we reviewed data on mumps cases reported to the registration system for notifiable infectious diseases in the netherlands ( osiris ) during september 1 , 2009august 31 , 2012 .
notification criteria for mumps include > 1 related symptom ( i.e. , acute onset of painful swelling of the parotid or other salivary glands , orchitis , or meningitis ) and laboratory confirmation of infection or an epidemiologic link to a laboratory - confirmed case ( 7 ) .
in addition to basic demographic information , notification data reported to osiris included vaccination status and student or contact with student status .
the questions on student / student contact status were made more specific on april 19 , 2010 . for cases reported before that date , the information for the new variable was obtained from open - format questions .
laboratory confirmation criteria included > 1 of the following : detection of mumps - specific igm ; detection of viral rna ; or isolation of the virus on cell culture .
genotyping targeting the gene encoding the small hydrophobic protein was performed on specimens submitted to the national institute for public health and the environment by using an in - house method .  
we used the  test for comparison of proportions and testing for trends over time and calculated a 3-week moving average to characterize trends and seasonality .
the odds ratio , which describes the association between complications / hospitalizations and vaccination status , was adjusted for age and sex ( when outcome was orchitis , adjustment was done for age only ) and estimated by using logistic regression . associations with p values of < 0.05 were considered statistically significant , and all reported p values are 2-tailed .
stata software version 12 ( statacorp , college station , tx , usa ) was used for the analyses .
during september 1 , 2009august 31 , 2012 , a total of 1,557 cases of mumps were reported in the netherlands ( figure ) ; 1,254 ( 80.5% ) of these were laboratory confirmed .
laboratory confirmation was most often by detection of viral rna ( 68.8% ) , followed by antibody detection ( 21.9% ) and virus isolation ( 7.3% ) . in 2% of cases ,
numbers of notified mumps cases , by week of onset , the netherlands , september 1 , 2009august 31 , 2012 ( n = 1,557 cases ) . seasons and
number of cases ( n ) are indicated ; black line indicates 3-week moving average .
most case - patients were male ( 59% ) and 1825 years of age ( 67.9% ) .
the average annual incidence per 100,000 population was 0.5 for the 03-year age group , 0.8 for the 414-year age group , 4.5 for the 1317-year age group , 21.4 for the 1825-year age group , and 0.9 for the > 25-year age group .
of the 1,474 cases for which patient vaccination status was reported , 998 ( 67.7% ) case - patients had received 2 doses of mmr ; 157 ( 10.6% ) had received 1 dose , and 242 ( 16.4% ) were unvaccinated .
genetic analysis of small hydrophobic gene sequences of 808 mumps - positive samples showed that most ( 98.5% ) outbreak strains belonged to the g5 subtype .
complications were reported in 126 cases ( 8.4% of 1,492 cases with known complication status ) ( table 1 ) .
orchitis was the most frequent complication ( 109 [ 12.7% ] male case - patients > 12 years of age ) and occurred significantly more often among unvaccinated case - patients than among case - patients who had received 1 vaccine dose ( p = 0.04 ) ; vaccination with 2 doses of mmr reduced the risk for orchitis even further ( p<0.01 ) .
other reported complications were meningitis ( n = 6 ) , pancreatitis ( n = 3 ) , thyroiditis ( n = 1 ) , and encephalitis ( n = 1 ) .
three case - patients had permanent unilateral hearing loss that was probably caused by mumps virus infection .
deafness and meningitis occurred more frequently among unvaccinated than vaccinated persons , but those numbers were probably too low for statistical significance ( table 1 ) .   *
only case - patients with known complications and vaccination status were included in the analyses . or , odds ratio ; ve , vaccine effectiveness ; ref , referent ; na , not applicable ;  , not analyzed ( insufficient sample size ) . 
adjusted for age ( age groups < 18 y , 1825 y , > 25 y ) and sex , except orchitis , which was adjusted only for age . 
a total of 31 patients ( 2.1% of 1,436 patients with known hospitalization status ) were hospitalized .
risk for hospitalization was significantly lower among case - patients who had received 2 mmr doses than for unvaccinated case - patients ( p<0.01 ) ; ve for preventing hospitalization was 82% ( table 1 ) .
three distinct epidemic seasons occurred during the outbreak : seasonal peaks in spring and late autumn and a decline in number of cases during summer and , to some extent , during the christmas holidays ( figure ) .
