outbreaks and, over time, can provide a measure of the effectiveness of vaccination control programs and monitor elimination. For example, genetic analysis of wild-type viruses detected in the United States from 1988 to 2000 helped document the interruption of endemic transmission in the United States. Comparison of genetic sequences from wild-type strains isolated in the United States with those isolated elsewhere in the world has suggested international importations of measles virus as sources of outbreaks. Measles surveillance in California during the 2019 measles outbreak identified 72 cases and 26 importations caused by two measles virus strains. Notably, targeted whole genome sequencing allowed for better discrimination between epidemiologically-linked and sporadically-introduced strains than conventional sequencing.

To facilitate the expansion of virologic surveillance activities, the WHO recommended a standard nomenclature and analysis protocol, and established a global database of measles virus sequences. In 2000, the WHO established the Global Measles and Rubella Laboratory Network to provide standardized procedures for case confirmation and virus characterization. This network was built on the existing network for global polio eradication and includes more than 700 laboratories in 191 countries. ^, Although virologic surveillance is incomplete, increased laboratory capability and improved surveillance since 2000 has allowed for monitoring the global distribution of measles virus genotypes ( Fig. 38.2 ). Following elimination efforts globally, circulating genotypes of wild-type measles virus have decreased. Twenty of the 24 measles virus genotypes were eradicated between 2005 and 2019 as a consequence of widespread vaccination, and only three measles virus genotypes were detected in 2020. Among 10,857 measles virus sequences reported to the global Measles Nucleotide Surveillance (MeaNS) database between 2016 and 2018, the number of MeV genotypes detected decreased from 6 in 2016 to 4 in 2018, reflecting this broader trend in the reduction of circulating measles virus genotypes. Although the biologic significance of differences in the genetic sequence of wild-type strains is not known, there is no evidence that strains vary by transmissibility or virulence. The immune response generated through vaccination protects against all measles virus strains.

Although measles virus is classified into 24 genotypes, the virus is monotypic with a single serotype, accounting for why vaccines derived from measles virus isolates from as far back as the mid-1950s remain highly protective. This stability results from constraints on measles virus genetic and antigenic diversity and is a shared characteristic of viruses in the family Paramyxovirinae, particularly for the hemagglutinin and fusion proteins on the virus surface that mediate cell attachment and entry. Conserved neutralizing epitopes have been identified across circulating genotypes, particularly in the hemagglutinin receptor binding site. Measles virus evolution is thus apparently constrained by several antigenic sites on the hemagglutinin protein critical for binding to the cellular receptors SLAMF1 and nectin-4. Changes to the receptor binding site of the hemagglutinin protein that permit escape from neutralizing antibodies also are correlated with loss of receptor binding and thus an inability to invade cells.

Measles virus infects multiple cell types, including dendritic, epithelial, endothelial, and activated B cells, T cells, and monocytes. Three cellular receptors that interact with the measles virus H glycoprotein are: (a) membrane cofactor protein or CD46; (b) signaling lymphocyte activation molecule 1 (SLAMF1/CD150); and 3) nectin-4, also known as poliovirus receptor-like 4 (PVRL4). CD46 is a human complement regulatory protein expressed on all nucleated cells and is an important cellular receptor used by measles vaccine strains but not by wild-type measles strains. Two receptors used by wild-type measles virus are SLAMF1 expressed on immune cells and nectin-4 expressed on epithelial cells. The SLAM family is a group of transmembrane receptors found in animals and humans, and were likely the major determinant for the evolution of the host-virus specificity of morbilliviruses. In humans, SLAMF1/CD150 is a membrane glycoprotein expressed on immune cells, including activated T and B lymphocytes, activated monocytes, immature thymocytes, and mature dendritic cells. SLAMF1/CD150 is used by both measles vaccine strains and wild-type viruses. Nectin-4 is a cellular receptor on epithelial cells and plays a critical role allowing measles virus to spread laterally in airway epithelium. Measles virus uses the adherens junction protein nectin-4/afadin complex to initiate a viral membrane fusion apparatus to open intercellular membrane pores and allow infected cytoplasm transfer between columnar epithelial cells. This results in large infectious centers in the tracheae and upper airway that likely eventually detach, triggering coughing and sneezing of aerosolized measles virus.

Because measles involves multiple organs and tissues, additional measles virus cellular receptors that play a role in measles pathogenesis likely exist but have not yet been identified. For example, CD147 was identified as potentially facilitating measles virus entry into epithelial and neuronal cells, a finding that could help explain central nervous system complications of measles.

