Abstract
Following decades of declining mumps incidence amid widespread vaccination, the United States and other high-income countries have experienced a resurgence in mumps cases over the last decade. Outbreaks affecting vaccinated individuals—and communities with high vaccine coverage—have prompted concerns about the effectiveness of the live attenuated vaccine currently in use: it is unclear if immune protection wanes, or if the vaccine protects inadequately against mumps virus lineages currently circulating. Synthesizing data from epidemiological studies, we estimate that vaccine-derived protection wanes at a timescale of 27 (95%CI: 16 to 51) years. After accounting for this waning, we identify no evidence of changes in vaccine effectiveness over time associated with the emergence of heterologous virus genotypes. Moreover, a mathematical model of mumps transmission validates our findings about the central role of vaccine waning in the re-emergence of cases: outbreaks from 2006 to the present among young adults, and outbreaks occurring in the late 1980s and early 1990s among adolescents, align with peaks in the susceptibility of these age groups attributable to loss of vaccine-derived protection. In contrast, evolution of mumps virus strains escaping pressure would be expected to cause a higher proportion of cases among children. Routine use of a third dose at age 18y, or booster dosing throughout adulthood, may enable mumps elimination and should be assessed in clinical trials.
One Sentence Summary The estimated waning rate of vaccine-conferred immunity against mumps predicts observed changes in the age distribution of mumps cases in the United States since 1967.
Introduction
Over the last decade, mumps outbreaks have thwarted the goal of eliminating indigenous mumps virus transmission in the United States by the year 2010 (1, 2). Whereas over 90% of US-born children experienced mumps infections by age 20 in the pre-vaccine era (3), incidence declined substantially after licensure of a live attenuated vaccine (Jeryl Lynn strain) in 1967, in particular after the recommendation for its routine use among infants in 1977 as part of the measles-mumps-rubella (MMR) vaccine (2). Outbreaks among vaccinated middle school-and high school-aged children arose in the late 1980s, followed by sustained reductions in incidence after children were recommended to receive a second MMR dose at ages 4-6y (4). However, an ongoing resurgence in mumps cases began with a series of outbreaks on university campuses in 2006 (2). An older age of infection (ages 18-29y, compared to the pre-vaccine average of 5-9y) has been a defining feature these outbreaks (5), similar to recent experience in Canada, western Europe, and high-income Asian countries with routine MMR vaccination (6–9).
These circumstances are troubling on two fronts. First, as many as 10% of mumps infections acquired after puberty may cause severe complications including orchitis, meningitis, and deafness, in contrast to a milder clinical course in children that typically involves fever and parotid gland swelling (10). Second, a majority of mumps cases in recent outbreaks have been reported among young adults who received two vaccine doses as recommended (11). This observation has prompted concerns about suboptimal performance of the Jeryl Lynn vaccine currently in use (12).
It is unclear whether recent breakthrough outbreaks in vaccinated communities are due to waning of vaccine-derived immunity or to the emergence of mumps virus strains escaping vaccine-driven immunological pressure. Distinguishing between these possibilities is critical to policymakers and members of the scientific and medical communities: at issue is whether mumps can be eliminated by modifying vaccine dosing schedules, or if a new vaccine must instead be developed (12). To this end, we sought to distinguish waning of vaccine-derived protection from long-term changes in vaccine effectiveness (VE) against circulating mumps strains using data from previous studies. We then measured the potential impact of waning on population immunity over the decades since vaccine licensure, and used mathematical models to assess whether recent mumps virus transmission dynamics are more consistent with hypotheses of waning immunity or vaccine escape. We used these findings to evaluate alternative vaccination policies aiming to enhance protection among adults.
Results
Evidence of waning immunity in studies of vaccine effectiveness
Uncertainty about the protective efficacy of the Jeryl Lynn mumps vaccine—ranging from 95% following a single dose in randomized controlled trials (13) to <50% 2-dose effectiveness during recent outbreaks (14)—has undermined efforts to gauge population immunity. This variation in estimates of effectiveness permitted us to evaluate several hypotheses about the reasons mumps cases have re-emerged among vaccinated persons (2, 12). Fitting a meta-regression model to data from prospective and retrospective cohort studies, we identified that the time elapsed since receipt of an individual’s last vaccine dose accounted for 66.4% of unexplained variation in published vaccine effectiveness estimates (Figure 1A-C). Applying our estimate of the vaccine waning rate to a model of exponentially-distributed durations of protection, we estimated that immunity persists, on average, 27.4 (95% confidence interval: 16.7 to 51.1) years after receipt of any dose. Among the 96.4% (94.0 to 97.8%) of individuals expected to mount primary responses to mumps vaccination, we thus expected 25% may lose protection within 7.9y (4.7 to 14.7y), 50% within 19.0y (11.2 to 35.4y), and 75% within 38.0y (22.4 to 70.8y).
