Hepatitis B vaccine and risk of relapse after a first
childhoodepisode of CNSinflammatorydemyelination
Y ann Mikaeloff,1Guillaume Caridade,1Saada Assi,1MarcTardieu and Samy Suissa2on behalf of the KIDSEP
study group of the French Neuropaediatric Society*
1Assistance publique-Ho “ pitaux de Paris, Service de Neurologie Pe ¤ diatrique, Ho “ pital Bice “ tre, INSERM U802,Universite ¤ Paris
Sud11, Le Kremlin Bice “ tre, France and2Division of Clinical Epidemiology, McGill University and Royal Victoria Hospital,
Correspondence to:Yann Mikaeloff,MD,PhD, Service de Neurologie Pe ¤ diatrique,CHUBice “ tre, Assistancepublique-Ho “ pitaux
de Paris, 78 avenue du Ge ¤ ne ¤ral Leclerc,94275 Le Kremlin-Bice “ tre Cedex, France
*Members listed at end of the article
Public concern about possible increases in the risk of multiple sclerosis associated with hepatitis B vaccination
has led to low vaccination coverage.We investigated whether this vaccination after a first episode of acute CNS
inflammatory demyelination in childhood increased the risk of conversion to multiple sclerosis.We studied the
French Kid Scle ¤ rose en Plaques (KIDSEP) neuropaediatric cohort of patients enrolled between 1994 and 2003
fromtheir first episode of acute CNS inflammatory demyelination (inclusion in the cohort) untilthe occurrence
of a second episode, up to 2005. A Cox proportional hazards model of time-dependent vaccine exposure was
used to evaluate the effect of vaccination (hepatitis B, tetanus) during follow-up on the risk of second episode
occurrence (conversiontomultiple sclerosis).The cohort included 356 subjectswith a mean follow-up of 5.8 years
(SD 2.7).Relapse occurredin146 (41%) subjects during follow-up; 33 subjects were exposedto hepatitis B vaccine
and 28 to tetanus vaccine at some time during follow-up.The adjusted hazard ratio (HR) for relapse occurring
within 3 years of hepatitis B vaccination was 0.78 (0.32^1.89) and during any time period was1.09 (0.53^2.24).The
adjusted HR for relapse occurring within 3 years of tetanus vaccination was 0.99 (0.58^1.67) and during any time
period was 1.08 (0.63^1.83).We conclude that vaccination against hepatitis B or tetanus after a first episode of
CNS inflammatory demyelination in childhood does not appear to increase the risk of conversion to multiple
sclerosis, although the possibility of a small increase in risk cannot be excluded.
Keywords: child; epidemiology; hepatitis B vaccine; immune-mediated demyelination; multiple sclerosis
Abbreviations: HB¼hepatitis B; MS¼multiple sclerosis
Received September 26, 2006. Revised November 6, 2006. Accepted December 5, 2006
Several reports have raised the possibility of an effect of
recombinant hepatitis B (HB) vaccine on the incidence and
severity of multiple sclerosis (MS). Most evaluated the
association between immunization and an increase in the
risk of incident MS, but found no increase in occurrence
in the short (mostly within 2 months) or long term
(41 year) in cohort or case–control designs (Zipp et al.,
1999; Sadovnick and Scheifele, 2000; Ascherio et al., 2001;
Touze ´ et al., 2002; DeStefano et al., 2003, 2005). However,
most of these previous studies could not exclude small
increases in the risk of MS. A recent nested case–control
study in adults reported an association between HB
vaccination and an increase in the incidence of MS
within 3 years of vaccination (Hernan et al., 2004). The
methodology of some of these epidemiological studies has
been criticized, due to imprecise case definition or timing
(date of diagnosis or date of first symptoms of MS), limited
statistical power and a lack of validation of vaccination
status (Hernan and Jick, 2006).
The safety of vaccination in patients with MS is another
question, which has been evaluated in only one study
of a large group of adult patients with established MS,
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at different stages of evolution, exposed to HB vaccine
a mean of 9.5 years after disease onset (Confavreux et al.,
2001). In this study with a case-crossover design, no
increase in the risk of subsequent relapse was demonstrated
for a 2-month period.