Measles virus can be cultured from clinical specimens and is best isolated in the Vero/hSLAM cell line comprised of Vero cells transfected with a plasmid encoding the gene for SLAMF1/CD150. The sensitivity of Vero/hSLAM cells for isolation of measles virus is equivalent to that of the previously used B95a cells, which were coinfected with Epstein-Barr virus. In addition, Vero/hSLAM cells can be infected with laboratory-adapted measles virus strains, including vaccine viruses. In cell cultures, the virus causes two distinct cytopathic effects. ^{, , ,} The first is formation of multinucleated syncytia (giant cells) containing numerous nuclei of fused cells. This corresponds to the predominant pathologic process observed in infected tissues, including skin and Koplik spots. When observed in lymphoid tissue, these giant cells are referred to as Warthin-Finkeldey cells. Whereas this cytopathic effect is characteristic of wild-type virus isolates, the cytopathic effects of passaged virus may additionally include spindle-cell transformation. This difference in cytopathic effects as well as other factors, such as ability to grow in chick embryo fibroblasts, plaque morphology, interferon production, and optimal growth temperature, help differentiate wild-type virus from attenuated vaccine virus strains, in addition to genetic sequencing. ^{, , ,}

Pathogenesis as It Relates to Prevention

Respiratory droplets and aerosols from infectious persons during coughing and sneezing transmit measles virus to the respiratory tract of susceptible hosts where measles virus first infects dendritic cells and macrophages. ^, These infected myeloid cells migrate to regional lymphoid tissues and infect T and B lymphocytes. Infected lymphocytes enter the blood stream, resulting in a cell-associated viremia and measles virus replication throughout lymphoid tissues, including lymph nodes, thymus and spleen. Infection of epithelial cells in the skin and submucosa of the respiratory tract results from migration of infected lymphocytes.

To gain access to new hosts, measles virus enters the basolateral side of epithelial cells in the upper respiratory track and spreads laterally through intercellular pores to adjacent epithelial cells, creating multinucleated epithelial giant cells that can be detected in nasal secretions and conjunctivae at the end of the incubation period, during the prodrome, and the first days of rash. Sloughing of material in the upper airway mucosa, including multinucleated giant cells containing infectious viral particles, induces coughing and sneezing of aerosolized respiratory droplets. ^, Attenuated measles virus strains infect myeloid cells but are restricted in subsequent infection and cell-to-cell transmission in lymphoid cells. ¹⁹⁷ Consequently, measles vaccine viruses do not lead to widespread infection of lymphoid tissues.

The innate immune responses during the prodromal phase include activation of natural killer (NK) cells but the nonstructural V and C proteins suppress interferon production, allowing viral replication and dissemination before the adaptive immune response. The onset of rash marks the start of the adaptive immune response and viral clearance.

The protective efficacy of antibodies to measles virus is demonstrated by the protection conferred from passively-acquired maternal antibodies and of exposed, susceptible individuals following administration of anti-measles virus immunoglobulin (Ig). Virus-neutralizing antibodies are directed against the transmembrane surface glycoproteins H and F. The first antibodies produced are of the IgM subtype, followed by predominantly IgG1 and IgG3 isotypes ( Fig. 38.3 ). The IgM antibody response is usually absent following re-exposure or revaccination and serves as a marker of primary infection. IgA antibodies to measles virus are found in serum and mucosal secretions. The most abundant and most rapidly produced antibodies are against the nucleoprotein (N) and this antigen is often used as a target in diagnostic enzyme immunoassays. Avidity, which refers to how tightly the antibody binds measles virus antigens, is an important characteristic of a mature antibody response. The development of a high avidity antibody response is important to the development of protective immunity and can be used to distinguish primary and secondary vaccine failure. ^{, ,}

The importance of cellular immune responses to measles virus is highlighted by recovery from measles by children with agammaglobulinaemia. In contrast, children with severe defects in T-cell function can develop severe or fatal measles. Because measles virus spreads largely by direct cell-to-cell viral transfer, antibody ^, mediated immune responses are not able to fully eliminate measles virus. Thus, while antibodies play a critical role in preventing infection, cellular immune responses are important in clearing infected cells. Monkeys depleted of CD8 ⁺ T lymphocytes and challenged with measles virus had a more extensive rash, higher viral loads, and longer duration of viraemia than immunocompetent monkeys.

The cellular immune response to measles virus is a dynamic process, with functionally distinct subsets of measles virus-specific CD4 ⁺ and CD8 ⁺ T cells prominent at different times following infection. CD4 ⁺ T lymphocytes secrete cytokines that modulate the humoral and cellular immune responses. Plasma cytokine profiles show increased levels of IFN-γ during the acute phase, with a shift to interleukin (IL)-4 and IL-10 during convalescence. The initial predominant type 1 response (characterized by IFN-γ) is essential for viral clearance and the type 2 response (characterized by IL-4) promotes development of measles virus-specific antibodies. Enhanced production of type 1 cytokines was observed in children with fatal measles virus infection.

Immunological memory to measles virus includes continued production of measles virus-specific antibodies and the circulation of measles virus-specific CD4 ⁺ and CD8 ⁺ T lymphocytes. The mechanisms involved in maintaining the long duration of protective immunity are not completely understood but repeat exposure to measles virus is not required. Fragments of the measles virus genome may persist and thus contribute to the prolonged immunosuppressive effects of measles as well as the induction of long-term memory immune responses. ^, Levels of naturally acquired measles virus-specific antibodies diminish slightly over time and rapid secondary humoral and cellular immune responses from long-lived memory cells provide protection from infection.

