Chapter 13: Measles

Introduction

Measles is an acute, viral, infectious disease. References to measles can be found from as early as the 7th century. The disease was described by the Persian physician Rhazes in the 10th century as "more to be dreaded than smallpox."

In 1846, Peter Panum described the incubation period of measles and lifelong immunity after recovery from the disease. John Enders and Thomas Chalmers Peebles isolated the virus in human and monkey kidney tissue culture in 1954. The first live, attenuated vaccine (Edmonston B strain) was licensed for use in the United States in 1963. In 1971, a combined measles, mumps, and rubella (MMR) vaccine was licensed for use in the United States. In 2005, a combination measles, mumps, rubella, and varicella (MMRV) vaccine was licensed.

Before a vaccine was available, infection with measles virus was nearly universal during childhood, and more than 90% of persons were immune due to past infection by age 15 years. Measles is still a common and often fatal disease in developing countries. The World Health Organization estimates there were 142,300 deaths from measles globally in 2018. In the United States, there have been recent outbreaks; the largest occurring in 2019 primarily among people who were not vaccinated.

Measles Virus

The measles virus is a paramyxovirus of the genus Morbillivirus. It is 120 to 250 nm in diameter, with a genome of single-stranded, negative sense RNA, and is closely related to the rinderpest and canine distemper viruses. Two membrane envelope proteins are important in pathogenesis. They are the F (fusion) protein, which is responsible for fusion of virus and host cell membranes, viral penetration, and hemolysis, and the H (hemagglutinin) protein, which is responsible for binding of virus to receptors on host cells.

There is only one antigenic type of measles virus. Although studies have documented antigenic changes in the H protein, these changes do not appear to be epidemiologically important (i.e., no change in vaccine efficacy has been observed).

Measles virus is rapidly inactivated by heat, sunlight, acidic pH, ether, and trypsin.

Pathogenesis

Measles is a systemic infection. The primary site of infection is alveolar macrophages or dendritic cells. Two to three days after replication in the lung, measles virus spreads to regional lymphoid tissues followed by a systemic infection. Following further viral replication in regional and distal reticuloendothelial sites, a second viremia occurs 5 to 7 days after initial infection. During this phase, infected lymphocytes and dendritic cells migrate into the subepithelial cell layer and transmit measles to epithelial cells. Following amplification in the epithelia, the virus is released into the respiratory tract.

Clinical Features

The incubation period of measles from exposure to prodrome averages 11 to 12 days. The time from exposure to rash onset averages 14 days, with a range of 7 to 21 days.

The prodrome lasts 2 to 4 days, with a range of 1 to 7 days. It is characterized by fever, which increases in a stepwise fashion often peaking as high as 103°F to 105°F, cough, coryza, and conjunctivitis.

Koplik spots, present on mucous membranes, are considered to be unique to measles. They occur 1 to 2 days before the measles rash (i.e., during the prodromal period), and appear as punctate blue-white spots on the bright red background of the buccal mucosa.

The measles rash is a maculopapular eruption that usually lasts 5 to 6 days. It begins at the hairline, then involves the face and upper neck. During the next 3 days, the rash gradually proceeds downward and outward, reaching the hands and feet. The maculopapular lesions are generally individually distinct but may run together, particularly on the upper body. Initially, lesions blanch (become white or pale) with fingertip pressure. By 3 to 4 days, most do not blanch with pressure. The lesions peel off in scales in more severely involved areas. The rash fades in the same order that it appears, from head to extremities.

Other symptoms of measles include anorexia and generalized lymphadenopathy.

Epidemiology

Secular Trends in the United States

Before 1963, approximately 500,000 cases and 500 measles deaths were reported annually, with epidemic cycles every 2 to 3 years. However, the actual number of cases was estimated at 3 to 4 million annually. More than 50% of persons had measles by age 6 years, and more than 90% by age 15 years. In the years following licensure of vaccine in 1963, the incidence of measles decreased by more than 95%, and 2- to 3-year epidemic cycles no longer occurred. From 1985 through 1988, 68% of cases in school-aged children (age 5 to 19 years) occurred among those who had been appropriately vaccinated – i.e., had received a single dose of measles vaccine as recommended. The occurrence of measles among previously vaccinated children (i.e., vaccine failure) led to a recommendation for a second dose in this age group in 1989.

