International Journal of Epidemiology Vol. 24, No.

6
© International Epidemiological Association 1995 Printed in Great Britain

Estimation of the Risk of Aseptic

Meningitis Associated with Mumps
Vaccination, France, 1991-1993
I REBIERE* AND C GALY-EYRAUD*

Rebiere I (Reseau National de Sante Publique, 14 rue du Val d'Osne, 94415 Saint-Maurice cedex, France) and
Galy-Eyraud C. Estimation of the risk of aseptic meningitis associated with mumps vaccination, France, 1991-1993.

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International Journal of Epidemiology 1995; 24: 1223-1227.
Background. Several published studies have recently shown a higher incidence of aseptic meningitis associated with
Urabe AM-9 vaccine strain than that estimated previously. In France, where all mumps vaccines produced and marketed
contain the Urabe AM-9 vaccine strain, little was known about the incidence of these side effects although several sur-
veillance systems exist.
Methods. The capture-recapture method can be used to estimate the total number of cases of a disease when at least
two independent data sources are available. Applying the capture-recapture method, data provided by the national net-
work of hospital virology laboratories (EPIVIR) and by the Pharmacovigilance Department of the vaccine manufacturer
(P.M.sv.) during a 3-year period between 1 January 1991 and 31 December 1993 have been used to obtain an estimate
of the total number of aseptic meningitis cases associated with Urabe AM-9 vaccine.
Results. The number of such aseptic meningitis cases was estimated at 116 (95% confidence interval [Cl]: 49-183). The
risk of aseptic meningitis can thus be assessed as 1 case per 28 400 doses of Urabe AM-9 sold (95% confidence interval
[Cl]: 1 case per 18 000-1 case per 67 200). The sensitivity of the systems was 21% for EPIVIR and 23% for P.M.sv. The
low number of cases recorded by either system makes it difficult to test the statistical independence of the two systems
by the calculation of the correlation coefficient of the sensitivity of the systems after stratification. However, the stratified
data by age, by sex, by geographical zone and by type of vaccine show that the totals after stratification are not very
different from the crude total.
Conclusions. The French Vaccination Committee has recommended promoting the practice of measles-mumps-rubella
vaccination in order to limit the circulation of the wild virus and to prevent an epidemic in insufficiently protected groups
of the population, whilst awaiting vaccine containing the Jeryl-Lynn strain.
Keywords: mumps vaccine, aseptic meningitis, adverse effect, capture-recapture method

The widespread use of the combined measles-mumps-
rubella vaccine in France seems to have stabilized the
incidence of mumps since 1987—an epidemic year—at
approximately 200 cases/100 000 inhabitants.1 Simul-
taneously the incidence of mumps-related meningitis—
a frequent complication with mumps—has decreased.
However, there is a possibility of meningeal reactions
to vaccination. In France, the incidence of post-
vaccination mumps-related meningitis is not known
although several side-effect reporting systems exist.
These include the National Pharmacovigilance System
(French Law 84-402 dated 24 May 1984), the Phar-
macovigilance Departments of vaccine manufacturers
* Roseau National de Sant£ Publique, 14 rue du Val d'Osne, 94415
Saint-Maurice cedex, France.
' Laboratoires Pasteur Mlrieux Se'rums et Vaccins, Pharmacovigilance
Department, 1541 avenue Marcel M^rieux, 69280 Marcy-l'Etoile,
France.
and the EPIVIR virological laboratories network co-
ordinated by the National Public Health Centre (RNSP).
Using data available from these different sources, we
have estimated the incidence of aseptic meningitis asso-
ciated with mumps vaccine.
MATERIAL AND METHODS
The capture-recapture method enables estimation of the
total number of cases of a given disease in a given
population provided that at least two independent
sources of information are available.2"4 By evaluating
the number of cases in common, C, plus the number of
cases in the first source, R, and in the second source, S,
one can obtain an accurate estimate of the total number
of cases N:

1223
1224 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
For small samples, Chapman5 and Seber6 suggest using:
N = (R+1)(S+1)
C+l
Var (N) =
<C+l)2(C
The use of the capture-recapture method must meet
three conditions: all identified cases are true cases, all
true matches and only true matches common to both
systems are identified, and the surveillance systems are
independent.
In this investigation two information sources were
used.
The Pharmacovigilan.ee Department of the
Vaccine Manufacturer
This surveillance system is based on spontaneous noti-
fication by practitioners to vaccine manufacturers. This
is a passive surveillance system: the proportion of
French practitioners who are aware of this system and
report side effects to the vaccine manufacturer is not
known. All monovalent and trivalent mumps vaccines
produced and marketed in France by Pasteur MeYieux
SeYums et Vaccins (P.M.sv.) contain Urabe AM-9 vac-
cine strain. The P.M.sv. Pharmacovigilance Department
collects suspected mumps-associated meningitis based
on clinical criteria. Serological or virological tests are
only undertaken in 4 1 % of cases. The P.M.sv. Phar-
macovigilance Department principally covers urban
paediatricians.
The EP1V1R Laboratory Network
This network includes two-thirds of hospital virology
laboratories. Every month, these laboratories report on
their virological activity to the RNSP. Since 1991,
whenever a case of mumps meningitis is reported, pre-
scribing practitioners have been questioned to find out
whether the children concerned had been vaccinated for
mumps. 5 The EPIVIR network records aseptic menin-
gitis for which the cerebro-spinal fluid (CSF) or the
serum were sent to virology laboratories to seek spe-
cific IgM or for viral isolation. The EPIVIR network
covers hospital paediatricians.
The National Pharmacovigilance System, a third re-
porting system, was not used because reports were
assessed during a different period: from 1983 until only
June 1992 and because the number of cases reported to
this system from January 1991 to June 1992 was very
low.
The following inclusion definition was used for this
study: a case of aseptic meningitis according to the
diagnosis of the practitioner, occurring between the
1 lth and 30th day following vaccination with an Urabe
AM-9 strain vaccine (trivalent measles-mumps-rubella:
ROR®, TRIMOVAX® or monovalent mumps vaccine:
IMOVAX OREILLONS®), collected by one of the two
surveillance systems described above, occurring 1 Jan-
uary 1991-31 December 1993.
To estimate the underassessment of the total number
of cases, we enlarged the EPIVIR network definition to
include all mumps meningitis (aseptic meningitis ac-
cording to the diagnosis of the practitioner + mumps
virus isolation in cerebro-spinal fluid (CSF) or mumps
IgMs in serum) occurring in children aged under
24 months. The probability that these children were
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given a measles-mumps-rubella vaccine is high and their
age is much lower than the usual age at which natural
mumps meningitis occurs (around 5 years in France7).
Data from both systems were compared to identify
matches (cases reported to both surveillance systems).
The comparison variables used were as follows: vac-
cine, date of vaccination, sex, age, hospital to which
the patient was admitted and the region in which the
notifier was working. A match was defined as an
aseptic meningitis reported to both systems for which
the vaccine administered was the same (ROR® or
TRIMOVAX® or IMOVAX OREILLONS®), the date
of vaccination was the same (year, month, day), the sex
was the same, the age in years was the same and the
region of the hospital to which the patient was admitted
and the region in which the notifier was working, were
the same.
All cases reported to the manufacturer have been
vaccinated, whereas some cases examined by the lab-
oratory may have lacked complete clinical information
and thus have been erroneously considered cases of
natural mumps meningitis. To avoid underestimating
the number of cases common to both systems, cases re-
ported to the manufacturer were compared to all cases
reported to the laboratory network regardless of vac-
cination status.
According to sales statistics for Urabe AM-9 strain
vaccines communicated by P.M.sv., 2 464 153 doses of
ROR®+ 244 148 doses of TRIMOVAX® + 582 169
doses of IMOVAX-MUMPS® were distributed in
France during 1991, 1992 and 1993.
RESULTS
In all, 27 aseptic meningitis cases following mumps
vaccination were reported to the P.M.sv. Pharmaco-
vigilance Department during 1991, 1992 and 1993.
Twenty-four cases were reported to the EPIVIR lab-
oratory network during this period.
 ASEPTIC MENINGITIS AND MUMPS VACCINATION 1225

TABLE 1 Aseptic meningitis related to mumps vaccination—France 1991-1992—1993. Estimation of the total number of cases and
sensitivity of the P.M.sv." Pharmacovigilance Department and the EPIVlRb network by age, sex, geographical zone of the casec and the
type of vaccine administered

