Mumps: an Update on Outbreaks, Vaccine Efficacy, and Genomic Diversity

Mumps is an acute viral infection characterized by inflammation of the parotid and other salivary glands. Persons with mumps are infectious from 2 days before through 5 days after parotitis onset, and transmission is through respiratory droplets. Despite the success of mumps vaccination programs in the United States and parts of Europe, a recent increase in outbreaks of mumps virus infections among fully vaccinated populations has been reported. Although the effectiveness of the mumps virus component of the measles-mumps-rubella (MMR) vaccine is suboptimal, a range of contributing factors has led to these outbreaks occurring in high-vaccination-coverage settings, including the intensity of exposure, the possibility of vaccine strain mismatch, delayed implementation of control measures due to the timeliness of reporting, a lack of use of appropriate laboratory tests (such as reverse transcription-PCR), and time since last vaccination.

SUMMARY

Mumps is an acute viral infection characterized by inflammation of the parotid and other salivary glands. Persons with mumps are infectious from 2 days before through 5 days after parotitis onset, and transmission is through respiratory droplets. Despite the success of mumps vaccination programs in the United States and parts of Europe, a recent increase in outbreaks of mumps virus infections among fully vaccinated populations has been reported. Although the effectiveness of the mumps virus component of the measles-mumps-rubella (MMR) vaccine is suboptimal, a range of contributing factors has led to these outbreaks occurring in high-vaccination-coverage settings, including the intensity of exposure, the possibility of vaccine strain mismatch, delayed implementation of control measures due to the timeliness of reporting, a lack of use of appropriate laboratory tests (such as reverse transcription-PCR), and time since last vaccination. The resurgence of mumps virus infections among previously vaccinated individuals over the past decade has prompted discussions about new strategies to mitigate the risk of future outbreaks. The decision to implement a third dose of the MMR vaccine in response to an outbreak should be considered in discussions with local public health agencies. Traditional public health measures, including the isolation of infectious persons, timely contact tracing, and effective communication and awareness education for the public and medical community, should remain key interventions for outbreak control. Maintaining high mumps vaccination coverage remains key to U.S. and global efforts to reduce disease incidence and rates of complications.

INTRODUCTION

Clinical Features and Complications

Mumps is an acute viral illness that presents classically with unilateral or bilateral inflammation of the parotid and other salivary glands (1). Nonspecific symptoms that can precede parotitis onset include fever, headache, malaise, and anorexia. The incubation period is typically 16 to 18 days, but it can range from 12 to 25 days (2). In the prevaccine era, up to 30% of infected individuals with mumps were asymptomatic (2, 3) and subclinical infections in which the infected individual exhibited nonspecific respiratory symptoms were more common in young children and older adults (3, 4). Other clinical features of mumps include orchitis among postpubertal males, mastitis and oophoritis among postpubertal females, and pancreatitis (3, 5, 6). On rare occasions, an association between the previous occurrence of mumps orchitis and testicular cancer has been suggested (7–10). An association between maternal mumps virus infection during the first trimester of pregnancy and an increased rate of spontaneous abortion or intrauterine fetal death was reported in the prevaccine era (11); however, this association was not found in another study conducted in the postvaccine era (12).

Other rare complications after mumps virus infection include neurological manifestations, such as sudden sensorineural deafness, aseptic meningitis, and encephalitis (13, 14). The transient hearing loss that occurs among mumps cases can also very rarely result in permanent deafness (15, 16). While aseptic meningitis due to mumps is generally benign, encephalitis is a potentially fatal complication (17, 18). During the prevaccine era, mumps was a leading cause of viral encephalitis in the United States, accounting for one-third of cases of encephalitis (19). Other clinical complications that have been reported include myocarditis, thyroiditis, and thrombocytopenia in the prevaccine era (20–23) and myocarditis, arthropathy, and autoimmune hemolytic anemia in the postvaccine era (5, 24, 25).

Transmission

Transmission of the mumps virus from persons with clinical symptoms is primarily through respiratory droplets (2, 4). People with mumps are infectious from 2 days before through 5 days after parotitis onset (26–28). Therefore, infected individuals should stay home and stay away from others for 5 days after symptom onset to prevent further transmission (28, 29). Furthermore, transmission also occurs from persons with asymptomatic infections, highlighting the challenges in preventing virus transmission (30). Infection has been reported after natural infection and in persons previously vaccinated with one or more doses of vaccine (31–34).