In 2019, 13 outbreaks of measles were reported, accounting for 663 cases; six were associated with underimmunized close-knit communities and accounted for 88% of all cases. Before 2019, the highest number of measles cases following elimination in the United States occurred in 2014 when 667 cases were reported. Increasing incidence of measles globally contributes to increased opportunities for measles importation into the United States. Fortunately, public health measures and a long-standing vaccination program has prevented outbreaks form imported cases.

Among children born during 2016–2017, 90.7% received measles, mumps, and rubella-containing vaccine by age 24 months; this was not statistically significantly different from the coverage of 90.3% for children born during 2014–2015.

Measles Vaccine

In 1963, both an inactivated ("killed") and a live, attenuated (Edmonston B strain) measles vaccine were licensed for use in the United States. The inactivated vaccine was withdrawn in 1967 because it did not protect well against measles. The original Edmonston B vaccine was withdrawn in 1975 because of a relatively high frequency of fever and rash in recipients. A live, further attenuated (Schwarz strain) vaccine was first introduced in 1965, but also is no longer used in the United States. Another live, further attenuated strain (Edmonston-Enders strain) vaccine was licensed in 1968. These further attenuated vaccines caused fewer reactions than the original Edmonston B vaccine. In 1971, measles vaccine was licensed as a combined measles, mumps, and rubella (MMR) vaccine. In 2005, a combination measles, mumps, rubella, and varicella (MMRV) vaccine was licensed.

Measles vaccine is available as measles, mumps, and rubella vaccine (MMR [MMR-II]) and measles, mumps, rubella, and varicella vaccine (MMRV [ProQuad]). Both MMR and MMRV vaccine contain live, attenuated viruses. Single-antigen measles vaccine is not available in the United States. The Advisory Committee on Immunization Practices (ACIP) recommends that MMR or MMRV vaccine be used when any of the individual components is indicated.

Vaccination Schedule and Use

MMR vaccine or MMRV vaccine can be used to implement the vaccination recommendations for prevention of measles, mumps, and rubella. MMR vaccine is licensed for use in persons age 12 months or older. MMRV vaccine is licensed for use in persons age 12 months through 12 years; MMRV vaccine should not be administered to persons age 13 years or older.

Two doses of MMR vaccine, separated by at least 4 weeks, are routinely recommended for children age 12 months or older. Dose 1 of MMR vaccine should be given at age 12 through 15 months. A second dose of MMR vaccine is recommended based on previous observations of the failure of some to generate an immune response to measles following dose 1. Dose 2 is routinely given at age 4 through 6 years, before a child enters kindergarten or first grade. All students entering school should receive 2 doses of MMR vaccine (with the first dose administered at age 12 months or older) before enrollment. Dose 2 of MMR vaccine may be administered as soon as 4 weeks after dose 1.

The minimum interval between doses of MMRV vaccine is 3 months, although when dose 2 is administered 4 weeks following dose 1, it can be considered valid. For the first dose of measles, mumps, rubella, and varicella vaccines at age 12 through 47 months, either separate MMR and varicella (VAR) vaccines, or MMRV vaccine, may be used. However, the risk of febrile seizures is about twice as high for children receiving MMRV vaccine versus separate MMR and VAR vaccines. Providers who are considering administering MMRV should discuss the benefits and risks of both vaccination options with the parents. Unless the parent or caregiver expresses a preference for MMRV, separate MMR vaccine and VAR vaccine should be administered for the first dose in this age group. For the second dose of measles, mumps, rubella, and varicella vaccines at any age and for the first dose at age 48 months or older, the use of MMRV generally is preferred over separate injections of its equivalent component vaccines (i.e., MMR vaccine and VAR vaccine).

