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157（ 29 ）〈Original Article〉

Incidence of aseptic meningitis following the Torii
strain-derived dried live attenuated mumps vaccine
Hideaki Kumihashi1, Munehide Kano1,* and Satoko Ohfuji2
1

Global Vaccine Business Unit, Takeda Pharmaceutical Co., Ltd.,
2–1–1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103–8668, Japan;
2
Department of Public Health, Osaka City University Faculty of Medicine,
1–4–3 Asahimachi, Abeno-ku, Osaka 545–8585, Japan(Received for publication July 24, 2018)

In Japan, the high incidence of aseptic meningitis associated with a mumps
vaccine strain led to the discontinuation of measles-mumps-rubella vaccine
administration in 1993, interrupting routine mumps immunization. Voluntary
immunization with monovalent mumps vaccines later resumed, and many Japanesepediatricians claim that the incidence of aseptic meningitis following immunization
with monovalent mumps vaccines (“postvaccinal aseptic meningitis incidence”) has
decreased. However, there are no reports verifying this contention. To investigatechanges in the annual postvaccinal aseptic meningitis incidence, we assessed theannual incidence of aseptic meningitis following vaccination with Torii strain from2004 to 2015. Our incidence estimates are based on the number of spontaneous
reports regarding suspected cases of adverse reactions due to Torii strain-derived
mumps vaccine and the number of vaccine shipments from Takeda Pharmaceutical
Company Limited. During this period, there were a total of 4,610,080 vaccine
shipments and 127 suspected cases of aseptic meningitis, yielding a mean annual
postvaccinal aseptic meningitis incidence of 2.8 ± 1.0 cases/100,000 doses (lowest
annual incidence: 1.3 cases/100,000 doses [2005]; highest annual incidence: 4.4
cases/100,000 doses [2007]). The annual incidence did not change signiﬁcantly
between 2004 and 2015. The cause for the possible decrease in comparison withincidence around 1990 requires further investigation.

*Corresponding author, Tel.: ＋81–3–3278–3624, Fax: ＋81–3–3278–2502, E-mail: munehide.kano@takeda.com

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Introduction
Mumps is designated as a category V sentinel-reporting infectious disease in Japan, andmajor epidemics of mumps have occurred every 4 to 5 years1). The main symptom of mumps ispainful salivary glands swelling on one or both sides, and the main complications include aseptic
meningitis, deafness, orchitis, and oophoritis2). The incidence of aseptic meningitis and deafness
due to natural mumps infection is approximately 1% to 5%2,3) and 0.01% to 0.5%4~6), respectively.
In Japan, voluntary immunization with monovalent mumps vaccines began in 1981, and subsequently the widespread immunization with measles-mumps-rubella (MMR) vaccines derived
from standardized strains began in April 1989. However, concerns that aseptic meningitis associated with a mumps vaccine strain was occurring at an incidence of at least 1/2,0007,8) led to theuse of MMR vaccines being discontinued in April 1993. Voluntary immunization with monovalent mumps vaccines was resumed in 1994, and two monovalent mumps vaccine products derived from Hoshino and Torii strains are currently used in Japan4). Vaccination is indicated forchildren aged ≥12 months and administered as one subcutaneous dose9), and the vaccination rate
is approximately 30%10). Recently, some practicing physicians in Japan made statements suggesting that the incidence of aseptic meningitis following immunization with monovalent mumps
vaccines has decreased over the past several years11). According to the post-marketing survey ofthe Hoshino strain-derived mumps vaccine, the incidence of aseptic meningitis was 8.8
cases/100,000 doses (134 cases/1.53 million doses) during 1994–2004 and 3.8 cases/100,000
doses (107 cases /2.83 million doses) during 2005–2012, suggesting a signiﬁcant decrease in eachperiod11). However, no reports have been published that verify these speculated changes in the annual incidence of aseptic meningitis with the Torii strain-derived mumps vaccine.
In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) collects safety information, such as adverse drug reactions, infections caused by use of pharmaceuticals and medical
devices and adverse events caused by medical devices from companies and healthcare professionals. That information is stored into a database for scientiﬁc analysis and investigation. Findings from investigations are reported to the Ministry of Health, Labour and Welfare, and would
result in administrative actions to ensure the safe use of pharmaceuticals and medical devices12).
This study was conducted using the Japanese Adverse Drug Event Report database (JADER)
compiled by the PMDA. It contains data on reports of adverse events that occur after the administration of medicinal products including vaccines licensed in Japan. The data are submitted according to Japanese regulations for medicinal products from all sources including companies,
healthcare professionals, or non-healthcare professionals (e.g., patients, vaccine recipients, andguardians) to the PMDA since April 200413).
Here, we retrieved the number of suspected cases of adverse reactions due to Torii strain-de-Aug. 2018

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159（ 31 ）rived mumps vaccine (Dried Live Attenuated Mumps Vaccine, “Takeda”) from the JADER postedon the PMDA website. Based on this number and the number of vaccine shipments from Takeda
Pharmaceutical Company Limited, we estimated the annual incidence of aseptic meningitis following vaccination with Torii strain for the 12 years from 2004 to 2015.