The gradual replacement of predominantly genotype A mumps virus in the pre-vaccine era by other genotypes after vaccine introduction has also been suspected to contribute to diminished protection. However, we did not find evidence of a decline in vaccine effectiveness over calendar years, in particular after controlling for the effect of vaccine waning (Figure 1D). We also did not identify a difference in the duration of protection after first and second doses (Figure 1E). Whereas second doses were originally recommended to bolster immunity in case of failed “take” of the first dose, our findings suggest the second dose also restores immunity to levels achieved prior to waning of the first dose, thus extending protection to older ages. Taken together, our findings supported the central role of waning immune protection as a driver of variation in estimated effectiveness of mumps vaccine.
Changes in population susceptibility to mumps virus after vaccine introduction
To understand the epidemiologic context of mumps resurgence in older age groups, we next sought to assess how waning vaccine-derived immunity and declining rates of natural transmission have impacted the susceptibility of the US population over the decades since vaccine introduction. We inferred the degree of immune protection as of 1967, when the vaccine was licensed, by fitting a mathematical model to reproduce epidemiological dynamics in the pre-vaccine era at steady state (15). We estimated that the basic reproductive number (R0) of mumps in the United States—the number of infections expected to result from an index case in a fully-susceptible population—was 4.79 prior to vaccine rollout, in agreement with previous estimates of 3–7 for high-income settings in the twentieth century (16, 17). Allowing for loss of naturally acquired immunity did not improve model fit (15), consistent with longer-term persistence of high antibody titers after natural infection in comparison to vaccination in children (18).
The ongoing resurgence in mumps among young adults corresponds with cohort-specific changes in susceptibility resulting from vaccine waning and declining transmission over the decades since vaccine rollout (Figure 2). We estimated that 52.8% (41.6% to 63.1%) of adults ages 20-24y and 52.6% (42.4% to 61.3%) of adults ages 25-29y were susceptible to mumps virus infection in 2006 at the outset of the ongoing resurgence, in contrast to 33.8% (30.4% to 37.6%) and 25.2% (22.8% to 27.5%), respectively, as of 1990, and <10% in each age group before vaccine introduction. Susceptibility has also permeated older age groups amid the replacement of cohorts that experienced mumps as children. Whereas most individuals ages 65 and older had natural immunity as of 2016, we estimated that 29.2% (24.7% to 32.3%) of those ages 40-64y were at risk of infection. We expect these levels to continue increasing as transient vaccine-derived immunity supersedes previous infection as the main determinant of mumps susceptibility in the US population.
In a further validation of model predictions, the emergence and disappearance of mumps outbreaks among adolescents during the late 1980s and early 1990s corresponds to a transient increase in predicted susceptibility at ages 10-19y (Figure 2). We estimated that susceptibility at ages 10-14y peaked in 1991, when 45.8% (39.3% to 52.4%) of children in this age group were at risk for infection, as well as 43.0% (37.3% to 49.0%) of adolescents ages 15-19y. These levels reflect 2.85 (2.65 to 3.30)-fold and 3.96 (3.43 to 4.52)-fold increases in age-specific susceptibility, respectively, compared to the pre-vaccination era. Whereas breakthrough outbreaks beginning in the 1980s were hypothesized at that time to reflect inadequate responses of children to their first vaccine dose (19), our findings instead suggest that vaccine waning and declining natural exposure explain why adolescents were the population at highest risk for infection at that time.
We estimate that as of 2016, prevalence of susceptibility among children ages 10-14y declined to 34.8% (24.3 to 45.7%) due to the recommendation in 1989 for children to receive a second dose at ages 4-6y (4). Whereas most adolescents experiencing cases during the initial resurgence had received one dose of vaccine in keeping with the recommendations at that time (20, 21), recent outbreaks have predominantly included individuals eligible to receive two doses (see Supplementary Material). Thus, the increasing age of infection in the US tracks with waning immunity after receipt of the second dose rather a continuation of cases within a single, under-immunized cohort.