Despite an effective immune response that clears measles virus and results in long-term protective immunity, abnormalities of both the innate and adaptive immune responses follow measles virus infection. Transient lymphopenia with a reduction in both T and B lymphocytes occurs in children with measles. Functional abnormalities of immune cells are also measurable. Dendritic cells, important antigen-presenting cells, mature poorly, lose the ability to stimulate proliferative responses in lymphocytes, and undergo cell death when infected with measles virus in vitro. ^{, ,} As a consequence of these abnormalities, effective immune responses to measles virus are paradoxically associated with depressed responses to unrelated antigens, lasting beyond the acute illness for at least several weeks to several months or longer. Delayed-type hypersensitivity responses to recall antigens, such as tuberculin, are suppressed, and cellular and humoral responses to new antigens are impaired. This state of immune suppression enhances susceptibility to secondary bacterial and viral infections that cause pneumonia and diarrhea and is responsible for much of the morbidity and mortality associated with measles.

Further contributing to the enhanced susceptibility to other infections, measles impacts memory immune responses to other pathogens. Measles virus infects CD150 ⁺ immune cells, including memory T and B lymphocytes ^, and results in incomplete genetic reconstitution of B-lymphocyte pools. Most importantly, measles results in depletion of a substantial fraction of circulating antibodies against multiple viruses and bacteria, reducing both antibody diversity and quantity. Measles thus diminishes immunological memory to previously encountered pathogens, resulting in what has been called “immune amnesia.” This mechanism may explain the increased morbidity and mortality for several years after measles.

Measles virus can be isolated from subcrevicular oral fluid, the nasopharynx, and blood during the latter part of the incubation period and during the early stages of rash development. ^, Although virus has been isolated from the urine as late as 4–7 days after rash onset, infectious virus generally clears 2–3 days after rash onset in parallel with the appearance of measles virus-specific antibodies. Persons with measles are generally considered to be infectious 4 days before through 4 days after rash onset. However, measles virus RNA can be detected in blood, urine and nasopharyngeal specimens for at least 3 months after infection in children, and for at least 6 months in rhesus macaques ^{, , , ,} predominantly within B cells but also in T cells and monocytes in both the circulation and lymph nodes ( Fig. 38.3 ). A biphasic pattern to measles virus RNA may reflect a transient increase in cell-associated measles virus RNA.

Diagnosis

Measles should be suspected in persons who present with an acute erythematous rash and fever, preceded by a 2–4-day prodrome of cough, coryza, conjunctivitis, and photophobia. Measles may be difficult to distinguish from other causes of febrile rash illness, particularly in areas where the incidence of measles has been low. Clinical features that support the diagnosis of measles include the presence of Koplik spots, the characteristic 2–4 days of intensifying prodromal symptoms, the progression of the rash from the head to the trunk and out to the extremities, and resolution of fever shortly after the appearance of the rash. A clinical case definition for epidemiologic purposes is the presence of rash lasting 3 or more days; a fever (temperature ≥38.4°C, if measured); and cough, conjunctivitis, or coryza. However, use for clinical diagnosis is limited, particularly because of the criterion requiring at least 3 days of rash before the diagnosis is made. The WHO defines a suspected measles case for public health surveillance as one in which a patient presents with fever and maculopapular (non-vesicular) rash, or in whom a health care worker suspects measles. Other definitions provided by the World Health Organization for public health surveillance include those for laboratory-confirmed measles, epidemiologically linked measles, clinically compatible measles, and nonmeasles discarded case. Other illnesses, such as infection with rubella, dengue, parvovirus B19, and human herpesvirus type 6 viruses, as well as measles vaccine reactions, can meet clinical case definitions.

Laboratory tests are necessary to confirm the diagnosis of measles. Although virus isolation, direct cytologic examination of clinical material, or demonstration of virus RNA or antigen can be used to diagnose measles, ^{, ,} detection of measles virus-specific IgM antibodies from a single blood specimen is the most commonly used diagnostic method. An increase in measles IgG antibodies between acute and convalescent serum specimens is also diagnostic. RT-PCR can be used to identify measles virus RNA in urine, blood, oral fluid, and nasopharyngeal mucus.

The recommended laboratory method for the confirmation of clinically diagnosed measles is a serum-based IgM enzyme immunoassay (EIA) collected at the time the patient is first seen for medical care. A single specimen is adequate to detect the presence of IgM antibody. ^{, ,} Many commercial kits are available. After discontinuation of the Siemens Enzynost IgM measles antibody kit, the WHO evaluated 7 EIA kits. The EIA kits included two IgM capture methods and five indirect methods. Assay sensitivity ranged from 75.0% to 98.1% and specificity from 86.6% to 99.5%. Parvovirus B19 IgM positive sera caused false-positive results, particularly with two EIA kits, and capture IgM EIAs had the optimal combination of sensitivity and specificity. However, if measles prevalence is low (e.g., 1%), even a modest reduction in the specificity of the assay from 99% to 95% will decrease the positive predictive value of the assay from 48% to 15% (i.e., only 15% of IgM-positive clinical cases will be true measles). The availability of commercially available rapid diagnostic tests for measles IgM antibodies would permit rapid outbreak detection and response. Such tests have been developed but are not widely used.