Materials and Methods
VaccineAt present, mumps is outside the scope of the routine vaccination program in Japan, so only
those whose parents request it receive a vaccination against mumps. Individuals aged 12 months
or more who have never had mumps are allowed to receive the mumps vaccine, regardless ofgender or age; however, it is considered preferable to receive one dose of mumps vaccine between the ages of 24 and 60 months9). In this study, we investigated a Torii strain-derived dried
live attenuated mumps vaccine produced by Takeda Pharmaceutical Company Limited. Each single vaccine dose contains 5,000 CCID50 or more of live attenuated mumps virus (Torii strain),stabilizers (lactose hydrate, monopotassium L-glutamate, dibasic sodium phosphate, and potassium dihydrogenphosphate), and antibiotics (kanamycin and erythromycin). This product, manufactured by Takeda Pharmaceutical Company Limited, was the only Torii strain-derived mumps
vaccine available during the study period.
Study period and information collection
Data that accumulated in JADER over the 12-year period from April 2004 to March 2015 on
the adverse reactions following immunization with Torii strain-derived mumps vaccine were analyzed in this study. Data before March 2004 were not included in JADER. Information on the “reporting year,” “date of vaccine administration,” “adverse reaction/adverse event,” “date of onset,”“gender” were obtained for each adverse reaction.
Annual number of aseptic meningitis cases following vaccination with the Torii strain
In the list of cases in JADER, all cases with any of the following adverse reaction terms
were regarded as “aseptic meningitis cases” for this study: “aseptic meningitis,” “mumps meningitis,” “viral meningitis,” and “meningitis.” All of these cases were included in the analysis, regardless of the time from vaccination to the onset of aseptic meningitis.
Annual number of administered Torii strain-derived vaccine doses
As the monovalent mumps vaccine is purchased as needed, very few doses are likely to bediscarded as unused in medical institutions. Therefore, in this study, it was assumed that all doses
shipped during the study period were administered and that the number of vaccine shipments

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each year was equivalent to the number of vaccine doses administered that year.
Statistical analysis
To calculate the annual incidence of postvaccinal aseptic meningitis per 100,000 doses, theannual number of aseptic meningitis cases was divided by the annual number of doses shipped
and then multiplied by 100,000. Chi-squared tests were performed to evaluate the statistical signiﬁcance of differences in the annual incidence of aseptic meningitis. In addition, to examine thedisproportionality of aseptic meningitis cases among all adverse events in the period from 2004
to 2015, we divided the 12-year survey period into two phases, the early 6-year phase (2004–2009) and the late 6-year phase (2010–2015), and compared the proportions of aseptic meningitis
between the two phases by the chi-squared test. The incidence of aseptic meningitis was also
evaluated by gender, and the number of elapsed days from vaccination. Differences in the incidence of aseptic meningitis by gender were tested for signiﬁcance using a chi-squared test. The
number of days elapsed from vaccination were counted as the number of days starting from vaccination to the onset of adverse reactions, and the median, minimum, maximum, and mode were
calculated. The mode was also determined for the time elapsed from vaccination based on a time
unit of 10 days.
A two-sided signiﬁcance level of 0.05 was used for all statistical tests. Statistical analyses
were performed using SAS version 9.3 software (SAS Institute Inc., Cary, NC, USA).

Results
Changes in the annual incidence of aseptic meningitis following vaccination with theTorii strain
The 127 cases identiﬁed as aseptic meningitis during the period 2004–2015 comprised 99
cases of aseptic meningitis, 12 cases of mumps meningitis, 9 cases of meningitis, and 7 cases ofviral meningitis.
The mean annual incidence of aseptic meningitis following vaccination with the Torii strain
was 2.8 ± 1.0 cases/100,000 doses, ranging from a minimum of 1.3 cases/100,000 doses in 2005
to a peak of 4.4 cases/100,000 doses in 2007. Over this 12-year period, the annual incidences of
aseptic meningitis following vaccination with the Torii strain were not signiﬁcantly different,suggesting that the incidence did not change during this time (Table 1).
Of patients with adverse reactions, the percentage of those with aseptic meningitis was
64.4% (47/73 cases) in the early phase (2004–2009) and 58.8% (80/136 cases) in the late phase(2010–2015); these percentages were not signiﬁcantly different (p＝0.43). Therefore, the percentage of aseptic meningitis cases among patients with adverse reactions was also stable from theviewpoint of the early and late phases.