data on sex , age , vaccination status , residence in a city with a university , student status , and contact with student status by season are shown in table 2 .
overall , the age distribution of mumps case - patients differed significantly between the seasonal peaks ( p = 0.007 ) .
the number of cases increased proportionally over time for the 1317-year age group ( p = 0.003 ) and the > 25-year age group ( p = 0.042 ) and decreased over time for the 1825-year age group ( p<0.001 ) .
the overall proportion of cases in vaccinated persons did not change ( table 2 ) , and the proportion of complications or hospitalizations did not differ by season ( data not shown ) . *
boldface indicates significance trends by  test , calculated by using proportions excluding unknowns . 
university cities : amsterdam , delft , eindhoven , enschede , groningen , leiden , maastricht , nijmegen , rotterdam , stichtse vecht , tilburg , utrecht , and wageningen . 
we found significant seasonal differences in the proportion of cases occurring in students and in persons with student contacts ( p<0.001 ) . during early spring 2010
, large clusters of cases were reported from university cities of leiden and delft , as described ( 6 ) . however , during 2011 and 2012 , proportionally more case - patients were not students and had no contact with students than during 2010 ( p<0.001 ) .
the proportion of student case - patients enrolled in higher education other than university or case - patients who had contact with these nonuniversity students increased after 2010 ( p<0.001 ) .
the absolute numbers of cases in these categories increased from 2010 to 2011 but stayed more or less constant , or decreased slightly , in 2012 .
the number of case patients who were university students or who had contact with university students decreased proportionally ( p<0.001 ) , and over time , proportionally more cases were reported from cities without universities ( p<0.001 ) .
in addition , the total number of cases from nonuniversity cities was higher in 2012 .
the epidemic of mumps in the netherlands during late 2009 through 2012 affected mainly vaccinated students . however , vaccination evidently offered protection against mumps - associated complications .
the epidemic showed a seasonal trend , although cases were identified throughout the years . over time , age , student status , and geographic distribution changed , which suggests a slight shift in transmission trends from student populations to younger and older nonstudent populations and to cities without a university .
this shift may relate to increased immunity in the primarily affected high - risk student population ; exposure to wild - type mumps virus may have boosted individual immunity and thus contributed to increased herd immunity . mumps outbreaks among vaccinated populations have been reported in other countries during recent years : a 2006 outbreak in the united states ( 8) , a 20092010 outbreak in canada ( 9 ) , and a 2012 outbreak in the united kingdom ( 10 ) .
description of an outbreak in 20092010 in the northeastern united states among a highly vaccinated population of orthodox jews indicated that intense exposure among boys in a religious school facilitated the transmission of mumps virus , which overpowered the vaccine - induced protection ( 11,12 ) .
similar to our findings , transmission in that outbreak shifted from adolescents to younger and older populations over time .
the intense social crowding among students ( e.g. , large indoor social gatherings ) partly explains why secondary vaccine failure occurred in the outbreak described in this study .
a subgroup of students , including those living with many other students and members of university fraternities , may be at increased risk for infection ( 6,7 ) . crowding in nonstudent populations may not be as intense as among students , and mixing is usually with more heterogeneous age groups . in these circumstances ,
. a lower rate of crowding may be one explanation for the relatively low numbers of cases among 412-year - olds , despite the generally lower igg titers in this group than in adolescent students .
still , even though lower antibody levels do not automatically mean higher risk for mumps virus infection ( 14 ) , a higher rate of illness would have been expected in the 412-year age group .
an additional explanation for the lower apparent illness rate among these younger children might be a higher frequency of unapparent and subclinical infections , which would lead to many undiagnosed cases in this age group .
most of the persons affected in the epidemic were male , a finding also observed in other studies ( 15,16 ) .
the reasons for male predominance are unclear , but significantly higher mumps antibody titers in female than in male persons have been demonstrated ( 13,17 ) ; this finding , in turn , may be linked to gender - associated genetic differences in immune response .
most cases occurred in persons who had received 2 doses of mmr , which suggests inadequate effectiveness of the vaccine .
recent studies indicate the effectiveness of mmr against mumps is moderate and lower than the clinical efficacy estimates ( 1,18 ) .
postlicensure studies of 2 doses ( jeryl - lynn strain ) of mmr have provided a median ve estimate of 88% ( range 79%95% ) ( 2 ) .
