Despite the established safety and efficacy of the measles-mumps-rubella vaccine after almost 50 years of widespread use, the United States is encountering higher levels of measles and mumps disease than has occurred for years. Return of disease threatens the health of those who remain unimmunized by choice as well as those who are immunized appropriately but experience loss of vaccine-induced immunity. The solution to continued threats of illness caused by these untreatable but readily preventable diseases is compliance with recommendations for administration of the measles-mumps-rubella vaccine. Here we examine trends in the epidemiology of measles, mumps, and rubella in recent years and consider the consequences of loss of protective immunity within our country.
Growing concern among health care professionals and the public regarding the severity and the contagiousness of measles and mumps, 2 previously controlled diseases in the United States, has focused attention on the role of the measles-mumps-rubella vaccine (MMR). The number of reported measles, mumps, and rubella cases decreased by >95% after introduction of each monovalent vaccine, yet disease continues to occur nearly 50 years after the 3 vaccines were combined into a single trivalent vaccine in 1971. Measles occurs mainly among unimmunized people exposed to a contagious traveler who arrives from a country outside the United States where measles virus is circulating.1,2 Mumps outbreaks occur after exposure to an index case in settings where people have close, prolonged contact, such as universities or close-knit communities, and may or may not have received 2 doses of MMR.2–4 The attenuated rubella virus contained in MMR (Wistar RA 27/3) is more effective at inducing protective immunity than the measles or mumps vaccine strains, and a single dose is ∼97% effective in prevention of clinical disease and is considered to provide lifelong protection against rubella.2 In view of the availability of MMR, a safe and effective vaccine, why does disease still occur, and what can be done to control the spread of measles, to control the outbreaks of mumps, and to sustain the elimination of rubella?
Before measles vaccines were licensed in 1963, childhood infection with measles was nearly universal, resulting in an estimated 3 to 4 million cases annually (the birth cohort), >500 deaths, and thousands of cases of measles-associated encephalitis in the United States.1 After licensure of the first measles vaccines, the incidence of disease declined rapidly. By 2000, the United States was certified to be free of measles, meaning that after importation of a case, no continuous transmission occurred for at least 12 months. Between 1997 and 2013 the incidence of measles remained remarkably low at <1 case per 1 million population.1 Starting in 2014, the number of cases increased, and in 2019, >1250 cases of measles were reported, representing the highest number in 17 years.5 Approximately 90% of reported cases occurred among people who were unvaccinated (70%) or whose vaccination status was unknown (20%).5
In the United States, a single dose of a measles-containing vaccine administered at 12 months of age has a vaccine effectiveness of ∼93% (and 97% when administered at 15 months of age). Primary measles vaccine failure (lack of seroconversion) occurs in ∼2% to 5% of vaccine recipients who receive 1 dose of the vaccine. Primary vaccine failure may be caused by passive antibodies in the vaccine recipient at the time of immunization (such as residual maternal antibodies), a damaged vaccine, or incorrect records (ie, administration of the incorrect vaccine). Secondary measles vaccine failure (waning antibody concentrations to unprotective levels after an initial response) seldom occurs. More than 98% of people who receive ≥2 doses of a measles-containing vaccine, according to the recommended immunization schedule, develop serological evidence of immunity.1 The second MMR dose is not a booster dose; rather, it is intended to induce immunity in the small number of people who do not develop protective immunity after the first dose.
The number of measles cases occurring in the United States in a given year is determined by 2 factors: first, the number of travelers who become infected abroad and travel to or return to this country while contagious; and second, the number of susceptible people who are exposed to the traveler.6,7 Clusters of disease are more likely to occur in communities with pockets of unvaccinated people. The majority of importations have not resulted in larger outbreaks in the United States because of high 2-dose immunization rates of MMR (that results in high rates of immunity in the community) and the rapid implementation of control measures from state and local health departments. However, these control measures are costly and draw resources away from other critical public health responsibilities.8
In the absence of antiviral therapy, treatment of measles consists of management of dehydration and nutritional deficiencies (including vitamin A) and antimicrobial therapy if secondary bacterial infections occur. Approximately 30% of reported measles cases result in one of the following complications: diarrhea, otitis media, pneumonia, and less commonly, acute encephalitis, degenerative neurologic disease (subacute sclerosing panencephalitis [SSPE]), or death.1 SSPE is an invariably fatal, persistent viral infection of neuronal and glial cells caused by a defective virus that occurs after a wild-type measles infection, particularly among children who are infected in the first few years of life. Reports from the prevaccine era suggested rates of SSPE of 5 to 10 cases per 1 million measles cases.1,9 This figure is considered now to be an underestimation because an average of 6 to 10 years occurs between the measles infection and the onset of symptoms of SSPE, making an association difficult to discern. In studies after the 1989–1991 measles outbreak in the United States and Europe, authors report that the rate of SSPE is more common than estimated previously, at least 1 case of SSPE per 5000 measles cases, and is perhaps as common as 1 case per 1000 measles cases among children infected in the first year of life.10,11 In countries where appropriate measles immunization programs have been established, SSPE is nearly undetectable.