DIAGNOSTIC TESTING

Laboratory testing can aid in the diagnosis of mumps to distinguish from noninfectious and other infectious etiologies of parotitis (i.e., parainfluenza virus types 1 and 3, Epstein-Barr virus, influenza A virus, coxsackie A virus, echovirus). Important diagnostic tests used in supporting mumps diagnosis include detection of mumps virus-specific immunoglobulin M (IgM) antibody and mumps virus detection by reverse transcription-PCR (RT-PCR) (35).

IgM Response in Vaccinated and Unvaccinated Individuals

Validated commercial assays are currently available for detection of mumps virus-specific IgM antibodies from serum. In a nonimmunized infected individual, virus-specific serum IgM levels are detectable within a few days of symptom onset, with peak levels occurring after 1 to 2 weeks and the levels declining 4 to 8 weeks thereafter, but they can remain elevated for several weeks to months (36–38). Percent positivity of IgM testing is impacted by the timing of specimen collection, with better performance being achieved with samples taken further from the time of symptom onset (32, 39, 40). Previous reports have shown that mumps virus-specific IgM was detected in 67% to 100% of unvaccinated mumps virus-infected cases (41–45).

Among immunized infected individuals, mumps virus-specific IgM levels are often not detectable during clinical presentation due to a transient or nondetectable IgM response in those with previous infection or vaccination. Detection of IgM varies by assay (39, 40); however, even the most sensitive assay using an IgM-capture technique reported a detection rate of approximately 50% among previously vaccinated persons (40). Studies have shown suboptimal IgM detection rates of as low as 4% among one-dose and two-dose mumps virus-containing vaccine recipients (31, 32, 44, 46–49). Therefore, negative mumps virus-specific IgM test results should not be used alone to rule out mumps in previously vaccinated individuals.

Importance of PCR Testing in Highly Vaccinated Populations

Since mumps virus-specific IgM may be undetectable in specimens collected from populations with high vaccination rates, the use of RT-PCR is often crucial and more reliable for diagnosis (50–52). RT-PCR has much greater sensitivity in detecting mumps virus infection than serological testing (32, 40, 44, 46, 53–57). Some evaluations have shown higher RT-PCR positivity rates among cases who had not received or who had received one dose of a mumps virus-containing vaccine than among those who had received two doses (32, 46, 58). However, Rota et al. did not find an association between PCR percent positivity and vaccination status (40).

The success of virus detection is dependent on the specimen quality, including the timing of collection, storage, and handling, as well as the assay used (32, 40, 46, 56). Provider education regarding procedures of buccal swab collection for RT-PCR testing is crucial for laboratory confirmation. Buccal swab specimens collected as soon as possible, ideally, within 3 days of parotitis onset, and after massaging of the parotid gland for approximately 30 s will yield better virus detection results. Mumps viral RNA may be detectable within 8 to 10 days of symptom onset in a primary infection (32, 35, 40, 46, 53). Assays targeting the nucleoprotein (N) gene of the mumps virus genome generally report a higher sensitivity than assays targeting the short hydrophobic (SH) gene, as a consequence of higher levels of expression of the N mRNA than of the SH mRNA (40).

IgG—a Poor Correlate for Protection

Among unvaccinated persons, the mumps virus-specific immunoglobulin G (IgG) antibody level often rapidly increases after symptom onset and peaks at about 2 to 3 weeks post-symptom onset (48). Standardized levels of IgG that correlate as a marker of protection against mumps currently do not exist (59). Thus, while a positive mumps virus-specific IgG result from commercial assays is used as a proxy for immunity, it may not consistently confirm protection, but a negative IgG result can be helpful in ruling out protection against mumps. This is in contrast to the international standards for protection against measles and rubella established through a correlation with the results of clinical studies (60–62). The enzyme-linked immunosorbent assay (ELISA) method is widely used for serological testing for IgG; however, this method is unable to distinguish between the levels of neutralizing antibodies and those of nonneutralizing antibodies and is therefore prone to unreliable results for immunity.