Correct interpretation of IgM antibody test results depends on proper timing of specimen collection relative to rash onset. This is especially important in interpreting negative IgM results. For example, in one study, the sensitivity of an antibody capture IgM assay was approximately 80% within the first 72 hours after rash onset but rose to 100% between 3 and 14 days after rash onset. If the validity of the initial measles IgM test is in doubt, a second convalescent specimen should be tested for IgM antibodies and for a rise in IgG titer compared with the initial specimen.

Two approaches provide alternatives to venipuncture for collection of diagnostic specimens: oral fluid and blood spots on filter paper. In the United Kingdom and elsewhere, commercial IgM EIA-based assays have been developed and used to test oral fluid specimens. Compared with serum IgM results, reported sensitivity of oral fluid IgM assays ranged from 90% to 92% and specificity from 95% to 100%. Use of oral fluid samples has appeal because the technique is noninvasive, can be used for rubella and mumps antibody testing, does not require processing in the field, can be shipped without cold chain, and can be used to detect not only measles IgM and IgG but also the measles virus genome for molecular characterization. Technical advances in the development of oral fluid serologic assays for SARS-CoV-2 may guide progress on the use of oral fluid for measles serology.

Dried blood spots collected by finger prick may be more acceptable to parents than phlebotomy. Blood spots collected onto filter paper do not require processing in the field, or a cold chain for transport to the laboratory, and can be used to test for measles and rubella IgG antibodies as well as for molecular characterization of the measles virus genome. ^{, ,} In addition, the eluted serum can be tested using many commercially available EIAs with minimal loss of sensitivity or specificity. A study in India showed that dried blood spots collected with the HemaSpot HF devices can generate accurate results for measles virus-specific IgG serology compared to sera. However, a systematic review that identified 28 studies comparing dried blood spots to a reference specimen, usually serum, for serological testing of a licensed vaccine-preventable disease concluded lack of standardization in collection, storage and testing methods limited systematic comparison across studies.

Treatment

Measles case management is focused on supportive care as well as the prevention and treatment of measles complications and secondary infections to reduce morbidity and mortality ( Table 38.1 ). Clinical outcomes improve with early case detection and treatment. High doses of vitamin A have been shown to decrease mortality and morbidity in young children hospitalized with measles in low- and middle-income countries. The WHO recommends vitamin A for children with acute measles. Vitamin A oral dosage is once daily for 2 days at 200,000 IU for children ages 12 months and older, 100,000 IU for infants 6–11 months of age, and 50,000 IU for infants younger than 6 months of age. In the United States, children with measles can have low levels of serum retinol, and those with more-severe illness have lower levels. The American Academy of Pediatrics (AAP) recommends using two doses of vitamin A (200,000 IU) on consecutive days, which is associated with a reduction in the risk of mortality in children younger than 2 years of age (relative risk [RR], 0.18; 95% CI, 0.03–0.61) and the risk of pneumonia-specific mortality (RR, 0.33; 95% CI, 0.08–0.92). A third dose of vitamin A is recommended 2–4 weeks later in children with clinical signs and symptoms of vitamin A deficiency. However, use of vitamin A for the treatment of measles is infrequent in the United States. There is no evidence that vitamin A in a single dose is associated with a reduced risk of mortality among children with measles. ^, In addition, vitamin A therapy should be administered to children with measles who are immunosuppressed, have clinical evidence of vitamin A deficiency, or have recently immigrated from areas with a high mortality rate from measles. The use of antibiotics for the treatment of measles without evidence of bacterial infection is not recommended by the WHO. However, a clinical trial in Guinea-Bissau found that patients who received prophylactic antibiotics (cotrimoxazole) had fewer episodes of pneumonia and conjunctivitis and greater weight gain, suggesting a beneficial role of prophylactic antibiotics in the treatment of measles in low-income countries.

Several preparations, such as interferon, ^, thymic humoral factor, thymostimulin, levamisole, ribavirin, and Ig, have been used to treat measles. None of these is commonly used to treat uncomplicated measles, although limited studies with ribavirin have shown reduced duration of illness. Ribavirin and interferon may be effective in treating severe measles in immunocompromised persons. Various chemotherapeutic agents have also been used in patients with SSPE in an attempt to treat or at least alter the clinical course of the disease. ^, Of these, inosiplex (Isoprinosine) and interferon have been the most extensively studied. Despite anecdotal evidence of their effectiveness, controlled trials are lacking. New drugs for the treatment of measles and SSPE, such as a pan-morbillivirus small molecule inhibitor that targets the morbillivirus RNA-dependent RNA-polymerase complex, are under development. ^,

Incidence and Prevalence Data

In the absence of an immunization program, measles is a ubiquitous, highly contagious, seasonal disease affecting nearly every person in a given population by adolescence. ^, Important exceptions are island and other isolated populations, which can remain free of measles for variable periods and then, after reintroduction of the virus, experience catastrophic outbreaks that involves all age groups not affected by the last wave of infection. ^{, , , ,} Thus, whereas peak transmission usually occurs among young children, outbreaks in isolated communities involve many older persons. This is exemplified by Peter Panum’s description of measles on the Faroe Islands, in which measles occurred in persons of all ages who were not affected by the last epidemic that had occurred 65 years earlier.