In reports from countries in Africa and elsewhere, authors describe higher morbidity and mortality rates among children who experience measles than among children who are not infected. This has been attributed to suppression of innate and adaptive immunity that is associated with natural measles virus infection.12 Some immunologic abnormalities resolve soon after infection, but epidemiological studies demonstrate a strong association between measles virus infection and increased morbidity and mortality for months to years after infection. In recent reports, authors describe immune abnormalities that appear to explain this increased risk of infection after recovery from measles.13–15 During an outbreak of measles in the Netherlands, unvaccinated children were evaluated before measles infection and again 2 months after recovery. Results revealed an impaired adaptive immune response, as evidenced by an 11% to 73% loss of antibody repertoire, after measles infection. This appears to be secondary to measles virus replication in and destruction of both naïve and memory B cells, cells responsible for production of circulating and secreted antibodies. This loss of humoral immunity leaves children at an increased risk for infection from pathogens to which they previously had been immune because of infection or vaccination. Recovery of lost immunity was restored after reexposure to pathogens. Remarkably, despite this immunosuppression, lifelong immunity to measles develops among survivors of acute measles infection. Measles vaccination is not associated with the immunologic deficits associated with wild-type measles infection.
The consequences to a community that does not maintain vaccine-induced protective immunity (herd immunity) to measles can be dramatic. In September 2019, several cases of suspected measles were reported in the Samoan islands, and by October 2019, a national measles outbreak was declared. By January 7, 2020, a total of 5655 cases were reported in the Independent State of Samoa, with an associated 83 deaths mostly in children <5 years of age.16 More than 2.5% of the population of 199 000 people in Samoa became infected. A decline in MMR immunization rates among Samoan children from 90% in 2013 to 34% in 2018 created the opportunity for an outbreak once the measles virus was introduced into the community. Because of the severity of the outbreak, a state of emergency was declared, schools were closed, a curfew was established, public gatherings were prohibited, airline passengers were denied entrance, unimmunized pregnant women were restricted from attending their place of employment, and measles vaccination became mandatory for priority groups. The Samoan Government noted the outbreak “[tears] at the very social fabric of society as every aspect of life is affected.”16
How can pediatricians and other health care experts best counsel families about measles vaccination to avoid the consequences of vaccine hesitancy, such as what occurred in Samoa? Parents must understand they have the power and the responsibility to protect their children from measles by ensuring adherence to the following recommendations from the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics1,17 :
• Routine administration of 2 doses of MMR (or measles, mumps, rubella, and varicella) is recommended as the standard of care for measles prevention. The first dose should be administered at 12 to 15 months, and the second dose should be administered at 4 to 6 years of age. The second dose can be administered as soon as 28 days after the first dose. Two doses of MMR confer long-lived immunity and meet the CDC definition of immune. Measurement of levels of serum antibodies to measles is not indicated in a person who has received 2 documented doses of MMR according to the recommended schedule.
• Special circumstances include the following:
∘ The first MMR dose may be administered as early as 6 months of age in a measles outbreak setting, before international travel, or as postexposure prophylaxis. A dose administered before 12 months of age should not be included as part of the routine 2-dose series. A minimum of at least 28 days should lapse between the first and second dose and between the second and third dose (for children immunized before 12 months). Some evidence suggests that measles vaccination before 12 months of age may be associated with a limited immune response after subsequent vaccine doses compared with measles vaccination at or after 12 months.18 This observation, as well as the low rates of measles occurring in children between the 12-month dose and the second dose at 4 to 6 years, forms the basis for the current recommended schedule in the United States.19
∘ Children and adolescents from kindergarten to 12th grade should have documentation of 2 doses of MMR. Adults 18 years of age and older should have documentation of at least 1 dose of MMR.