Plaque reduction neutralization (PRN) has been suggested to be a reasonable marker for immunity against mumps virus infection (59). In contrast to ELISA, the PRN method measures the level of IgG antibody needed to neutralize 50% of the mumps virus plaque formed in cell cultures (63–65). Although such virus neutralization assays are likely the most predictive technique for assessing immunity against mumps, these assays are not routinely commercially available, and methods of PRN are not standardized internationally and are difficult to scale up due to the extensive time and skilled labor required. To further complicate the process, the level of virus-neutralizing antibody is dependent on the virus strain used, which may vary between assays (66–70). In addition, the precise level of neutralizing antibody required for protection has been difficult to establish (67, 71, 72).

GENOMIC DIVERSITY

Introduction to Mumps Virus Genome

With the advancement of molecular methods, there has been growing interest in the characterization of the mumps virus genome to better understand transmission pathways and the potential uses of such molecular techniques to distinguish wild-type from vaccine-associated cases (52, 73, 74). The mumps virus is an enveloped, negative-strand RNA virus that belongs to the genus Orthorubulavirus in the subfamily Rubulavirinae and the family Paramyxoviridae (75). The mumps virus genome is 15,384 nucleotides in length and encodes seven types of structural proteins, consisting of one membrane-associated small hydrophobic (SH) protein, two surface glycoproteins (fusion [F] and hemagglutinin-neuraminidase [HN]), and four core proteins (nucleoprotein [N], phosphoprotein [P], matrix [M], and large protein [L]), as well as V, a nonstructural protein that plays a role in combating the innate immune responses of the host cell (76).

The HN protein is a target site for mumps virus-specific neutralizing antibodies as part of the humoral immune response. Laboratory studies have shown the F and HN proteins to be virulence factors through viral neutralization by antibodies and the HN gene to be a genetic target of a recombinant vaccine against mumps that could potentially be developed using molecular techniques (77–81). The gene in the mumps virus genome with the most variable sequence is the SH gene; this variability was used to standardize the nomenclature for the mumps virus (82) and is used to differentiate between wild-type and vaccine-associated strains (83–85). Furthermore, the variability in the SH gene is responsible for mumps virus genomic diversity, with differences between the nucleotide sequences of the different mumps virus genotypes of 5% to 21% being detected (52). Recent studies have reported greater genotyping resolution by adding F and HN gene sequences to the SH gene sequences and using molecular markers based on genomic noncoding regions (NCRs) (86, 87).

Mumps Virus Genotypes and Nomenclature

In 2012, WHO updated and assigned to the 12 genotypes of mumps virus a standard nomenclature designated by the letters A to N (excluding E and M), based on the SH and HN sequences of the mumps virus genome (52). Genotypes E and M, which were originally based only on SH sequences, were later invalidated and reclassified as genotypes C and K, respectively, because of updated phylogenetic analysis of SH sequence data. Genotyping of mumps virus is now primarily based on the nucleotides of the SH sequence, except when the HN gene sequence is used for further characterization when samples have equivocal results (52).

Standardization of the nomenclature for individual mumps virus strains is important, as it enables direct sequence comparisons between strains and helps delineate the transmission pathways of virus strains. The naming of strains of mumps virus follows procedures similar to those used for measles virus, where the source of the specimen (a clinical or cell culture isolate), the location (city and country) and the time (week and year) of disease onset, and genotype assignment (wild-type or vaccine virus) are indicated in the nomenclature (88).

Intra- and Intergenomic Diversity and Global Distribution of Wild-Type Genotypes

More than 1,250 mumps virus sequences have been established and stored in a centralized open access database, GenBank, along with full-length coding sequences and a phylogenetic tree of the viral genomes (76, 89). Based on the whole-genome sequences, substantial intragenotype variation exists within the SH and HN sequences. The greatest intragenotype variation was 11%, based on the nucleotide sequences of the SH genes of genotype H strains (52). As for genomic differences between genotypes, the highest intergenomic difference, based on SH gene nucleotide sequences, was 7% between genotypes A and F (76).