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161（ 33 ）Table 1. Annual incidence of aseptic meningitis following vaccination with the Torii strain from2004 to 2015

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Comparisons of the numbers of aseptic meningitis cases following vaccination with theTorii strain between males and females
Of the 127 patients who developed aseptic meningitis following vaccination with the Torii
strain, there were 83 males, 41 females, and 3 individuals with an unrecorded gender (Table 2).
Assuming that the number of males receiving the vaccine was the same as that of females,
the incidence of postvaccinal aseptic meningitis in males was signiﬁcantly higher (2.0-fold; p＝0.03) than that in females.

Table 2. Comparison of the annual number of aseptic meningitis following vaccination with theTorii strain between males and females

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163（ 35 ）Suspected cases of adverse reactions following vaccination with the Torii strain from2004 to 2015
From 2004 to 2015, 40 types of suspected adverse reactions were reported in 209 cases after
vaccination with the Torii strain (Table 3).
The three most commonly reported adverse reactions, in descending order, were aseptic
meningitis, encephalitis, and fever. These three adverse reactions and aseptic meningitis alone accounted for 71% and 61%, respectively, of all cases.
Number of days from vaccination to the onset of aseptic meningitis
We were able to calculate the number of days from vaccination to the onset of aseptic meningitis in 102 of the 127 cases of aseptic meningitis following vaccination with the Torii strain.
The median time was 23 days (range: 4 to 67 days), and the mode, composed of 11 cases, was 25days (Figure 1).
When based on a time unit of 10 days, the mode of the time from vaccination to the onset of
aseptic meningitis was the period from 17 to 26 days, which occurred in 69 cases (54.3%). Aseptic meningitis has been reported to develop two to three weeks after mumps vaccination2); however, our results suggest that a follow-up observation should be required for recipients of the Torii
strain-derived vaccine at or greater than three weeks after vaccination.
Outcome of aseptic meningitis cases following vaccination with the Torii strain
The 127 patients who developed aseptic meningitis following vaccination with the Torii
strain in the 12-year period from 2004 to 2015 had the following outcomes: 58 patients (45.7%)
recovered, 40 patients (31.5%) were still recovering, no patients (0%) recovered with sequelae, 1patient (0.8%) did not recover, and 28 patients (22.0%) had an unrecorded outcome.

Discussion
Evaluations and analyses of the safety of mumps vaccines are often fraught with problems
and limitations14). Because spontaneous reporting often leads to failed reporting and, consequently, an underestimation of cases, a prospective cohort study generally produces a more accurate assessment; however, this type of analysis is not always possible. Although the present study
relied on spontaneous reporting, and therefore has limitations in this regard, no signiﬁcant change
in the aseptic meningitis incidence was observed over the 12-year period, regardless of whether
comparisons were performed for the annual incidence or the disproportionality of aseptic meningitis cases between the early and late phases. This ﬁnding suggests that, at least for the durationof the study period, consistency was maintained in the quality of the mumps vaccine, the criteria
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Table 3. Number of suspected cases of adverse reactions following vaccination with the Torii
strain from 2004 to 2015

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Fig. 1. Case distribution for time from vaccination with the Torii strain to aseptic meningitis
onset

The number of cases of aseptic meningitis following vaccination with the Torii strain is shown for various lengths of timefrom vaccination with the Torii strain to the onset of aseptic meningitis.

with Torii strain, which under these conditions was 2.8 ± 1.0 cases/100,000 doses. The yearly incidence did not change signiﬁcantly during this time. The difference of incidence of aseptic meningitis by vaccine lot number could not be analyzed in this study because the vaccine lot number
is not described in JADER.
To verify the speculated decrease in the incidence of aseptic meningitis following mumps
vaccination during the several decades, it is preferable to analyze long-term follow-up data collected using a uniform research method. Existing research conducted in Japan on the incidence of
aseptic meningitis following vaccination with the Torii strain includes a prospective cohort study
on the MMR vaccine containing the Torii strain-derived mumps vaccine produced by Takeda
Pharmaceutical Company Limited7,8), a prospective cohort study on the Torii strain-derived monovalent mumps vaccine3), and a passive surveillance study of the Torii strain-derived monovalent

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ND, no data.