∘ Students and staff in a college or other type of post–high school education should have documentation of 2 doses of MMR. If college students or others at increased risk of exposure do not have written documentation of immunization, history of infection, or antibody evidence of immunity, 2 doses of MMR should be administered. People at increased risk who do not have evidence of vaccination or of a measles infection can either be tested for immunity or can be administered 2 doses of MMR 28 days apart without serological testing. There is no increased risk of harm from administering MMR to a person who is already immune to any or all 3 of the viruses.
∘ Health care personnel born in 1957 or later should have serological evidence of immunity or documentation of receipt of 2 doses of MMR. Birth before 1957 is generally considered acceptable evidence of measles immunity.
∘ Persons who received a measles vaccine in 1963–1967 (presently 53–57 years of age) and are unsure of the type of vaccine should receive 1 (if at low risk) or 2 doses (if at high risk) of MMR. The inactivated (killed) measles vaccine used from 1963 to 1967 was not effective.
Before initiation of the mumps vaccination program in this country in 1967, ∼186 000 cases of mumps were reported annually, but the actual number was likely much higher because of underreporting. In addition, 15% to 27% of mumps cases were asymptomatic, but an unvaccinated, infected, asymptomatic person was contagious and able to transmit the virus to susceptible contacts. Parotitis is the most common complication of mumps, followed by orchitis, oophoritis, mastitis, viral meningitis, encephalitis, pancreatitis, and deafness. In the prevaccine era, mumps was the leading cause of viral encephalitis and sudden-onset hearing loss in the United States.20 Breakthrough mumps infection in a fully vaccinated person is less likely to result in severe symptoms or complications compared with infection in an incompletely vaccinated or unvaccinated person. Whether a vaccinated person who experiences asymptomatic breakthrough infection can transmit virus to susceptible contacts is not clear.21 Mumps infection during pregnancy is no more severe than that in women who are not pregnant, and no consistent complication in the fetus is recognized among pregnant women who are infected during gestation. Median mumps vaccine effectiveness is estimated to be 78% after 1 dose and 88% after 2 doses.20
In 2006 a multistate mumps outbreak resulted in >6500 cases mainly involving students on several college campuses in the Midwest.20 In 2009–2010, >3000 people were infected in an outbreak among a close-knit community in New York City. The following year, an outbreak involved 500 people in the United States territory of Guam. Since 2015, an increase in the number of mumps outbreaks has continued to occur in the United States, primarily where people have close, prolonged contact after introduction of mumps into the community.20 Outbreaks often involve populations with high rates of having received 2 doses of MMR. The continued introduction of mumps into this country is demonstrated by the 2019 report that mumps outbreaks occurred among staff and detained migrants in detention facilities in 7 states.22
In 2018 the CDC issued guidance on the use of a third dose of MMR among persons at increased risk for acquiring mumps because of an outbreak.3 The existing recommendation for 2 doses of MMR was determined to offer adequate control of mumps in the general population, and a formal recommendation for a third dose of a mumps-containing vaccine was not issued. However, because of possible waning vaccine immunity after 2 doses of MMR, mumps protection may be lost in a high-intensity exposure setting, such as during an outbreak. Guidance was revised to state that a person previously vaccinated with 2 doses of MMR who is identified by public health authorities to be at increased risk because of a continuing mumps outbreak (such as a college campus or among military personnel) should receive a third dose of MMR. This recommendation was based on experience during previous mumps outbreaks when a third dose of MMR was administered (with institutional review board approval) to the affected populations and subsequent attack rates were lower than those in individuals who had received 2 doses. A third dose appears to temporarily boost immunity and assist in control of an outbreak. However, a third dose is unlikely to confer prolonged immunity. No available evidence indicates additional benefit from >3 doses of a mumps-containing vaccine.