Although a limited number of countries conduct molecular surveillance activities, distinct genetic lineages of mumps virus have been reported globally. With the increasing use of sequencing techniques, a growing knowledge of the geographic distribution of mumps virus has been made possible (76). Wild-type mumps viruses of genotypes C, D, G, H, J, and K have been described to circulate predominantly in the Western Hemisphere, and those of genotypes B, F, G, I, and L have been described to circulate predominantly in Asia. Genotype sequencing has also identified the cocirculation of various mumps virus genotypes in the same country and the direct importation of wild-type mumps virus across national borders (76). However, in recent outbreaks among vaccinated populations, genotype G was the most widely circulated mumps virus genotype detected globally in several outbreaks, particularly in the United States, Western Europe, and Japan (76, 90, 91). As more sequence data become available, our understanding of the geographical distribution and the global transmission pathways of mumps virus will continue to improve. Application of next-generation sequencing (NGS) methods will also provide greater resolution and accuracy in mapping transmission pathways (89).

PREVENTION BY VACCINATION

Vaccine Development and Evidence of Immunity

The first routinely used live attenuated mumps virus vaccines were developed in the 1950s and 1960s (65, 92). The most commonly used mumps vaccine strains worldwide include the Jeryl Lynn, Urabe AM9, and Leningrad-Zagreb strains (93–95). Other vaccine strains, such as the Rubini and Hoshino strains, have had limited use due to their poor immunogenicity (96–98). In addition, the high reactogenicity of the Urabe AM9 strain led to its withdrawal in Japan, which does not currently vaccinate against mumps and which only supplies the measles-rubella (MR) vaccine (99). Mumps virus-containing vaccines are supplied as lyophilized powders requiring reconstitution with sterile water. Reconstituted vaccine is stable at 4°C for only 8 h once it is reconstituted; if it is not administered within this time frame, the vaccine must be discarded. The vaccine is given by subcutaneous administration. Currently, mumps vaccines are manufactured as a monovalent vaccine, a bivalent formulation with the measles vaccine, a trivalent formulation with the measles and rubella vaccines (MMR vaccine), and a quadrivalent formulation with the measles, rubella, and varicella vaccines (MMRV vaccine). In the United States, only the MMR and MMRV vaccines are currently available.

By the end of 2018, 122 of the 194 (63%) WHO member states had implemented at least one dose of a mumps virus-containing vaccine into their national immunization programs (100). Globally, the first dose of the mumps vaccine is typically administered at ages 12 to 18 months and a second dose is administered at ages 2 to 6 years (101). Seroconversion rates in children ages 6 months or younger are lower than those in children ages 9 months or older (70% and >90%, respectively), likely due to interference from maternal mumps antibody and potentially also from an intrinsic deficiency in the humoral immune response (102). The recommended schedule for the second dose of mumps vaccine in each country is often driven by measles prevalence and, hence, varies globally, with over a third (48/145) of countries administering the second dose at 10 to 23 months of age (99). In the United States, the Advisory Committee on Immunization Practices (ACIP) recommended one dose of the MMR vaccine for children aged 12 to 15 months in 1977 and updated the recommendation to a two-dose schedule in 1989, with the second dose being administered at 4 to 6 years of age to decrease measles transmission and help achieve the goal of measles elimination (1, 103).

Acceptable evidence of immunity against mumps generally includes one of the following: laboratory evidence of immunity or disease, birth before 1957, or written documentation of adequate vaccination, which includes two doses of a mumps virus-containing vaccine for school-age children and adults at high risk (i.e., university students, health care personnel, and international travelers) or one or more MMR doses administered on or after the first birthday for preschool-age children and adults not at high risk (1). Verbal reports of vaccination without written documentation should not be accepted as presumptive evidence of immunity.

Vaccine Effectiveness

Depending on the specific vaccine strain used, the median effectiveness of the mumps vaccine is 78% (range, 49% to 92%) for one dose and 88% (range, 66% to 95%) for two doses, which is generally lower than the effectiveness of its measles and rubella vaccine counterparts (1, 104–106).

Although primary vaccine failures have been reported, mumps vaccine recipients who do not seroconvert after the first dose typically produce an immune response after the second dose of the MMR vaccine (107–109). Studies have shown lower rates of seroconversion to mumps with administration of the combination MMRV vaccine than with the concomitant administration of MMR and varicella vaccines separately; however, the differences in seroconversion rates were not statistically significant and were not observed after administration of a second dose (110–113). In regards to the timing of the two-dose MMR vaccine series, delaying the second MMR vaccine dose from 4 years to 7 years of age did not produce any improvement in the mumps virus-specific neutralizing antibody levels over a 12-year period (114).