Contraindications and Precautions to Vaccination

As with other vaccines, a history of a severe allergic reaction (anaphylaxis) to a vaccine component or following a prior dose is a contraindication to further doses. Moderate or severe acute illness (with or without fever) in a patient is considered a precaution to vaccination, although persons with minor illness may be vaccinated.

MMR and MMRV vaccines both contain minute amounts of neomycin and gelatin. Persons with alpha-gal allergy may wish to consult their physician before receiving a vaccine that contains gelatin.

Severe immunocompromise (e.g., from hematologic and solid tumors, receipt of chemotherapy, congenital immunodeficiency, long-term immunosuppressive therapy or patients with HIV infection who are severely immunocompromised) is a contraindication for MMR and MMRV vaccination. If the person's level of immunocompetence is uncertain, the decision to vaccinate should be made by the health care provider that prescribed the immunosuppressive medication for those patients whom immunocompromise is due to medication. Patients who have not received chemotherapy for at least 3 months, whose disease remains in remission, and who have restored immunocompetence, may receive MMR or MMRV vaccine. Healthy, susceptible close contacts of severely immunocompromised persons should be vaccinated.

Persons receiving systemic high-dose corticosteroid therapy (2 milligrams per kilogram of body weight or more per day or 20 milligrams or more per day of prednisone) for 14 days or more should not receive MMR or MMRV vaccine because of concern about vaccine safety. MMR or MMRV should not be administered for at least 1 month after cessation of systemic high-dose corticosteroid therapy. Although persons receiving high doses of systemic corticosteroids daily or on alternate days for less than 14 days generally can receive MMR or MMRV immediately after cessation of treatment, some experts prefer waiting until 2 weeks after completion of therapy.

Available data indicate that vaccination with MMR has not been associated with severe or unusual adverse reactions in HIV-infected persons who are not severely immunosuppressed, although antibody responses have been variable. MMR vaccine is recommended for susceptible HIV-infected persons age 12 months or older with no evidence of current severe immunosuppression ("no evidence of current severe immunosuppression" is defined as CD4 percentages greater than or equal to 15% for 6 months or longer for persons age 5 years or younger; and CD4 percentages greater than or equal to 15% and CD4 count greater than or equal to 200 cells/mm³ for 6 months or longer for persons older than age 5 years). MMR vaccine is not recommended for HIV-infected persons with evidence of severe immunosuppression.

MMRV is not approved for and should not be administered to a person known to be infected with HIV.

A family history of congenital or hereditary immunodeficiency in first-degree relatives (e.g., parents and siblings) is a contraindication for MMR or MMRV vaccine, unless the immune competence of the potential vaccine recipient has been substantiated clinically or verified by a laboratory.

A history of thrombocytopenic purpura or thrombocytopenia is a precaution for MMR and MMRV vaccine. Such persons may be at increased risk for developing clinically significant thrombocytopenia after MMR or MMRV vaccination.

Simultaneous use of aspirin or aspirin-containing products is a precaution for MMRV vaccine due to the varicella component. The manufacturer recommends that vaccine recipients avoid the use of salicylates for 6 weeks after receiving MMRV vaccine because of the association between aspirin use and Reye syndrome following chickenpox.

A personal or family (i.e., sibling or parent) history of seizures of any etiology is a precaution for MMRV vaccine but not MMR. Children with a personal or family history of seizures of any etiology should ideally be vaccinated with separate MMR and VAR vaccines because the risks for using MMRV vaccine in this group of children generally outweigh the benefits.

MMR vaccine may be administered to egg-allergic persons without prior routine skin testing or the use of special protocols.

Vaccine Safety

Studies have shown MMR and MMRV vaccines are safe and well-tolerated. The National Academy of Medicine, formerly called the Institute of Medicine, reviewed the evidence between MMR vaccination and certain adverse events. The experts determined that evidence supports a causal relation between MMR vaccination and anaphylaxis, febrile seizures, thrombocytopenic purpura, transient arthralgia, and measles inclusion body encephalitis in persons with demonstrated immunodeficiencies.