MMR contains the genotype A Jeryl Lynn mumps virus vaccine strain. Among the 12 recognized mumps virus genotypes, genotype G currently is the most common genotype detected in the United States.3 Studies reveal that antibodies induced by the Jeryl Lynn vaccine strain neutralizes genotype G strains, but the antigenic differences between genotype A and genotype G strains may contribute to the lower effectiveness of the Jeryl Lynn vaccine strain, particularly if waning immunity occurs.23 Suggestions have been proposed for a change in the Jeryl Lynn strain to a live attenuated genotype G strain or an inactivated genotype G strain that might provide a superior immune boost compared with a second dose of the Jeryl Lynn strain.24
Rubella is generally a mild viral illness occurring among susceptible children and young adults. Complications of rubella include arthritis in up to 70% of infected adult women, encephalitis, thrombocytopenia, and orchitis.25 The public health importance of rubella is due to the severe complications associated with congenital rubella syndrome (CRS), which occurs in up to 85% of infants born to a woman infected in the first trimester of pregnancy. The last major rubella epidemic in the United States occurred during 1964–1965 and resulted in an estimated 12.5 million cases and 20 000 infants born with CRS. Relative to measles, rubella is less contagious, but like measles, rubella has only a single antigenic type.25
After introduction of the live attenuated rubella vaccine in 1969, reported cases of rubella and CRS declined, but clusters continued to occur among unvaccinated older adolescents and young adults.3 When rubella immunization was directed at adolescent girls or women of childbearing age, the epidemiology remained largely unchanged; CRS still occurred because of infection among unimmunized individuals, enabling the virus to continue to circulate, and recommendations were changed to a routine immunization. During 1989–1991, a global resurgence of rubella occurred, with spread to unvaccinated adolescents and young adults. After initiation of a routine 2-dose MMR schedule in the United States in 1989, cases of rubella and CRS fell to an all-time low. In 2004, endemic rubella was declared eliminated from the United States.26
Estimates from the World Health Organization suggest that >100 000 infants worldwide are born annually with CRS.27 Rubella virus continues to circulate widely in Africa, the Middle East, and South and Southeast Asia. Because >90% of children in the United States have received ≥1 dose of MMR, rubella elimination has been sustained in this country despite the continued circulation of rubella in other parts of the world. In recent years, the few infants born in the United States with CRS generally were born to mothers who were infected while pregnant before coming to this country. The entry of residents from rubella-endemic countries emphasizes the risk of reemergence of CRS if vaccination rates decline. Between 2013 and 2015, a median of 6 imported cases of rubella were reported annually, and a total of 3 cases of CRS were identified in the United States.28 Sporadic cases of CRS occur in the United States, and physicians should be alert to this possibility in the appropriate epidemiological setting. To maintain elimination, high immunization rates among children should be maintained, and unvaccinated women of childbearing age born outside the United States should be vaccinated. Because 2 doses of MMR are recommended in the immunization schedule, most children receive >1 dose of rubella-containing vaccine. Pregnant women without evidence of rubella immunity should be vaccinated immediately post partum.
The success of the MMR vaccination program in eradicating disease in the United States has resulted in complacency, erasing concern regarding the potentially debilitating and fatal illnesses caused by these viruses. Among children 19 to 35 months of age (born in 2015–2016) in the United States, 90.4% have been immunized with ≥1 doses of MMR, but unimmunized and under-immunized children in certain subpopulations have resulted in clusters of measles outbreaks in vulnerable communities where immunization rates are low.29 Data from this survey revealed that 20 states had MMR coverage of <90%. Measles virus transmission will not occur in communities where at least 95% of the population are appropriately immunized.2 Mumps virus infection is less likely to be associated with lifelong consequences compared with measles or rubella infections, but severe disease still may occur in under-vaccinated populations. The tragic complications of CRS are avoided by ensuring that women of childbearing age have received at least 1 dose of MMR. The spread of false concerns by antivaccine activists regarding vaccine safety, particularly on social media, has led to unfounded anxiety regarding vaccine adverse events. In other countries, health care systems have collapsed because of political unrest and armed conflict, resulting in inadequate immunization rates. Wherever immunization rates are suboptimal, the tragic consequences of infection by measles, mumps, and rubella are likely to follow.
The current worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 has brought death, suffering, and economic calamity to much of the globe. Ultimate control of this novel virus likely will depend on the availability of a safe and effective vaccine. Immunity against coronavirus disease 2019 will be acquired 1 of 2 ways: infection by the virus or immunization. In the absence of proven antiviral therapy, immunization will play a pivotal role in ending this epidemic.
In contrast to the high number of infections caused by severe acute respiratory syndrome coronavirus 2, most pediatricians practicing today rarely see a case of measles, mumps, or rubella, a tribute to the effectiveness of MMR. After administration of hundreds of millions of doses, the safety and effectiveness of MMR is without question. The necessity for continued administration of MMR according to the immunization schedule cannot be overstated. Reemergence of these once-controlled diseases is not a legacy that should be left to future generations.
Drs Perrone and Meissner conceptualized and designed the study, drafted the initial manuscript, reviewed the revised manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Meissner serves as ex-officio to the Committee on Infectious Diseases, is a member of the National Vaccine Advisory Committee, is a member of the Vaccine and Related Biological Products Advisory Committee, and is chair of the Vaccine Injury Compensation Program; and Dr Perrone has indicated she has no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.