Cellular Immune Response

Vaccine-induced cell-mediated responses may play a protective role against mumps virus infection, although their precise role remains unclear. The levels of mumps virus-specific CD4⁺ T cells, gamma interferon, and interleukin-10 following vaccination have been reported to be as high as those following natural infection (115, 116). However, the lymphoproliferative responses induced postvaccination with the Rubini vaccine strain were similar to those induced following vaccination with the Jeryl Lynn strain, thereby suggesting a poor correlation between cellular immunity and vaccine effectiveness against mumps disease (117). It has been suggested that mumps virus infection, rather than childhood vaccination, induces persistent polyfunctional CD8⁺ T-cell memory; however, evaluation of mumps virus-specific T-cell responses in a mumps outbreak setting may provide evidence of whether the levels of polyfunctional T cells could be a correlate of protection against mumps (118).

UPDATE ON MUMPS OUTBREAKS

Impact of Vaccine Introduction

In the prevaccine era, the incidence of mumps ranged from 100 to 1,000 per 100,000 population per year globally, with outbreaks occurring every 2 to 5 years during the winter and spring months in countries with temperate climates (52, 119, 120). Young school-aged children were the most affected group before mumps vaccine introduction (1, 121). In the United States, more than 185,000 mumps cases were reported each year prior to vaccine introduction, affecting predominantly children aged 5 to 9 years. In addition, mumps also affected adults in close-contact settings, such as U.S. military troops on active duty during World War I (122).

Since vaccine introduction, the incidence of mumps has been reduced globally by more than 88% with one-dose vaccination schedules and by 97% with two-dose vaccination schedules (119). A dramatic reduction in mumps cases was observed in the United States following vaccine introduction in 1967 and the routine use of one dose of the MMR vaccine in 1977 (1, 123). In 1986 and 1987, a resurgence of measles cases among unvaccinated individuals in the United States resulted in the implementation of a two-dose MMR vaccination policy in 1989, which subsequently led to a further reduction in the incidence of mumps to 0.1 case per 100,000 population by 2001 (123–125). Following the introduction of the recommendation for vaccination with two doses of the MMR vaccine in the United States, nearly one-third of reported mumps cases were among those aged 15 years and older, resulting in an epidemiological shift to older age groups, a pattern that was also observed for measles and rubella as a result of immunization programs targeting preschool-aged children and reducing virus transmission among individuals in younger age groups (126). In the postvaccination era, outbreaks among adolescents and young adults, particularly among college students, were reported, suggesting an epidemiological shift toward an older age group (5, 32, 127–129).

Recent Increase in Disease Incidence

Despite the success of the U.S. mumps vaccination program, there have been increasing numbers of mumps outbreaks in the United States among fully vaccinated young adults living and interacting in congregate settings, such as postsecondary education institutions and close-knit communities. In the United States, a number of outbreaks of mumps have been reported since 2006 (5, 53, 54, 130). A large multistate outbreak in 2006 with over 6,500 cases was the largest mumps outbreak in the United States in nearly 2 decades and primarily affected vaccinated university students aged 18 to 24 years, of whom ∼84% had previously received two doses of the mumps vaccine (30, 131). Another large multistate outbreak in 2009 and 2010 with over 3,500 cases disproportionally involved vaccinated adolescents 13 to 17 years of age in a religious community, of whom 89% had previously received two doses of a mumps virus-containing vaccine (53). The recent phenomenon of outbreaks of breakthrough disease among highly vaccinated populations, however, was previously reported in populations in large urban areas, such as New York City, as early as 1998, with over 90% of cases in a single outbreak having at least one previous dose of a mumps virus-containing vaccine (132).

These outbreaks may have been of a greater magnitude, had a wider spread, and been of a longer duration if the affected communities had not had high vaccination coverage rates. Previous reports have suggested some value of mumps vaccination in limiting attack rates and the scope of outbreaks (26, 30, 133, 134). In addition, the rates of complications following mumps disease were lower among those who had previously been vaccinated (53, 87, 135–137). During the 2009 and 2010 outbreak referenced above, persons infected with the mumps virus who had received two doses of the MMR vaccine were less likely to report orchitis, deafness, meningitis, and oophoritis than unvaccinated persons or persons who had received one dose of vaccine (53).