HB vaccination coverage was recently reported to have
fallen below 50% in children and adolescents in France,
due to public anxiety about possible increases in the risk
of MS years after vaccination and despite high levels of
morbidity and mortality due to the HB virus worldwide
(Kane et al., 1993; Denis, 2004). Moreover, although no
official recommendation had been issued, it was widely
thought that HB vaccination should be avoided in children
who had had an episode of acute CNS inflammatory
demyelination, to minimize the risk of relapse and of the
subsequent onset of MS.
None of these previous epidemiological studies focused
on children or on specific questions about the risk of
conversion to MS when immunization follows a first
episode of demyelination. Using an observational study
based on the KIDSEP neuropaediatric cohort, we investi-
gated whether HB vaccination increases the risk of a second
episode, i.e. conversion to MS, in children after a first
well-identified episode of acute CNS inflammatory demye-
lination. We compared the effects of HB vaccination with
those of tetanus vaccination, over short- and long-term risk
Material and methods
Design, subjects and source of data
We conducted an observational cohort study among patients with
a first episode of acute CNS inflammatory demyelination in
childhood from the French national KIDSEP neuropaediatric
cohort, evaluating whether risk of relapse was greater after HB
vaccine exposure than after tetanus vaccine exposure, if these
vaccines were administered after inclusion in the cohort. The
inclusion and exclusion criteria of this cohort have been described
elsewhere (Mikaeloff et al., 2004a, b, 2006). This cohort included
467 patients with a first episode of acute CNS inflammatory
demyelination occurring between January 1, 1990 and December
31, 2003, before the age of 16 years. For the present study, we
excluded patients enrolled in the main study before January 1,
1994, because levels of HB vaccination were low in France before
that date (Denis, 2004). This resulted in a cohort of 422 patients.
Patients were followed up from inclusion until December 2005,
by means of routine clinical visits and regular telephone
interviews. Five patients did not complete the follow-up period
and no more than 2 years of data are available. However, these
data were used in this study (relapses in four of the five patients).
Several of the characteristics of the patients (Table 1) were
recorded at inclusion, as previously described (Mikaeloff et al.,
2004a, b, 2006). Episodes, including a description of symptoms,
were all reported by a trained paediatric neurologist. For this
particular study, we also included information on economic
activity for the head of the family, based on the categories defined
by INSEE (the French National Institute of Statistics and
Economic Studies), assessed with a standardized questionnaire
unemployed people, labourers and low-income employees—was
compared with all other categories. Place of residence at inclusion
was known for all patients, but we used a dichotomous variable:
living within or outside the Parisian region, as the capital city
and its suburbs might display specific patterns of health service
use. Data were input into a computerized system approved by
the ‘Comite ´ National Informatique et Liberte ´’ (the French data
Assessment of exposure to vaccines
All families were contacted by letter and telephone, to provide
them with information about the study and to request a copy of
the child’s vaccination certificate (‘carnet de sante ´’). A vaccination
was defined as the administration of a commercial preparation of
vaccine, whether as a single vaccination or part of a series, and
whether for primary immunization or as a booster.
Outcome of the study
The outcome studied was the occurrence of relapse—generally
considered as conversion to MS—defined as a second episode of
neurological symptoms lasting more than 24h and then partially
or completely stabilized or resolved, as previously described
(Mikaeloff et al., 2004a, b, 2006). New symptoms occurring
within 1 month of clinical onset were considered to be part of the
Descriptive data were compared, using the ?2test or Fisher’s exact
test for proportions and the t-test or the Wilcoxon test for
continuous measures. For the study cohort, time zero was taken as
the date on which the first episode of acute CNS inflammatory
demyelination was considered to have ended, corresponding to 1
month after the onset of symptoms for the cohort-defining
episode. The end-point was the date on which the outcome,
relapse, occurred. For event-free subjects, the follow-up period
ended on the date of the last known visit.