Most adverse events reported following MMR vaccination (such as fever and rash) are attributable to the measles component. After MMR vaccination, 5% to 15% of susceptible persons develop a temperature of 103°F (39.4°C) or higher, usually occurring 7 to 12 days after vaccination and generally lasting 1 or 2 days. Most persons with fever do not have other symptoms. MMR vaccine is associated with a very small risk of febrile seizures; approximately one case for every 3,000 to 4,000 doses of MMR vaccine administered. The febrile seizures typically occur 6 to 14 days after vaccination and do not appear to be associated with any long-term sequelae. Children with a personal or family history of febrile seizures or family history of epilepsy might be at increased risk for febrile seizures after MMR vaccination.

MMR vaccine may cause a transient rash in approximately 5% of vaccine recipients, usually appearing 7 to 10 days after vaccination. Laboratory testing can confirm the presence of measles or mumps vaccine virus in a recently vaccinated and potentially exposed individual.

Allergic reactions following the administration of MMR vaccine are rare. Most of these are minor and consist of a wheal and flare or urticaria at the injection site. Immediate, anaphylactic reactions to MMR vaccine occur in 1.8 to 14.4 cases per million doses.

Arthralgias and other joint symptoms are reported in up to 25% of adult women following MMR vaccination and are associated with the rubella component. Transient lymphadenopathy sometimes occurs following receipt of MMR or other rubella-containing vaccine, and parotitis has been reported rarely (less than 1%) following receipt of MMR or other mumps-containing vaccine.

Rarely, MMR vaccine may cause thrombocytopenia within two months after vaccination. The clinical course of these cases is usually transient and benign, although hemorrhage occurs rarely. Based on case reports, the risk for MMR vaccine-associated thrombocytopenia may be higher for persons who have previously had immune thrombocytopenic purpura, particularly for those who had thrombocytopenic purpura after an earlier dose of MMR vaccine.

Measles inclusion body encephalitis has been documented after measles vaccination in persons with immune deficiencies. The illness is also known to occur within 1 year after initial infection with wild-type measles virus and has a high death rate. In the cases after MMR vaccination, the time from vaccination to development of measles inclusion body encephalitis was 4–9 months, consistent with development of measles inclusion body encephalitis after infection with wild-type measles virus.

In MMRV vaccine prelicensure studies conducted among children age 12 to 23 months, fever (reported as abnormal or elevated greater than or equal to 102°F oral equivalent) was observed 5 to 12 days after vaccination in 21.5% of MMRV vaccine recipients compared with 14.9% of MMR vaccine and VAR vaccine recipients. Two postlicensure studies indicated that one additional febrile seizure per 2,300 to 2,600 children age 12 through 23 months occurred 5 to 12 days after the first dose of MMRV vaccine, compared with children who had received the first dose of MMR vaccine and VAR vaccine administered as separate injections at the same visit. Data from postlicensure studies do not suggest that this increased risk exists for children age 4 to 6 years receiving the second dose of MMRV vaccine.

Multiple studies, as well as a National Academy of Medicine Vaccine Safety Review, refute a causal relationship between autism and MMR vaccine or between inflammatory bowel disease and MMR vaccine.

Vaccine Storage and Handling

For MMR-II and Proquad storage and handling specifics, refer to the manufacturer. For complete information on storage and handling best practices and recommendations, please refer to CDC’s Vaccine Storage and Handling Toolkit [56 pages].

Surveillance and Reporting for Measles

For information on guidance for state and local health department staff who are involved in surveillance activities for vaccine-preventable diseases, please consult the Manual for the Surveillance of Vaccine-Preventable Diseases.

Acknowledgements

The editors would like to acknowledge Jennifer Hamborsky and Valerie Morelli for their contributions to this chapter.

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