Recent mumps outbreaks among young adults worldwide also illustrate a resurgence of mumps in countries that once had successfully controlled viral transmission (137–146). In contrast to recent U.S. outbreaks among highly vaccinated adolescents and young adults, some of these outbreaks were due to additional factors, such as the use of vaccines with poor immunogenicity (i.e., vaccines containing the Rubini strain); declining rates of vaccine coverage; and failure to vaccinate, including because of noncompliance with vaccination schedules, vaccine shortages, missed catch-up vaccination, or removal of the mumps virus antigen from vaccination schedules due to a reactogenic vaccine (i.e., the vaccine containing the Urabe AM9 strain) (130, 137–139, 141–149).

Factors Contributing to Outbreaks among Vaccinated Populations

Although a failure to vaccinate with the two recommended doses of the MMR vaccine may have contributed to a small number of cases in U.S. outbreaks, recent large protracted outbreaks have predominantly been in populations with high rates of coverage with two doses of the vaccine (5, 32, 53, 150–153). Settings with a high population density or prolonged person-to-person contact can facilitate viral transmission due to the nature of transmission of the mumps virus through respiratory droplets (53, 54, 154–156).

The mumps virus is serologically monotypic, suggesting the possibility of cross-neutralization of various genetically different strains of the virus by antibodies induced by one particular strain, although different vaccine strains produce various levels of neutralizing antibodies (157). However, recent molecular and structural biology studies have reported key differences in antigenic epitopes between the vaccine and wild-type strains in recent outbreaks among vaccinated populations, thereby suggesting the possibility of antigenic mismatch (158–162).

A factor contributing to the large number of recent mumps virus infections among previously vaccinated young adults is likely waning immunity. The levels of mumps virus-neutralizing antibody induced by vaccines are generally lower than the levels induced following a natural infection (163–165). Reports have also shown declining levels of anti-mumps virus antibody with the period of time following vaccination (69, 107, 114, 166–169). Recent studies have demonstrated an increased risk of mumps virus infection as a result of time since vaccination (31, 131, 144, 170, 171). In a recent university mumps outbreak, students who had received their second MMR vaccine 13 years or more prior to the outbreak had a 9-fold greater risk of mumps disease than those who were vaccinated after that time frame (172). However, time since vaccination may not be the sole contributing factor for all recent outbreaks, as some studies have not demonstrated waning immunity as a risk factor for disease (164, 173–178).

The intensity of exposure may also be a factor contributing to the recent upsurge of mumps outbreaks. Previous studies have reported lower vaccine effectiveness and a higher risk of mumps virus infection in congregate exposure settings, such as household contacts and close-knit religious communities, where intense transmission is more likely to occur (53, 154, 179). Such densely populated environments with prolonged face-to-face contact can facilitate larger doses of mumps virus exposure during social interactions, which may overcome vaccine-mediated protection and result in secondary vaccine failure.

Delays in the recognition of mumps cases as a result of low rates of awareness of RT-PCR and a reliance on serological testing alone may have also contributed to recent outbreaks (54, 56, 156, 180, 181). A negative result for mumps virus-specific IgM should not be a sole criterion to rule out a mumps diagnosis because of the low sensitivity of serological testing for mumps virus in previously vaccinated persons (32, 40, 53, 54). The failure to use RT-PCR for diagnostic testing has resulted in missed diagnoses and delays in the implementation of control measures in previously reported outbreaks among individuals in highly vaccinated populations (56, 180).

Early recognition and reporting to local health departments may also help facilitate the rapid implementation of control measures (56). In light of all the possible contributing factors, a combination of various elements, including waning immunity, intense close-contact exposure, the limitations of existing diagnostic tests for mumps, the possibility of vaccine and wild-type virus antigenic mismatch, the insufficient use of PCR testing, and delayed recognition and reporting, likely contributes to mumps outbreaks that occur in an era with historically high rates of vaccination coverage, where boosting of immunity through natural reinfection is not as common.