Predicted transmission dynamics under vaccine waning and vaccine escape
Our analyses have suggested that reduced vaccine effectiveness relates primarily to waning protection rather than the emergence of mumps virus genotypes escaping vaccine-driven immunity. However, our ability to compare these hypotheses using data from previous studies is limited by a lack of data about genotype-specific protection. To better understand whether recent outbreaks are more consistent with vaccine waning or vaccine escape, we used a stochastic transmission model to compare expected epidemiologic dynamics under these scenarios in the year 2006, when the ongoing resurgence began. Using the approach taken above to update population immunity and transmission parameters in the absence of vaccine waning, we simulated the spread of mumps virus strains against which the vaccine provided partial protection in a population of 1 million. Strains capable of vaccine escape would be expected to cause higher-than-observed incidence among young children (Figure 3A-E): in contrast to a median age of 22y among cases reported in 2006, the predicted median age of cases approached 14.2y (8.3y to 21.7y) as strain-specific vaccine effectiveness declined to 0%. Although strains with lower ability to escape immune pressure may not concentrate to such an extent among children, our model predicted such strains would cause low incidence in a population unaffected by waning immunity (Figure 3F). Model-predicted overall rates of mumps incidence exceeded reported rates at lower degrees of cross-protection. Overall, model-predicted dynamics under vaccine waning provided a closer match to reported overall and age-specific incidence, with an expected median age of 22.3y (17.7y to 26.3y) among cases.
Potential impact of booster vaccination
If vaccine derived immunity wanes or confers shorter-lasting protection against genotypes currently in circulation as compared to those circulating in 1967, then administering additional vaccine doses may help control transmission by extending immune protection to older ages. Based on analyses of the effective reproductive number (RE), we found that immunity from two doses alone is unlikely to support elimination of endemic mumps virus transmission from the US in the long term. As birth cohorts exposed to high rates of transmission in the 20th century are replaced by individuals whose protection comes only through vaccination, we expect RE to approach 1.11 (1.04 to 1.13) (Figure 4). While administering a third dose by age 18y would not necessarily confer life-long protection based on our estimate of the time to loss of immunity, we nonetheless predict that this intervention could extend protection through young adulthood, thereby protecting age groups at risk in recent outbreaks. Low (56%) uptake of a third dose— matching adult compliance with recommended tetanus-diptheria toxoid booster doses—would be expected to sustain RE around 0.88 (0.83 to 0.91), based on transmission dynamics in the US as of 2016. Under a more optimistic scenario of 88% third-dose coverage—where third-dose uptake equates second-dose uptake among already-immunized individuals—we expect RE to approach 0.77 (0.72 to 0.79) as cohorts previously exposed to high transmission rates age out of the population.
Whereas we estimate most older adults are currently immune to mumps virus due to previous infection, our modeling suggests neither a two-dose nor three-dose vaccination program would be expected to protect over 50% of adults beyond the age of 40y in the long term. This concern may motivate the use of routine booster doses in adulthood (Figure 4). Based on our model, we expect that administering additional doses every 10y or 20y would lead to sustained protection in, at minimum, 68.0% (58.5% to 77.6%) and 55.2% (44.1% to 68.4%) of the population, respectively, under a scenario of 88% vaccine coverage; at the lower (56%) coverage level, we estimated protection among, at minimum, 59.0% (48.2% to 71.2%) and 45.5% (34.3% to 60.5%) of adults with dosing every 10y or 20y, respectively. Maintaining high levels of immunity in the population through repeated dosing may also help to contain emergence of novel mumps virus strains (Figure 4E). To sustain RE≥1 under three-dose schedules, we estimated that an emerging strain would require, at minimum, 8.5% (7.6% to 9.8%) to 15.7% (11.9% to 20.3%) probability of causing infection in exposed persons otherwise protected by vaccination. Adding 10y booster doses increase this threshold probability to between 16.6% (12.5% to 20.8%) and 22.9% (16.4% to 29.7%) at varying levels of vaccine coverage.
Discussion
Resurgent outbreaks centered among young adults have brought renewed attention to mumps following decades of progress toward its elimination from the US (2, 12). Understanding why cases have re-emerged is essential for determining how to contain the disease through vaccination. Our analyses show that vaccine derived immune protection wanes over time, provide estimates of the waning rate, and demonstrate that this waning immunity accounts for susceptibility in the age groups experiencing outbreaks over the decades since vaccine introduction in the US. In contrast, changes in the circulating genotypes of mumps virus over this same period have not been associated with reductions in vaccine effectiveness; moreover, our modeling suggests vaccine-escape mumps virus strains would be expected to cause disproportionate incidence among younger children. Guided by these findings, we identify that routine use of a third dose vaccine dose around age 18y, with or without regular dosing in adulthood, could help maintain immune protection in the population.
