Vaccine waning and mumps re-emergence in the United States

Abstract

After decades of declining mumps incidence amid widespread vaccination, the United States and other developed 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 whether immune protection wanes or whether the vaccine protects inadequately against currently circulating mumps virus lineages. Synthesizing data from six studies of mumps vaccine effectiveness, we estimated that vaccine-derived immune protection against mumps wanes on average 27 years (95% confidence interval, 16 to 51 years) after vaccination. After accounting for this waning, we found no evidence that the emergence of heterologous virus genotypes contributed to changes in vaccine effectiveness over time. A mathematical model of mumps transmission confirmed the central role of waning immunity to the vaccine in the re-emergence of mumps cases. Outbreaks from 2006 to the present among young adults, and outbreaks in the late 1980s and early 1990s among adolescents, aligned with peaks in mumps susceptibility of these age groups predicted to be due to loss of vaccine-derived protection. In contrast, evolution of mumps virus strains escaping immune pressure would be expected to cause a higher proportion of cases among children, not adolescents and young adults as observed. Routine use of a third vaccine dose at 18 years of age, or booster dosing throughout adulthood, may be a strategy to prevent mumps re-emergence and should be assessed in clinical trials.

Fig. 1. Synthesis of prospective and retrospective cohort studies estimating the relative risk of clinical mumps in vaccinated and unvaccinated individuals

We illustrate the results of our meta-analysis of studies of mumps vaccine effectiveness, from which we estimated rates of vaccine waning. (A) Shown here is how estimates of vaccine effectiveness (defined as one minus the relative risk of experiencing mumps for a vaccinated individual, relative to an unvaccinated individual) differ across the six studies analyzed here. Time since last dose accounts for 66.4% of residual variation in estimates after accounting for random sources of between-study heterogeneity. Points representing study-level estimates are scaled in size to reflect differences in sample size. Lines signify 95% confidence intervals and are truncated where they exceed the plotted range (arrowheads). (B) At 6 months after vaccine receipt (the earliest time point assessed in primary studies), we estimate 96.4% (94.0 to 97.8%) of recipients are protected; we apply this as our estimate of the probability of vaccine “take”. (C) A parsimonious model of exponentially distributed durations of protection predicts loss of protection after, on average, $\frac{1}{{\omega }_V}=27.4$ years (95%CI: 16.7-51.1), as indicated by the yellow plotted area. The blue plotted area illustrates the distribution of times to loss of protection for vaccinated individuals, generated by pooling exponential distributions parameterized using estimates of ω_V. (D) Contrary to the hypothesis of reduced effectiveness against diverse mumps genotypes currently in circulation, we did not identify evidence of a decline in vaccine effectiveness over time, whereas evidence of waning vaccine-derived immunity persisted in a model adjusting for calendar year. Unadjusted estimates of the relative risk (RR) of clinical mumps given vaccination—and estimates adjusted for time since vaccination, years since 1964, and doses received—are calculated via meta-regression using incidence data from the original studies (, , –54). (E) Using this meta-regression framework, we identified no difference in the waning rate (as defined by the inverse of the association between time since vaccination and relative risk of mumps given vaccination; see Materials and Methods) after receipt of a first or second dose (95% CI: 33% decrease to 72% increase in the relative risk of mumps given vaccination per log-year since vaccination; p>0.1).

Fig. 2. Mumps incidence and estimates of population susceptibility over time

Here we illustrate changes in the proportion of the population, by age, predicted to be susceptible to mumps based on the estimated waning rate of vaccine-derived immune protection and the incidence of mumps infection in the population. (A) Overall rates of reported cases declined following vaccine licensure in 1967, punctuated by outbreaks primarily among adolescents from 1984-1992 and recent outbreaks (2006 onward) centered among young adults. These outbreaks have corresponded with (B) peaks in the model-inferred proportion of individuals susceptible to mumps infection at ages 10-19 and 20-29 years of age, respectively and (C) reductions in the proportion of infections that cause symptoms and are reported due to vaccine protection against symptoms. (D) Changes in the proportion of individuals susceptible to infection across different ages are plotted against case notification rates.

Fig. 3. Anticipated transmission dynamics under scenarios of vaccine escape and vaccine waning

Here we use a stochastic simulation model to predict the epidemiology of mumps outbreaks under the scenario of mumps virus escaping vaccine-induced immune pressure and the scenario of waning vaccine-derived immunity (A) A stochastic model of an emerging vaccine-escape strain of mumps virus in a vaccinated population predicts excess incidence in young age groups, in keeping with their higher historical burden of mumps. (B) In contrast, the fit of a model incorporating waning vaccine-derived immunity matches the observed age distribution. (C) Higher overall incidence rates and (D) a younger age distribution of cases are predicted when immune responses to the vaccine offer minimal cross-protection against the circulating strain, as compared to the fit of the model with waning vaccine immunity. (E) Whereas the model with a viral-escape strain can reproduce the age distribution of cases at low degrees of immunological mismatch, (F) lower-than-reported incidence is expected under this scenario, again in contrast to the fit of a model with waning vaccine immunity. Lines in (E) and (F) signify 95% confidence intervals.

Fig. 4. Age-specific immunity and transmission dynamics under two- and three-dose vaccine schedules

Waning vaccine-derived protection in the population raises the question of how additional vaccine doses would impact mumps transmission. To address this question, we evaluated several scenarios. (A) Cohorts over 40 years of age as of 2016 were exposed to endemic transmission prior to and shortly after vaccine rollout and likely retain life-long protection. However, a population protected only by 2-dose vaccination would be expected to experience high prevalence of susceptibility over age 20 years. (B and C) Our modeling suggests the duration of protection can be extended through young adulthood by adding a third dose around age 18, whereas routine booster doses every 10 years or 20 years would be expected to sustain longer-term protection. Lines and shaded areas delineate median estimates and 95% confidence intervals, respectively. (D) Under transmission dynamics estimated as of 2016, protection in young adult age groups achieved through the use of a third vaccine dose is expected to reduce the effective reproductive number (R_E) below 1. We however predict R_E to approach 1.10 under the two-dose schedule as cohorts that experienced high rates of mumps infection age out of the population; larger reductions in R_E are sustained at higher coverage and with more frequent dosing. Colors are the same as in panels A-C. (E) In turn, these extensions of protection provide a stronger barrier against emergence of strains escaping vaccine immunity. A new strain with 8.5% (CI 7.6% to 9.8%) probability of evading vaccine-induced immunity and infecting a vaccine-protected individual would be expected to succeed under a three-dose schedule with low coverage. We however estimate that a novel strain would require 22.9% (CI 16.4% to 29.7%) probability of infecting such an individual to emerge in a population with 88% uptake of the third dose and 10-year boosters. Lines denote 95% confidence intervals and shaded areas represent distributions around R_E estimates.