Role of a Third Dose of MMR in Outbreak Control

Mumps virus-containing vaccines have been used for outbreak control among unvaccinated populations (150–153, 178). Postexposure prophylaxis with vaccination has not been shown to reduce the risk of infection or the severity of disease after exposure to mumps and is not recommended (106). New strategies to avert future outbreaks are now being considered due to an increase in the incidence of mumps outbreaks involving fully vaccinated populations. Proposed strategies include changes in vaccination policy, such as the addition of a third MMR dose to the two-dose recommendation during either outbreaks or the adolescent years, as well as the development of a more effective mumps vaccine (5, 54, 131, 182–184). A new inactivated or killed mumps virus-containing vaccine which would allow for more targeted control of the disease would require a significant amount of time and resources for development, clinical trials, and licensure, as well as extra vigilance for potential adverse events that have been seen with previously licensed or tested inactivated or killed virus vaccines (i.e., measles and respiratory syncytial virus vaccines) (160, 185).

A few studies have described the immune response following a third dose of the MMR vaccine; however, the interpretation of such findings is limited, given the lack of clear correlates of protection against mumps (167, 186). Evidence for recommendation of a third dose of the MMR vaccine has been limited. However, recent mumps outbreaks among highly vaccinated individuals in university settings have provided opportunities to evaluate the effectiveness of a third MMR dose for reducing viral transmission in congregate settings (54, 172, 183, 184, 187).

Reductions in attack rates after implementing a third dose of the MMR vaccine have been demonstrated in several school-based outbreaks; however, the intervention began when cases started to decline and after the peak of the outbreak. Other methodological weaknesses included small sample sizes, large confidence intervals, nonsignificant statistical analysis results, and selection bias, making it difficult to draw conclusions about its effectiveness (183, 184). During a more recent mumps outbreak in a highly vaccinated university setting, a formal evaluation was conducted to determine the effectiveness of a third MMR dose if it was given prior to the peak of an outbreak (172). In this study, the attack rate was significantly lower among the students who had received three doses (6.7 cases per 1,000 population) than among those who had received two doses (14.5 cases per 1,000 population). Furthermore, the students in this outbreak who had received three doses had a 78% lower risk of mumps than the recipients of two doses of the MMR vaccine. Vaccine-induced waning immunity was demonstrated, with students having a greater risk of mumps if they had received their second MMR dose 13 years or more before the outbreak. The limitations of this study included the fact that only 25% of the students were vaccinated with a third dose and the findings that recipients of the third dose also developed mumps.

Recently, the ACIP in the United States recommended that persons previously vaccinated with two doses of a mumps virus-containing vaccine who are identified by public health agencies to be at increased risk for mumps because of a mumps outbreak should receive a third dose of a mumps virus-containing vaccine to improve protection against mumps disease and related complications (188). Identification of those at increased risk for mumps during an outbreak for the purposes of targeting individuals who should receive a third dose should be made in discussions with public health agencies and affected institutions. The recommendations for the use of a third MMR vaccine dose for individuals at an increased risk of mumps during an outbreak were recently published (188). Guidance to help with the decision of whether to recommend a third dose of the MMR vaccine during a mumps outbreak is based, in part, on being able to identify groups of persons likely to be in close contact with a mumps patient and evidence and the likelihood of ongoing mumps transmission (189). Additional data on the impact of a third MMR vaccine dose on the incidence of mumps and adverse events, as well as its programmatic implications and cost-effectiveness, are needed.

In 2013, France recommended a targeted policy for administration of a third dose of the MMR vaccine for individuals who had received their second dose more than 10 years earlier during outbreaks in congregate settings (146). Standard public health measures, such as rapid identification and social isolation of infectious patients, effective contact tracing, ensuring up-to-date MMR vaccination of the populations at the highest risk, and educational awareness for providers and public, should remain the standard outbreak control measures (28, 29, 35, 180).

CONCLUSION

A recent increase in outbreaks of mumps virus infections among fully vaccinated populations has been reported in the United States. Vaccination should, ideally, provide lifelong humoral and cellular immune protection; however, the humoral immune response to a mumps virus-containing vaccine is lower than that following natural infection and appears to wane with time. At present, there is also a limited understanding of the role of cell-mediated immunity to mumps following vaccination.