Distinguishing between the contributions of vaccine waning and the emergence of vaccine-escape virus strains to mumps resurgence helps to inform whether novel vaccines are needed to control transmission (22, 23). Our findings that vaccine effectiveness has not declined amid the replacement of genotype A mumps viruses (from which the Jeryl Lynn vaccine strain was derived), and that the age distribution of recent cases is inconsistent with expectations under vaccine escape, are in agreement with several lines of evidence that mumps vaccination protects broadly against heterologous strains (24). Neutralizing antibody responses to the Jeryl Lynn strain are effective in vitro against wild-type mumps virus strains responsible for recent outbreaks among vaccinated individuals (25, 26), and genetic distinctions have not been identified between strains isolated from vaccinated and unvaccinated mumps patients (27). Similar, high levels of efficacy and effectiveness have been estimated for the Jeryl Lynn and Urabe (genotype B-derived) vaccines, further substantiating the notion of cross-neutralizing or monotypic immune responses (12). Nonetheless, epidemiological studies of outbreaks caused by distinct virus lineages, and in populations exposed to different circulating mumps viruses, can better characterize genotype specificity in the strength or duration of vaccine protection.
Although the clinical efficacy of a third dose has not been assessed in a trial, several observations suggest effectiveness of extended vaccine schedules. First, whereas congregated US military populations resemble high-risk groups based on their age distribution and close-contact environments, no outbreaks have been reported in the military since a policy was adopted in 1991 of administering an MMR dose to incoming recruits, regardless of vaccination history (28). Second, in limited observational studies of vaccine campaigns undertaken in response to recent outbreaks, third-dose recipients have tended to experience lower incidence rates than non-recipients (29–32. However, trials demonstrating the clinical effectiveness of adult vaccine doses are needed to guide policy. Third-dose campaigns undertaken at the tail end of outbreaks have not been designed optimally to measure vaccine effectiveness (29, 31), and conflicting evidence about immune responses to third doses in adulthood has proven difficult to interpret without known immunological correlates of protection (33–35. If a third dose at age 18y does not confer adequate protection, modifying MMR vaccines to improve the magnitude or duration of immune responses against mumps virus may present a viable alternative. Notably, the mumps component of the MMR vaccine induces lower-avidity antibody responses, and weaker specific memory B-cell proliferation, than the measles and rubella components (36, 37).
Our findings support previous observations of waning vaccine-derived immunity against mumps virus (38) and are validated by consistency between the age distribution of reported cases and model-predicted susceptibility over time. Several limitations of the analysis should be considered. Our use of aggregated rather than individual-level data from vaccine effectiveness studies contributed to an imprecise estimate of the time to loss of immunity, in turn limiting the precision of our estimates of population susceptibility. Individual-level data from post-licensure vaccine studies could support better inferences about the magnitude and duration of vaccine protection, thus aiding policy decisions. Identifying immunological correlates of protection from such datasets would also aid evaluations of alternative vaccination schedules and measurements of population immunity. Last, our analysis addresses mumps epidemiology in the United States, where levels of immunity within particular birth cohorts may differ from levels in settings that introduced routine mumps vaccination later or use different vaccine schedules. The burden of cases and prevalence of immunity across ages or birth cohorts should be considered to guide vaccination policy within specific countries.
Analyzing nationally-aggregated incidence datasets also limited our ability to investigate how geographic or socioeconomic differences in vaccine uptake and contact rates contribute to the dynamics of focal outbreaks, as might occur in close-contact settings such as university dormitories (39). However, our inferences about vaccine waning and the changing age distribution of mumps cases offer insight into why mumps resurgence has been possible throughout geographically and socioeconomically distinct communities. In this regard, the widespread re-emergence of mumps in vaccine-compliant communities stands in stark contrast to the focal re-emergence of measles in communities with low vaccine coverage (11).
Changes in the epidemiology of mumps have implications for disease surveillance. Diminished clinical awareness of mumps, expectations that it appears in pediatric rather than adult populations, and protection against symptoms in vaccinated individuals (40) may limit routine detection of cases, and thus bias disease reporting. Indeed, serological surveys have provided evidence of higher-than-reported rates of mumps virus infection in the US prior to 2006 (28, 41). The tendency to identify outbreak-associated cases through contact tracing may also favor detection of cases in university campuses and other closely-connected populations, underscoring the importance of serosurveys to assess the extent of transmission in the community. Serological datasets can also help establish whether lower rates of immunological “boosting” through natural exposure, which our analysis does not address, have contributed to population susceptibility.