Number of cases reported Estimation of total Sensitivity of the systems

number of cases
P.M.sv. EPIVIR Doublet N P.M.sv. EPIVIR P.M.sv. + EPIVIR

Total 27 24 5 116 23 21 .40

(95% CI) (49-183) (15-55) (13-49) (25-94)
Age
<24 months 14 13 3 52 27 25 46
2-4 years 5 9 1 29 17 31 45
5+ years g 2 1 12 67 17 75

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Total 93
Sex
M 20 17 5 62 32 27 52
F 7 7 0 63 11 11 22
Total 125
Geographical zone
Zone 1 15 12 3 51 29 24 47
Zone 2 6 6 2 15 40 40 67
Zone 3 1 0 0 1 100 0 100
Zone 4 5 6 0 41 12 15 27
Total 108
Type of vaccine
ROR® 23 23 5 95 24 24 43
TRIMOVAX® 1 1 0 3 33 33 67
IMOVAX ORE1LLONS® 3 0 0 3 100 0 100
Total 101

a
P.M.sv.: Pharmacovigilance centres of Pasteur MeYieux Scrums et Vaccins laboratories.
b
EPIVIR: Reseau National de Same Publique (RNSP) virological laboratory network.
'Geographical Zone: given the low number of cases, France was divided into four geographical zones: Zone 1 = Northwest, Zone 2 = North-East,
Zone 3 = Southwest, Zone 4 = South-East.