Although the effectiveness of the mumps virus component of the MMR vaccine is suboptimal, a range of contributing factors have led to outbreaks occurring in high-vaccination-coverage settings, including the intensity of exposure; the possibility of a vaccine strain mismatch; the delayed implementation of control measures due to the timeliness of reporting and a lack of use of appropriate laboratory tests, such as RT-PCR; time since last vaccination; and a lack of natural boosting of responses as a result of the reduced circulation of wild-type virus. Expansion of enhanced surveillance activities and advanced molecular testing can also improve our understanding of the transmission pathways of mumps virus as well as its global distribution.

The resurgence of mumps virus infections among previously vaccinated individuals over the past decade has prompted discussions for new strategies to mitigate the risk of future outbreaks and also prevent public mistrust of vaccines. The need for a better-performing mumps vaccine has been suggested; however, further characterization of the vaccine-induced immune response against mumps, including a reliable correlate of protection, would aid the development of such a vaccine.

The decision to implement a third dose of the MMR vaccine as an outbreak response may be considered in discussions with local public health agencies. Traditional public health measures, including the isolation of infectious persons, timely contact tracing, and effective communication and awareness education for the public and medical community, should remain key interventions for outbreak control. Additional studies evaluating the long-term protection provided by three MMR doses and the cost-effectiveness of implementation of a policy recommending a third dose of the MMR vaccine will be beneficial for making future recommendations to prevent mumps transmission. As more evidence emerges for new strategies to address the resurgence of mumps in the postvaccination era, it is important to remember that the mumps vaccine has been responsible for a marked reduction of the incidence of disease and rates of complications in many countries that have successfully implemented its use.

Biographies

Eugene Lam, M.D., M.P.H., received his doctor of medicine at the University of Alberta, Canada, and his master of public health training at the London School of Hygiene and Tropical Medicine in the United Kingdom. He was the Unit Chief of Surveillance (2016 to 2018) in the Bureau of Immunization at the New York City Department of Health and Mental Hygiene while this review was written. Dr. Lam previously served as an Epidemic Intelligence Service Officer and Medical Epidemiologist at the U.S. CDC (2011 to 2016), providing technical support to WHO, UNICEF, UNHCR, and various Ministries of Health in Asia, Africa, and the Middle East in strengthening surveillance systems for vaccine-preventable diseases, routine immunization programs, and outbreak response and control activities. In 2018, he was appointed as a Technical Officer in Vaccine Safety at the WHO Regional Office for Europe in Copenhagen, Denmark. Currently, Dr. Lam works as an Associate Director in Vaccine Clinical Research and Development at Pfizer.

Jennifer B. Rosen, M.D., received her medical degree from the Stony Brook School of Medicine and completed her B.S. degree from Cornell University. She completed a residency in internal medicine at New York University. Dr. Rosen served as an Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention with the Respiratory Diseases Branch from 2007 to 2009, where she investigated outbreaks of infectious diseases. In 2009, she joined the New York City Department of Health and Mental Hygiene as the Unit Chief for Vaccine Preventable Disease Surveillance in the Bureau of Immunization. Since 2012, Dr. Rosen has served as the Director of Epidemiology and Surveillance for the Bureau of Immunization and oversees and guides surveillance and epidemiological analyses and leads investigations of outbreaks of measles, mumps, and other vaccine-preventable diseases. She also oversees the monitoring of compliance with immunization requirements in schools and day care centers.

Jane R. Zucker, M.D., M.Sc., earned her medical degree from the Mount Sinai School of Medicine and her master’s in epidemiology from the Harvard School of Public Health. She completed an internal medicine residency and infectious disease fellowship and is a Fellow in the Infectious Disease Society of America. Dr. Zucker started with the CDC in 1990 as an Epidemic Intelligence Service Officer in the Malaria Branch and was later assigned to the United Nations Children’s Fund in 1996 to oversee its global polio eradication initiative. In 2000, she joined the Bureau of Immunization, New York City Department of Health and Mental Hygiene, as the Medical Director. Dr. Zucker is currently the Assistant Commissioner for the Bureau of Immunization and responsible for leadership of the immunization program, including policy development and program management. Under her leadership, vaccination coverage for routinely recommended vaccines across the lifespan has increased and access to vaccination has expanded.