Measles incidence has declined globally following the widespread use of measles-containing vaccines (MCVs) but there is wide spatial and temporal heterogeneity in measles cases driven by large national and regional outbreaks. Measles surveillance is weak in many countries. Just over half (52%) of countries that reported a discarded case (i.e., a suspected case that was determined not to be measles or rubella) met the surveillance sensitivity indicator target of two or more discarded cases per 100,000 population in 2019 and fewer than one-third achieved this indictor in 2020. As a consequence, reported measles cases are estimated to be less than 5% the true number. Nevertheless, reported measles cases decreased 84% from 853,479 cases in 2000 to 132,490 cases in 2016, and annual measles incidence decreased 88%, from 145 cases per 1 million people in 2000 to a low of 18 cases per 1 million people in 2016. But as a consequence of several large measles outbreaks and virus transmission around the world, the number of measles cases increased 556% from 132,490 in 2016 to 869,770 in 2019 (the most reported number of cases since 1996) and measles incidence increased 567% to 120 per million in 2019 (the highest global incidence since 2001). These increases occurred in all WHO Regions, with the largest relative increase in measles cases in the Region of the Americas (19,739%) and the smallest in the South-East Asia Region (6%). The percentage of countries with annual measles incidence of <5 cases per 1 million population increased from 38% in 2000 to 70% in 2016 but dropped to 46% in 2019.

However, reported measles incidence decreased to 22 cases per one million population in 2020 during the COVID-19 pandemic. Low reported global measles cases in 2020 ³²³ during the COVID-19 pandemic likely resulted from poor quality measles case surveillance, reductions in international travel, and public health measures such as masking and social distancing to prevent transmission of SARS-CoV-2. However, the COVID-19 pandemic disrupted routine immunization services and led to the cancellation or delay of measles and rubella mass vaccination campaigns in many countries, increasing the number of susceptible children and the risk of measles outbreaks. The World Health Organization and UNICEF estimated that 22.7 million children missed out on basic vaccines through routine immunization services in 2020, the highest number since 2009. Intensive efforts will be needed to vaccinate children missed because of COVID-19 pandemic and prevent a resurgence of measles.

High-Risk Groups

Before the introduction of measles vaccines in most high-income countries, school-age children had the highest risk of infection and accounted for the largest proportion of cases. ^, However, in dense urban areas, transmission among preschoolers took on greater importance. Although serious complications did occur, they were relatively rare compared with the situation in low-income countries. In the United States before the introduction of measles vaccine in 1963, major epidemics occurred approximately every 2–3 years. ^, Each year, disease peaked in late winter and early spring. The highest occurrence of disease was in school-age children 5–9 years of age, who accounted for more than 50% of reported cases. More than 95% of cases had occurred by age 15 years. ^,

Measles virus is so contagious that it can be expected to circulate wherever a relatively large number of susceptible persons congregate, even in the face of low population susceptibility. This explains the outbreaks that were typical among military recruits before the institution of routine measles vaccination. Outbreaks among high school and college students, most of whom were vaccinated, demonstrate the virus’s capability to seek out the small number of remaining susceptible persons. An investigation of measles outbreaks in the United States in 2019, a highly vaccinated population with overall measles vaccination coverage of >91% among children aged 19–35 months, found that 6 of the 13 outbreaks were associated with underimmunized close-knit communities, accounting for 88% of all cases. The median age of measles was 6 years (interquartile range [IQR] = 2–22 years), and 13% were infants aged <12 months, 31% were children aged 1–4 years, 27% were school-aged children aged 5–17 years, and 29% were adults aged ≥18 years. This distribution of cases, with some below the age of routine immunization and a high proportion of cases in adults, poses challenges to vaccination programs.

Before widespread vaccination, in many low- and middle-income countries, the average age at infection was much lower than that observed in high-income countries. ^, In some urban areas of sub-Saharan Africa, more than 50% of 2-year-old and 100% of 4-year-old children had measles. Poor nutrition and rapid loss of maternal antibody may explain why a greater proportion of these infants are susceptible at an earlier age, ^, and infection, in turn, results from the early age at which infants are exposed to the community at large. Young age at infection contributes to the high risk of serious complications and death. Malnutrition, especially vitamin A deficiency, may also be an important factor leading to the marked severity of measles because of defects in cellular (and possibly humoral) immunity. ^, However, there is some evidence that crowding, which leads to a potential increased dose of transmitted virus, may also be a significant determinant of the severity of infection.

The epidemiologic and public health importance of measles virus transmission in health care settings is increasingly recognized. ^, Persons who work in healthcare facilities are at greater risk for acquiring measles than the general population. During 1985–1989, physicians had an eightfold increased risk and nurses a twofold increased risk of measles compared with nonhealthcare workers of the same age. In the 120 measles outbreaks that occurred from 1993 through 2001, healthcare facilities were the most commonly reported settings, with 24 reported outbreaks. In the postelimination years from 2001 to 2014, 78 reported measles cases resulted from transmission in healthcare facilities, and 29 healthcare personnel were infected from occupational exposure, one of whom transmitted measles virus to a patient. These health facility cases comprised 6% of nonimported measles cases in the United States during this period. The economic impact of preventing and controlling measles virus transmission in healthcare facilities in the United States was $19,000–$114,286 per case. During the recent global measles resurgence, several studies identified the risk of nosocomial transmission of measles virus and the unacceptably low measles vaccine coverage and high susceptibility among health care personnel.