Cox proportional hazards models were used to evaluate the
prognostic value of each vaccination studied and to estimate crude
and adjusted hazard ratios (HRs). A time-dependent Cox model
was used to assess the effect of each vaccine over time, taking
intoaccount the exact date
recommended in observational studies, to avoid immortal time
bias (Suissa, 2003, 2004).
The analysis was adjusted for all the covariates reported in
Table 1 potentially affecting the prescription of vaccines and/or
outcome. Covariates were separately entered into the model.
Analyses were carried out for different durations of exposure
to vaccine: 3 and 6 months, 1 and 3 years and for the entire
follow-up period after the date of vaccine exposure, to facilitate
comparison with results from previous studies considering short-
and long-term risk periods.
of onsetand duration,as
We excluded 10 patients of foreign origin with different
patterns of exposure to vaccination and 56 patients
Page 2 of 6Brain (2007) Y . Mikaeloff et al.
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who did not provide vaccination information from the
initial cohort of 422 patients. The study cohort therefore
included 356 patients, 350 of whom provided a copy of
their vaccination records, the remaining six providing
precise vaccination information by telephone. The other
56 French patients (13.6%) who did not participate had a
similar frequency of relapse (38% versus 41%) and other
variables, but were less likely to be living in the Paris region
at disease onset (9% versus 30%) than the participants.
For the study cohort, the mean age at onset was 9.2?4.6
years with an onset before 6 years of age recorded in 109
of the 356 (30.6%) and an onset before 2 years of age
recorded in 23 of the 356 (6.5%) patients (see Table 1 for
other characteristics at onset). The mean follow-up period
for this cohort was 5.8?2.7 years, and second episode
occurred during this period in 146 patients (41%). Relapse
occurred during the first year for 92 patients (63%) and
during the first two years for 115 patients (79%). The
symptoms of relapse were multiple (n¼48, 33%), trans-
verse myelitis (n¼3, 2%), optic neuritis (n¼42, 29%),
severe mental status change (n¼11, 8%) and brainstem
dysfunction (n¼33, 23%). None of the patients died
during follow-up period.
HB vaccination, when administered during follow-up
(n¼33), was given in isolation [GlaxoSmithKline: Engerix
B?(n¼16); Aventis Pasteur MSD: GenHevac B?(n¼11);
HB VAX?(n¼5); Hevac B?(n¼1)], whereas tetanus
vaccination (n¼165) was combined with other vaccina-
tions in all but one case [combined with diphtheria and
polio (n¼98); diphtheria, polio and pertussis (n¼45);
diphtheria, polio, pertussis and Haemophilus influenzae B
The baseline characteristics of patients as a function of
vaccine exposure are reported in Table 1: 33 of the 356
(9.3%) patients were exposed to HB vaccine after onset
(25 for the first time and eight through booster injections)
and 165 patients (46.3%) were exposed to tetanus vaccine
(three for the first time and 162 through booster
injections). Patients exposed
significantly from those not exposed to this vaccine: they
were more likely to be living in the Parisian region and
to have disease onset before 1997. In most cases, this post-
disease onset exposure to HB vaccine was their first
exposure to this vaccine (Table 1). Patients exposed to
HB vaccine were also more likely to have transverse myelitis
at onset, and less likely to have received high-dose steroids
as treatment for the first episode. Patients exposed to
tetanus vaccine also differed significantly from patients
not exposed to this vaccine. They were more likely to have
suffered from infections during the month before onset,
to HB vaccine differed
T able 1 Comparison of characteristics of the study population (n¼356) exposed or not exposed to HB or tetanus vaccine
after disease onset (first episode)
No HB vaccine
after onset (n¼323)
n (%) or mean (SD)
HB vaccine after
n (%) or mean (SD)
No tetanus vaccine
after onset (n¼191)
n (%) or mean (SD)
Tetanus vaccine after
n (%) or mean (SD)
Familial MS history
Infection during the month before onset
Low economic activity for the
head of the family
Severe mental status change
Oligoclonal bands in CSF*
Cells in CSF510?l
Proteins in CSF 5 500
Child-MS MRI criteriay
Three Barkhof MRI criteriaz
Irreversible disability after inclusion
Prior use of vaccine
98 (30)16 (49)61 (32) 53 (32)
1 17 (36)
1 17 (36)
1 19 (37)
1 1 (0.5^16)
1 1 (33)
*264 patients studied.yCorpus callosum long axis perpendicular lesions or presence of well-defined lesions only (Mikaeloff et al., 2004).