Five matches were identified by cross-comparing
data. One minor difference in one of the comparison
variables was observed in two matches for the date of
vaccination: difference of one day for one match, day
not available in P.M.sv. report for the second match.
The capture-recapture method enabled the total num-
ber of cases to be estimated at 116 (95% confidence
interval [CI] : 49-183) (Table 1). The efficiency of the
P.M.sv. Pharmacovigilance Department is 23% and that
of the EPIVIR network 21%. Combining the two
systems of surveillance thus identified 40% of the total
number of cases (95% C I : 25-94%). Thus, the risk of
aseptic mumps meningitis related to vaccination can be
assessed as 1 case per 28 400 doses of Urabe AM-9
vaccine (95% CI : 1 case per 18 000 doses-1 case per
67 200 doses).
After stratification by the age at which meningitis
occurred, by the sex of the patient, by geographical
zone of residence or by the type of vaccine admin-
istered, totals are somewhat different from the crude
estimate although within the 95% CI for this latter
(Table 1).
The specific risks related to monovalent and trivalent
vaccines were estimated. For the monovalent vaccine
(IMOVAX OREILLONS®), the total estimated number
of cases was three for the 3-year period covered, i.e.
a risk of 1/194 000 doses. For the trivalent vaccine
(ROR®, TRIMOVAX®), the total estimated number of
cases was 103 (95% C I : 44-162), i.e. a risk of 1 case per
26 300 doses (95% C I : 1 case per 16 700 doses-1 case
per 61 000 doses).
The extension of the definition of the EPIVIR
network cases to all mumps meningitis occurring in
children aged under 24 months enabled assessment of
underestimation due to the lack of vaccination reports
in clinical files and permitted inclusion of three addi-
tional cases in the 3-year analysis. This changes the
total number of cases estimated from 116 to 130 (95%
C I : 54-206). The inclusion rate of both surveillance
systems is identical—21%. Collating the two systems
1226 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
enabled 38% of all cases to be identified (95% C I : 24-
91%). The estimated risk of aseptic meningitis asso-
ciated with mumps vaccination was thus 1 case per
25 300 doses of Urabe AM-9 vaccine (95% C I : 1 case
for 16 000 doses-1 case for 60 900 doses).
The systematic comparison of the 27 cases recorded
by the P.M.sv. Pharmacovigilance Department to all
cases of mumps meningitis reported to EPIVIR regard-
less of vaccination status did not enable identification
of additional matches.
DISCUSSION
Recently published studies carried out in Japan and
Great Britain show a higher incidence of aseptic
meningitis related to the Urabe vaccine strain than pre-
vious assessments. In Japan the incidence of aseptic
meningitis for which virological tests were positive for
mumps virus was estimated to be 3/1000 doses in 1989;
in Great Britain the incidence of aseptic meningitis was
estimated to be 1/11 000 doses in laboratory studies,
the incidence of viral meningitis to be 1/21 000 doses
in hospital studies and 1/143 000 doses in notifications
to the Communicable Disease Surveillance Centre
(CDSC). 89
In France, where mumps vaccines all use the Urabe
strain the incidence of spontaneously reported aseptic
meningitis associated with mumps vaccine has recently
been estimated at 1 case per 122 000 doses (French
Regional Pharmacovigilance Centres, Unpublished
data). Applying the capture-recapture statistical method
to Pharmacovigilance data provided by vaccine manu-
facturers and virology laboratories in the EPIVIR net-
work enabled a more accurate estimate to be obtained,
i.e. between 1/18 000 and 1/67 200 doses.
It should be noted that in the studies referred to
above, the definitions used and the way in which cases
were reported were different: the surveillance was pas-
sive in the French study while the surveillance was
active in the British study.
In this study, the specificity of the definition of
aseptic meningitis associated with mumps vaccine is
good. However, this definition was not identical in both
systems: the definition used by the EPIVIR network
was more specific but less sensitive than that used by
P.M.sv. Pharmacovigilance and leads to a lower rate of
inclusion (Table 1). This can cause underestimation of
the number of cases unconfirmed by microbiological
investigation.
Identifying the matches was easy due to the good
discriminative comparison variables, the high number
of data points available for each case and the low num-
ber of cases concerned.
The relatively restrictive definition used by the
EPIVIR network could explain the low number of
matches because the requirement that previous mumps
vaccination be fully documented could have led to the
loss of the cases for which this information had not
been noted in clinical files. Nevertheless, any case was
identified by comparison of the cases reported to the
manufacturer and all the cases reported to the lab-
oratory network, regardless of vaccination status.
The difference in the collection circuits—the P.M.sv.
Pharmacovigilance Department mostly covers urban
paediatricians whereas the EPIVIR network covers
paediatric hospitals—could have led to overestimation
of the total number of cases. However, the stratified
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data (Table 1) show that this effect does not seem very
important because the estimated totals are little differ-
ent from the total without stratification.
The risk is calculated on the number of doses sold
and not on the number of doses administered which
underestimates the real risk of post-vaccination mumps
meningitis. The incidence of this error is totally un-
known because no French study has ever been carried
out to evaluate the percentage of combined measles-
mumps-rubella vaccines or mumps vaccines which
were not administered after sale.
Finally, it has been shown that the capture-recapture
method gives much more reliable results when three or
more sources of information are used.10 The use of the
data from the National Pharmacovigilance Centres
would have enabled validation of our capture-recapture
estimate had they been available for the same study
period.
CONCLUSION
In France, the risk of aseptic meningitis from mumps
vaccination has not been estimated precisely. For the
first time we estimated, using the capture-recapture
method, this risk at 1/28 400 vaccines sold. Due to the
limits of this study, it is more reasonable to conclude
that the risk lies somewhere between 1/18 000 and
1/67 000.
It should be remembered that post-vaccination
meningeal reactions are spontaneously reversible and
sequellae-free, that the frequency of meningitis due to
wild virus is much higher (approximately 1-3 per
lOOO""13) and that the efficacy of measles-mumps-
rubella vaccination has been demonstrated by a sub-
stantial decrease in the number of cases of mumps,
measles and rubella and a reduction in the number of
complications due to these diseases. 1 ' 1415
To make vaccination more acceptable, some coun-
tries such as Canada, Australia and, more recently,
 ASEPTIC MENINGITIS AND MUMPS VACCINATION
Great Britain, Ireland and Luxembourg exclusively use
the Jeryl-Lynn strain which is less prone to unwanted
effects.16"19 This strain has been available in France
since November 1994. Given the insufficient level of
mumps vaccination (in 1991, mumps vaccine coverage
was only 64% in 2-year old children in France 20 and
33% in children in their last year at their primary school
in Paris 21 ), the French Vaccination Committee (Comite
Technique des Vaccinations) recommended, in Septem-
ber 1992, promoting the practice of measles-mumps-
rubella vaccination in order to limit the circulation of
the wild virus and prevent an epidemic in insufficiently
protected groups of the population whilst awaiting
vaccine containing the Jeryl-Lynn strain.
ACKNOWLEDGEMENTS
We would like to thank the Directors of EPIVIR net-
work Virology Laboratories, reporting practitioners and
J-C Desenclos, B Hubert, P Saddier and R Salmi for
their contributions.
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