Reservoirs of Infection

Measles virus is sustained through an unbroken chain of human-to-human transmission and no animal or environmental reservoir exists. However, nonhuman primates can be infected with measles virus and develop clinical illness similar to humans. Many nonhuman primate species can be infected. In addition to the ability to infect nonhuman primates experimentally, serological studies demonstrated evidence of prior measles virus infection in free-ranging populations of nonhuman primates. One-quarter of 47 rhesus macaques in southern India and one-third of 15 wild macaques in Indonesia had serological evidence of measles virus infection, likely resulting from human-to-animal (anthroponotic) transmission, followed by limited spread within the primate population. The conclusion that wild primate populations do not serve as natural reservoirs is based on the critical community size necessary to sustain measles virus transmission. Wild populations of nonhuman primates consist of up to several hundred individuals and thus are not of sufficient size to sustain measles virus transmission.

Significance as a Public Health Problem

Although remarkable control of measles has been achieved in many areas of the world, ^, as recently as 2000 measles was still the leading cause of vaccine-preventable deaths in children and the fifth leading cause of all deaths among children younger than 5 years of age. Measles is also responsible for much diarrhea, respiratory disease, and blindness. ^{, ,} Epidemiological evidences from population-level data in high-income countries suggests nonmeasles infectious disease mortality may be increased for up to 2–3 years after acute measles. If true, the public health significance of measles has been grossly underestimated.

Through mass vaccination campaigns and increased routine immunization coverage with two doses of MCVs, the estimated number of measles deaths worldwide dropped 62% from 539,000 deaths in 2000 to 207,500 deaths in 2019 and measles vaccination was estimated to have prevented 25.5 million measles-related deaths during this period. In 2020, annual global measles deaths declined dramatically during the COVID-19 pandemic to its lowest level, an estimated 60,700 deaths, and 31.7 million measles deaths were estimated to have been averted by measles vaccination from 2000 to 2020. A comparison of the proportion of all-cause mortality resulting from measles among children younger than 5 years of age found that measles accounted for approximately 7% of all child deaths in 1990 and 1% in 2008, contributing 23% to the overall reduction in mortality in this age group. In an updated analysis, measles accounted for 1.2% of all deaths in children younger than 5 years of age in 2015 and reductions in measles deaths were again found to be one of the major drivers of the overall reduction in child mortality from 2000 to 2015.

In the United States in the prevaccine era, approximately 500,000 cases of measles were reported each year, but, in reality, an entire birth cohort of approximately 4 million persons was infected annually. Associated with these cases were an estimated 500 deaths, 150,000 cases with respiratory complications, 100,000 cases of otitis media, 48,000 hospitalizations, 7000 seizure episodes, and 4000 cases of encephalitis, which left up to one quarter of patients permanently brain damaged or deaf. Although endemic measles has been eliminated in the United States, importations continue to result in small but costly outbreaks. These outbreaks result from clusters of people with low vaccination coverage and imported measles cases. From January to September 2019, 1249 measles cases were reported in the United States, the highest annual number since 1992. Eighty-nine percent of cases were unvaccinated or had an unknown vaccination status, and 10% required hospitalization.

Measles outbreaks are costly. A review of cost estimates associated with 11 measles outbreaks in the United States from 2001 through 2018 found that the median total cost per measles outbreak was $152,308 (range $9862–$1,063,936), the median cost per case was $32,805 (range $7396–$76,154), and the median cost per contact was $223 (range $81–$746). The cost of a measles outbreak of 649 cases to the Department of Health and Mental Hygiene in New York City in 2018 and 2019 was $8.4 million. The overall societal cost of a measles outbreak with 72 cases in Clark County, Washington was approximately $3.4 million, with much of the cost ($2.3 million) attributable to the public health response.

A cost-of-illness study in Uganda was the first to quantify the economic burden of measles in a low-income country. The cost for a child hospitalized with measles was $60 and the cost for an outpatient visit for measles was $15. Caregivers of a child with measles incurred approximately $44 in economic costs, including $23 in out-of-pocket expenses. In 2018, 2614 cases of measles were confirmed in Uganda, resulting in $135,627 in societal costs, including $59,357 in economic costs to households. A similar study in Bangladesh found that the cost from a societal perspective for a child hospitalized with measles was $159 and the cost for an outpatient visit for measles was $18. Seventy-eight percent of the poorest caregivers of a child with measles faced catastrophic health expenditures compared to only 21% of the richest. In 2018, 2263 cases of measles were confirmed in Bangladesh, totaling $348,073 in economic costs, with $121,842 in out-of-pocket payments for households.