zThree of four criteria: at least one gadolinium-enhancing T1lesion or 59 T2lesions, at least one infratentorial T2lesion, at least one
juxtacortical T2lesion, 3 periventricular lesions (Barkhof et al.,1997).
Hepatitis B and childhood demyelination1Brain (2007) Page 3 of 6
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more frequently from families of a low socio-economic
level, younger at onset and less likely to have a disease onset
after 1997 (Table 1).
significant increase in the risk of relapse, regardless of
exposure duration (from 3 months to any time since the
onset of exposure; Table 2). The adjusted HR for relapse
associated with HB vaccine exposure was 0.68 for a
3-month exposure period [95% confidence interval (CI):
0.09–4.98], 0.78 for a three-year exposure period (95% Cl:
0.32–1.89) and 1.09 for any time period (0.53–2.24).
Relapses were recorded within 3 years of exposure in six
patients vaccinated against HB, and during any time period
in 10 such patients: the upper limit of the 95% CI could
exclude increases of 1.9 times (for the 3-year period) and
2.3 times (for the any time period), but not a lower
increase. Confounding factors potentially accounting for the
difference between crude and adjusted HR values included
the presence of optic neuritis at onset, child-MS MRI
or Barkhof MRI criteria and oligoclonal bands in CSF
analysis. Tetanus vaccine exposure was not associated with
a significant increase in the risk of relapse, regardless of the
duration of exposure studied (Table 2).
We provide, for the first time, an evaluation of the
potential risk of second episode occurrence, i.e. conversion
to MS, associated with administration of the HB and
tetanus vaccines after a first episode of acute CNS
inflammatory demyelination. This study was carried out
in children, a population with a higher exposure to vaccines
than adults, who had not previously been analysed.
Previous studies, concerning association between HB
vaccine exposure and increase of MS incidence, concerned
the general population. Our population of first episode of
CNS inflammatory demyelination could be more suscep-
tible to the effect of a studied potential risk factor, such as
HB vaccine. Only one other epidemiological study has been
published to date on the safety of vaccinations in patients
with MS. This previous study had a different design—
evaluating patients with long-term MS, at different stages,
some of whom were in the secondary progressive course,
and evaluating the risk of relapse in a 2-month short-term
risk period, in a case-crossover design (Confavreux et al.,
2001). No increase in the risk of relapse was found to be
associated with exposure to HB vaccine (15 of 643 MS
patients were exposed within the 2-month risk period
before the index relapse; relative risk: 0.67, 95% CI, lower
limit: 0.20, upper limit 2.17). This led to the recommenda-
tion issued by the American Academy of Neurology that
patients with MS should follow Centers for Disease Control
indications for immunization in the general population for
all vaccinations, including HB vaccine (Rutschmann et al.,
2002). However, this recommendation did not take into
account the specific issues of vaccination in the early phase
of the disease and in children. Moreover, a recent study by
Hernan et al. (2004) reported an increase in the risk of MS
incidence within 3 years of vaccination (in this study, 11 of
the 143 MS cases were exposed to HB vaccine within the 3-
year risk period), suggesting that risk periods longer than 2
months should be evaluated in studies on vaccination safety
in MS patients.
The paediatric context of our study is one of its strong
points. It is based on a large, recognized cohort of children
and adolescents from an ongoing study (not focusing on
vaccination), with a long period of follow-up. Precise dates
and descriptions were provided by a paediatric neurologist
for both first and second episodes, and the risk of
underreporting of episodes was minimized by exhaustive
inclusions in participating centres (Mikaeloff et al., 2004a,
b,2006). This made it possible to circumvent previously
identified methodological limitations and to minimize
potential bias due to the time elapsed from the onset of
the first symptoms and the onset of MS or its diagnosis
(Naismith and Cross, 2004; DeStefano et al., 2005; Hernan
and Jick, 2006).