The ongoing resurgence in mumps among young adults has undermined previous enthusiasm about near-term elimination of this disease from the US (1). Our analysis suggests that vaccinated individuals lose protection against infection on average 27 years after receipt of their last dose, and that this rate of vaccine waning explains susceptibility in adolescent and young-adult cohorts at the time of post-licensure outbreaks in these age groups. Re-emergence of mumps among older, previously-vaccinated individuals whose immunity has waned parallels recent experience with varicella outbreaks affecting immunized communities as a result of waning vaccine-derived protection (42). As demonstrated in mumps epidemiology, immunity in previously infected cohorts may buffer transmission and delay breakthrough epidemics from occurring until decades after vaccine introduction. These observations indicate the need for either innovative trial designs to measure the benefit of extending vaccine dosing schedules or novel vaccines to address the problem of waning vaccine-induced protection (43).
Materials and Methods
Full technical details pertaining to our analyses are presented in the Supplementary Materials; a brief summary is provided here.
Meta-analysis of vaccine effectiveness studies
We performed a systematic review of prospective and retrospective cohort studies calculating effectiveness of the Jeryl Lynn-strain mumps vaccine via a PubMed search and citation tracking. We used an inverse variance-weighted meta-regression model, accounting for study-level heterogeneity, to measure unadjusted and multivariate-adjusted associations of the following variables with study-level estimates of the relative risk of infection associated with vaccination:
Time since receipt of the last vaccine dose, indicating vaccine waning;
Time from 1964 (when the Jeryl Lynn vaccine was developed) to the year of mumps exposure, indicating long-term changes in vaccine effectiveness associated with changes in circulating genotypes; and
Vaccine doses received, interacted with time since last dose to test for differential waning of first and second doses.
Regression model summary statistics indicated the proportion of variance explained by these covariates. We used our estimate of the association between instantaneous risk of infection and time since vaccination to fit an exponential distribution to the duration of vaccine derived immune protection, and used this fitted distribution as the basis for further modeling.
Modeling population immunity and mumps virus transmission
We used a system of ordinary differential equations to describe changes in the population of susceptible and immune persons, partitioned into those who had and had not received mumps vaccine doses based on reported vaccine coverage. We back-calculated changes in natural immunity in the population based on the relation between reported incidence rates (A) in age group i and year t and the force of infection to which individuals were exposed (λ), the populations of susceptible unvaccinated (S) and vaccinated (F) persons, and the probabilities (πU and πV, respectively) for these individuals to experience symptoms if infected. Age-specific incidence reports were collated from nationwide surveillance (44). We inferred starting levels of immunity in the population (as of 1967) by fitting a mathematical model of mumps transmission to recapitulate age-specific incidence in the pre-vaccine era at steady state. We implemented stochastic realizations of an extended version of the model to compare predicted incidence during an introduced outbreak against observations from the year 2006, under scenarios where we assumed waning of immunity or circulation of strains with differential risk of infecting vaccinated persons.
Assessing extended-dose strategies
We compared the long-term performance of different vaccination schedules including the addition of a third dose by age 18y and the use of routine boosters at 10y or 20y intervals through adulthood. We calculated the prevalence of age-specific immune protection achieved under these strategies and resulting values of the effective reproductive number (RE), describing the number of cases an infectious individual would be expected to cause under prevailing conditions. We also calculated the minimum probability of immune escape a novel mumps virus strain would need to invade a population protected under these different strategies, defined as the minimum probability of infecting a vaccinated, protected individual upon exposure such that RE≥1.
Funding
This work was supported by National Institute of General Medical Sciences award U54GM088558 (JAL) and a Doris Duke Charitable Foundation Clinical Scientist Development Award (YHG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or National Institutes of Health. JAL discloses receiving funding from Pfizer to Harvard University for work unrelated to this analysis.
Author contributions
JAL and YHG conceived of the study, JAL performed the analyses with input and discussion from YHG, and JAL drafted and YHG edited the manuscript.
Competing interests
The authors declare no competing financial interests.
Data and materials availability
Code for replicating analyses and figures is available at github.com/joelewnard/mumps.
Acknowledgments
The authors thank Lucy Li, Sarah Cobey, Pardis Sabeti, Shirlee Wohl, Nathan Yozwiak, Greg Armstrong, and Marc Lipsitch for input.
References and Notes
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