History of Measles Vaccine Development

Edmonston Measles Vaccine Strains

After the isolation and propagation of measles virus in tissue culture by Enders and Peebles in 1954, vaccine development, testing, and licensure quickly followed. The Edmonston strain, named after the youth from whom the virus was isolated, was used for many of the vaccines developed worldwide ( Fig. 38.4 ). To make the Edmonston B vaccine, Enders and colleagues ^{, ,} further passaged the Edmonston strain at 35°C–36°C 24 times in primary kidney cells and 28 times in primary human amnion cells, and then adapted it to chicken embryo cells through six passages. This attenuated Edmonston B vaccine was licensed in the United States in March 1963 along with another Edmonston B virus strain that had been adapted to primary dog kidney cells. Although the administration of the Edmonston B vaccine was associated with a high rate of fever (temperature of 39.4°C or higher in 20%–40% of vaccinees) and rash (approximately 50%), similar to a mild case of measles, the recipients remained well. However, simultaneous administration of a small dose of Ig with the vaccine reduced the occurrence of high fever and rash by approximately 50%. ^{, , , , , ,} Approximately 18.9 million doses of Edmonston B vaccine were administered in the United States between 1963 and 1975.

Measles Vaccine Constituents

Preparation methods for the Merck measles vaccine provide generally applicable information regarding the production and constitution of measles vaccines. Although there are minor differences in dose, antibiotic content, and other details among manufacturers, there are no reports of significant differences in side effects or vaccine effectiveness. The vaccine virus is cultured in primary chick embryo cells. After an initial cell growth phase, the cultures are inoculated with the further attenuated Moraten strain of measles virus. After incubation for several days at 32°C, the cells are washed to remove fetal bovine serum, and the medium is replaced with one containing 50 µg/mL of neomycin, sucrose, buffered salts, amino acids, and human albumin.

In 1996, the existence of reverse transcriptase in several vaccines grown in chick embryo fibroblast tissue culture was reported, including measles vaccine. This reverse transcriptase activity is associated with the endogenous avian retrovirus EAV-0 ⁴⁴⁹ and the endogenous avian leukosis virus ALV-E. Extensive efforts to identify a transmissible virus failed to link the reverse transcriptase activity with a transmissible virus. A study of 206 recipients of combined MMR vaccine found no evidence of infection with either avian leukosis virus or endogenous avian retrovirus. These findings and the fact that transmission of retroviruses across disparate species may be restricted indicate no apparent risk to vaccine recipients.

Process of Measles Vaccine Manufacture

To manufacture measles vaccines, fluids containing vaccine virus are removed from cultures and frozen until determinations of the virus titer have been performed on retained aliquots. Harvested virus fluids having sufficient virus potency and satisfactorily passing tests are thawed, pooled, sampled for safety testing, clarified, dispensed, and refrozen. When bulk vaccine has passed all quality control tests, the vaccine is thawed, dispensed into vials, and lyophilized. At the time of use, the vaccine is reconstituted with sterile distilled water provided by the manufacturer. Rare and careless errors in reconstitution, such as with the neuromuscular blocking drug atracurium, have resulted in tragic deaths after measles vaccination. A preservative-containing reconstitution fluid is not recommended for general use because it may inactivate the vaccine. Each vaccine dose contains approximately 25 µg of neomycin. Sorbitol and hydrolyzed gelatin are added as stabilizers. When reconstituted with the provided diluent, the vaccine is clear and yellow in color. Measles, mumps, and rubella vaccines do not and never did contain thimerosal or any other mercury compound.

Producers and Trade Names of Measles Vaccines

Producers and trade names of measles vaccine are shown in Table 38.2 .

Dosage and Route of Administration

According to regulations in the United States, measles vaccine must contain at least 1000 median tissue culture infective doses (TCID ₅₀ ) at the end of the expiration date of the vaccine. The minimum dose required to immunize a seronegative child has been found to be as low as 20 TCID ₅₀ in some studies but higher in others. The regulated minimum dose in the commercial product is designed to compensate for some deterioration of vaccine virus that may result either from improper storage or reconstitution or from exposure to light or heat before injection.

The recommended route of administration is subcutaneous injection. Although there are only limited data on the intramuscular route, it appears to be as effective as subcutaneous vaccination. Studies with the Edmonston B and further attenuated vaccines have examined the effectiveness of other routes of administration, such as intranasal and conjunctival inoculation. ^{, , , , , ,} Most of the results were not favorable. In contrast, aerosol administration, which was evaluated during the early 1960s and 1970s, initially showed promising results. During the 1980s, studies were undertaken to determine whether aerosol administration of measles vaccine could overcome maternal antibody and immunize younger infants. Many of these studies found the Edmonston-Zagreb vaccine strain to be more immunogenic than the Schwarz strain when it is administered by aerosol, perhaps due to its passage in human diploid cells. Whereas some investigators reported high seroconversion rates after administration by this route in young infants, ^, others found it inferior to subcutaneous administration. Subsequently, aerosol administration of measles vaccine in South Africa and of combined measles and rubella vaccines in Mexico were shown to boost antibody responses among schoolchildren. These studies led to enthusiasm about the possible use of aerosol administration as a less-invasive alternative to needle-and-syringe administration during mass vaccination campaigns, especially among schoolchildren. Further enthusiasm was generated when aerosol administration of the Edmonston-Zagreb strain was shown to induce a primary immunization response at 9 months of age. However, in a randomized clinical trial, aerosolized measles vaccine was inferior to the subcutaneous vaccine with respect to the rate of seropositivity. After the disappointing results from this clinical trial, efforts to further investigate or promote aerosol administration of measles vaccines have slowed, replaced by efforts to advance the development and use of intradermal microarray patches (see “Future Vaccines” below).