Fig. 2. Post-vaccination aseptic meningitis incidence in the present study, the Maruyama Report, and the Nakayama ReportAug. 2018
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mumps vaccine based on nationwide spontaneous reports15). However, the research time for eachof these studies was only three to four years in the period from 1990 to the ﬁrst half of 2000.
Maruyama et al. reported that the incidence of aseptic meningitis following immunization
with the Torii strain-derived monovalent mumps vaccine produced by Takeda was 7.9
cases/100,000 doses in the period from 1989 to 199315). We consider the comparison between thepresent study using JADER data and the report by Maruyama et al. to be valid because both thestudy by Maruyama et al. and the JADER data were derived from passive surveillance based onnationwide spontaneous reports (Figure 2).
Results of this comparison showed that the incidence of aseptic meningitis following mumps
vaccination in the period from 2004 to 2015 was lower than that following immunization with theTorii strain-derived monovalent mumps vaccine around 1990, i.e., the former was 1/2.8 of the latter.
Regarding the difference between the Hoshino strain and Torii strain, the postvaccinal reactions may vary because different attenuation methods are used to produce the vaccine strains4).
However, according to the Nakayama Report, the incidence of aseptic meningitis associated with
the Hoshino strain was 3.8 cases/100,000 doses during 2005–2012, while that associated with theTorii strain during the same period in this study was 2.9 cases/100,000 doses11), revealing no signiﬁcant difference between the two strains. The incidence of aseptic meningitis following vaccination with the Hoshino strain was 8.8 cases/100,000 doses (134 cases/1.53 million doses) during
1994–2004 and 3.8 cases/100,000 doses (107 cases/2.83 million doses) during 2005–2012, revealing a signiﬁcant reduction11). The risk of aseptic meningitis following vaccination is not considered to be as high as that reported before 2003, regardless of whether the Hoshino strain or
Torii strain is used (Figure 2).
In Japan, aseptic meningitis following mumps vaccination is regarded as an adverse reaction
caused by the vaccine. However, strict virological veriﬁcation is not performed in all cases,
meaning that unveriﬁed cases should be considered to reﬂect “suspected aseptic meningitis
caused by vaccination.” The 127 patients identiﬁed as aseptic meningitis cases in the present
study included those with mumps meningitis (12 patients), meningitis (9 patients), and viral meningitis (7 patients), in addition to those with aseptic meningitis (99 patients). A causal relationshipwith the vaccine strain was veriﬁed in 12 cases, but remained unveriﬁed in the other 115 cases,
which is a limitation of the present study. A deﬁnitive virological diagnosis can be achieved by an
identiﬁcation test that mainly distinguishes between vaccine strains and wild-type strains. The
reason for performing this identiﬁcation test is that some cases of aseptic meningitis are known tobe caused by mingling of wild-type strains16), but this test is only performed in certain cases. In
addition, enteroviruses account for approximately 80% of the pathogens that can cause community-acquired aseptic meningitis, while the mumps virus accounts for only about 10%17). Therefore, aseptic meningitis caused by mingling of pathogens is more likely to be caused by enterovi-Aug. 2018

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169（ 41 ）ruses than by the mumps virus. However, an identiﬁcation test of the mumps virus is only
performed in certain cases, and a deﬁnitive virological diagnosis of enteroviruses is rarely performed. For accurate safety assessment of mumps vaccines with regard to aseptic meningitis, adeﬁnitive virological diagnosis of enteroviruses, in addition to an identiﬁcation test of the mumps
virus, should be performed in all patients with postvaccinal aseptic meningitis.
There were more boys than girls in the population that developed aseptic meningitis. The
male : female ratio for these 10 patients was 9 : 1, as previously reported by Nagai et al.3). In
Japan, because immunization with the monovalent mumps vaccine is voluntary, neither the injection history nor the injected number by gender is tracked, so, unfortunately, we cannot comment
about them here. One likely reason for the higher number of cases reported among boys is that,
because of concern about orchitis, guardians of boys in Japan may have a higher awareness of theimportance of mumps vaccination, resulting in a higher vaccination rate among boys. However,there is also a gender difference in the incidence of aseptic meningitis following natural infection(wildtype strain), with the male : female ratio reported as 3 : 12). This suggests that the mumps
virus has a higher afﬁnity for the central nervous system in males than in females, which may
also contribute to raising the incidence of aseptic meningitis in boys.
Prognosis of postvaccinal aseptic meningitis is generally good4), there was no case of sequelae and one case was unrecovered in this study. However, 22% of the outcomes are “unknown”, which is considered a limitation of this study due to spontaneous reports.When recommending the voluntary mumps vaccination, it is necessary to properly explain to guardians therisk for developing adverse reactions, including aseptic meningitis potentially associated withvaccination, as well as the risk of natural mumps infection if they decline the vaccination. The
ﬁndings of the present study contribute to medical practice in Japan by providing useful information to Japanese pediatricians for explaining to the guardians of potential vaccine recipients asthey weigh the pros and cons of electing to have their child vaccinated with the mumps vaccine.
Conﬂict of Interest
Hideaki Kumihashi and Munehide Kano are employees of Takeda Pharmaceutical Company
Limited.

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