a recent study of an outbreak of mumps at a student party in the netherlands estimated a ve of 68% for 2 doses of mmr ( 6 ) .
this estimate is , however , uncertain because of the low number of unvaccinated case - patients .
we attempted to provide ve estimates against clinical mumps applying the screening method ; however , because this method is most vulnerable to error when proportions of the population and case - patients vaccinated are high ( 19 ) , as in this study , the estimates became inaccurate and thus are not included in our results .
the possible causes for lower than expected ve include secondary vaccine failure ( waning immunity ) , intense exposure to high virus inoculum , and a possible mismatch between the vaccine genotype and circulating strains ( 1,2,18,20 ) .
however , because the level of antibodies correlating with protection remains unknown ( 12,21 ) , we are unable to further elucidate the role of these factors .
orchitis was the most common complication , consistent with previous outbreaks in a population with a similar age structure ( 1 ) .
however , orchitis occurred significantly more often among unvaccinated than vaccinated case - patients , and the vaccine was effective in preventing orchitis , which has previously been shown in a study based in part on the same study population ( 22 ) and in other studies ( 11,23 ) .
a previous report described 3 cases of deafness ( 0.19% of all notified infections ) , 2 in unvaccinated persons ( 24 ) .
the frequency of 0.005% for unilateral deafness commonly cited in the literature ( 25 ) is considerably lower than that found in our study , but this difference is likely attributable to a different denominator population .
a higher incidence of deafness has been reported from japan using more appropriate denominators ( 26 ) .  
one limitation of our study was the short time span for assessing changes over time .
mumps cases have continued to occur after our study period , but the number of cases reported after september 2012 ( 180 as of august 31 , 2013 ) is much lower than that reported during the previous years .
recent numbers indicate that a similar trend in changing patterns of age and geographic distribution is ongoing ; most of the more recent cases have occurred in nonstudents and in age groups other than 1825 years ( data not shown ) . however , because of lower case numbers , this comparison must be interpreted with caution .  
a further limitation of our study is that it is likely that many mumps cases are not notified because they are subclinical infections or because of reluctance to seek medical care ; thus , these cases are not included in our analyses .
furthermore , complications that occurred after the notification date are not included ; however , because vaccination status is probably not associated with the reporting of complications , we regard our ve estimates against complications as unbiased .
although ve for mumps vaccination is not optimal for preventing clinical disease , our results support previous findings that vaccination limits the severity of disease . because complications are the primary mumps - associated public health problem , these findings support the current vaccination recommendations .
still , this epidemic demonstrates that mumps virus can cause large outbreaks even in highly vaccinated populations .
the observation that the incidence after the third season studied has been considerably lower than during previous seasons is consistent with the development of herd immunity among high - risk students resulting from the high rate of natural symptomatic and asymptomatic infections . however , the annual inflow of new susceptible students  unvaccinated and vaccinated  who start their studies could again lower overall immunity .
a recent study suggested that use of a third mmr dose might be an effective control measure in certain outbreak situations ( 27 ) .
introduction of a third mmr dose to the vaccination schedule has been considered in the netherlands ( 6 ) but was not recommended because of relatively low overall illness rates associated with mumps and other factors , including an expected low vaccine uptake .
although the vaccine remains effective in most settings and significantly reduces the risk for complications , further research is needed to understand the limitations of mmr , and modeling is warranted to understand the dynamics of mumps virus transmission in future .
 to analyze the epidemiology of a nationwide mumps epidemic in the netherlands , we reviewed 1,557 notified mumps cases in persons who had disease onset during september 1 , 2009august 31 , 2012 . 
 seasonality peaked in spring and autumn . 
 most case - patients were males ( 59% ) , 1825 years of age ( 67.9% ) , and vaccinated twice with measles - mumps - rubella vaccine ( 67.7% ) . 
 nearly half ( 46.6% ) of cases occurred in university students or in persons with student contacts . 
 receipt of 2 doses of vaccine reduced the risk for orchitis , the most frequently reported complication ( vaccine effectiveness [ ve ] 74% , 95% ci 57%85% ) ; complications overall ( ve 76% , 95% ci 61%86% ) ; and hospitalization ( ve 82% , 95% ci 53%93% ) . over time , the age distribution of case - patients changed , and proportionally more cases were reported from nonuniversity cities ( p<0.001 ) . 
 changes in age and geographic distribution over time may reflect increased immunity among students resulting from intense exposure to circulating mumps virus . 