Combination With Rubella, Mumps, and Varicella Vaccines

In the United States, vaccination against measles is accomplished with combined attenuated measles vaccines that also contain attenuated rubella and mumps vaccine viruses (MMR), or a combination with attenuated measles, mumps, rubella, and varicella (MMRV) viruses for children 12 months through 12 years of age. Combined MMR vaccines were first licensed in the United States in 1971. The MMR vaccine contains at least 1000 TCID ₅₀ of the measles Moraten strain, at least 5000 TCID ₅₀ of the mumps Jeryl Lynn strain, and at least 1000 TCID ₅₀ of the RA27/3 strain of rubella vaccine virus. Currently, the only licensed MMR vaccine in the United States is produced by Merck (M-M-RII). In September 2005, a combined MMRV vaccine produced by Merck was licensed for use in the United States. The measles, mumps, and rubella vaccine viruses in this quadrivalent vaccine are identical and of equal titer to those in MMR vaccine but the titer of Oka/Merck varicella-zoster virus is higher in MMRV vaccine than in single-antigen varicella vaccine (see Chapter 63 ).

Combination products also were developed as other countries began vaccinating children against rubella or mumps along with measles. ^{, ,} The Serum Institute of India manufactures a combined measles-rubella vaccine (Edmonston-Zagreb measles strain and RA27/3 rubella strain) that is widely used in resource-limited settings as part of measles and rubella control and elimination efforts. GlaxoSmithKline (Research Triangle Park, NC) produces a vaccine that contains Schwarz measles vaccine, RIT4385 mumps vaccine strain (derived from the Jeryl Lynn strain), and the RA27/3 strain of rubella vaccine (Priorix) that is licensed in more than 100 countries outside the United States. In Japan, several formulations of combined vaccines are available, including one containing the AIK-C measles virus, the Hoshino mumps virus, and the Takahashi rubella virus strains. Two other combined vaccines are also licensed: one containing the CAM-70 measles strain and one containing the Schwarz F88 strain. A triple vaccine with the Edmonston-Zagreb strain of measles vaccine is produced by the Institute of Immunology (Zagreb) and the Serum Institute of India (Mumbai; Leningrad-Zagreb mumps strain and RA27/3 rubella strain).

Safety and immunogenicity data indicate that combining the measles antigen with rubella and mumps antigens in the MMR vaccine is both safe and efficacious. Initial results also showed similar safety and efficacy for MMRV vaccine compared with MMR given with varicella vaccine at the same time but at different injection sites. However, when given as the first dose to young children, later studies showed that the risk of febrile seizures ^, was higher after MMRV compared with MMR and varicella vaccine administered simultaneously at separate sites (see “Vaccine Safety”).

Stability of Measles Vaccines

Measles vaccines are extremely stable between −70°C and −20°C. Although measles vaccines are affected adversely by higher temperatures, the introduction of more heat-stable vaccines in 1979 led to increased stability under normal working conditions, which is especially important in resource-constrained settings in tropical climates. The WHO has a requirement that lyophilized measles vaccine, after exposure to 37°C for at least 1 week, cannot lose more than 1 log ₁₀ and must maintain a titer of at least 1000 TCID ₅₀ .

For the currently available MCVs in the United States, a minimum titer of 1000 TCID ₅₀ can be maintained in un-reconstituted vaccine for 2 years or more when stored at 2°C–8°C. This potency can be maintained for 8 months at room temperature (20°C–25°C) and 4 weeks at 37°C. Reconstituted vaccine loses 50% of its potency in 1 hour at 20°C–25°C and almost all its potency at 37°C for 1 hour. Measles vaccines are also sensitive to sunlight; however, colored glass vials minimize loss of potency.

As stated in the package insert, Merck recommends that its product be shipped at a temperature of 10°C or less and stored, before reconstitution, at 2°C–8°C and protected from sunlight. Reconstituted measles vaccines (M, MR, and MMR) should be used immediately. If reconstituted vaccine is not used within 8 hours, it must be discarded. MMRV vaccine must be stored frozen at an average temperature of less than or equal to −15°C. Unlike other measles-containing vaccines, MMRV vaccine cannot be stored at refrigerator temperature, and once reconstituted, it should be used immediately to minimize loss of potency and discarded if not used within 30 minutes.

Measles vaccines are commonly provided in 10-dose vials but health care workers may be reluctant to open a multidose vial if few children are to be vaccinated on a given day to prevent wastage. A study in Zambia found that switching to five-dose vials for MCV improved coverage, decreased wastage, and improved health care worker willingness to open a vial. Health care workers in Senegal, Vietnam, and Zambia preferred measles vaccine vials with fewer doses to reduce wastage and increase the likelihood of vaccinating every eligible child.