Another strength of this study is that vaccination status
was validated, in most cases, by a paper copy of the
vaccination certificate, as recommended (Chen et al., 2005).
The risk of vaccination not being specified on the certificate
was very low because all vaccinations must be recorded on
this document (the ‘carnet de sante ´’) in France (Denis,
2004). Moreover, the ‘carnet de sante ´’ is highly valued by
families, is presented systematically to the physician at
all medical consultations during follow-up and contains
certificates opening access to maximal reimbursement by
the universal health insurance system.
The exclusion of patients for whom a copy of the
introduced a bias, because the probability of exposure
may depend on the geographic and economic activity of
parents (Denis, 2004). However, analyses were adjusted for
geographic differences, the socio-economic level of parents,
the aggressiveness of initial disease and other previously
described predictors of relapse (Mikaeloff et al., 2004a, b).
Time was rigorously taken into account, using multivariate
survival analysis and time-dependent vaccine exposure, and
considering various durations of follow-up in the cohort
and timing and duration of vaccine exposure.
Analyses were performed for several different durations
of vaccine exposure: 3 and 6 months, 1 and 3 years and the
entire follow-up period after vaccination. This aspect is
particularly important because MS has a variable rate of
relapse over time and the true risk period after HB
vaccination has not been established (Compston and Coles,
2002; Mikaeloff et al., 2004a, b; Strohm, 2005). The time
sequences of white matter and axonal destruction in MS
following stimulation with external antigens, such as
vaccines, has also not been defined (Piaggio et al., 2005;
Schattner, 2005). We considered the 3-year risk period
specifically due to the report of an association with an
Page 4 of 6 Brain (2007)Y . Mikaeloff et al.
by guest on June 2, 2013
increase in MS incidence during this time period in a recent
study (Hernan et al., 2004).
We found that HB vaccination did not increase the risk
of relapse and conversion to MS, either within 3 years of
vaccination or at any time point after vaccination, in
subjects with first episode of CNS inflammatory demyelin-
ation in childhood. However, a certain lack of power
should be taken into account when interpreting our results.
Indeed, only six patients relapsed within 3 years, and 10
within the entire follow-up period. The upper boundary of
the 95% CI indicates that increases in risk by a factor of 1.9
(for the 3-year period) and 2.3 (for the any time period)
could be excluded, but that it is not possible to exclude a
smaller increase in risk. Our study had the same magnitude
of statistical power than previous studies. Finally, the risk of
an initial episode of demyelination after HB vaccination in
childhood requires further study.
The study was funded by grants from the ‘Association pour la
Recherche sur la Scle ´rose En Plaques’ (ARSEP, France), the
‘Direction de la Recherche Clinique’, ‘Assistance publique-
Ho ˆpitaux de Paris’ (AP-HP, France) and the ‘Agence
Franc ¸aise de Se ´curite ´ Sanitaire des Produits de Sante ´’
(AFSSAPS). S.S. holds a Distinguished Scientist award from
the Canadian Institutes of Health Research (CIHR).
We wish to thank all the participants of the KIDSEP study
Pediatric neurology departments (France): D. Amsallem
(Besanc ¸on); P. Aubourg (Ho ˆpital Saint-Vincent de Paul,
Paris); M. A. Barthez, P. Castelnau (Tours); P. Berquin
(Amiens); O. Boespflug (Clermont-Ferrand); J. C. Carrie `re,
C. Cances, Y. Chaix (Toulouse); J. M. Cuisset, J. C.
Cuvelier, L. Valle ´e (Lille); A. de Saint-Martin (Strasbourg);
I. Desguerre, O. Dulac (Necker-Enfants Malades, Paris); V.
Des Portes, C. Rousselle, D. Ville (Lyons); B. Echenne,
F. Rivier (Montpellier); P. Evrard (Ho ˆpital Robert Debre ´,
Paris); A. Joannard (Grenoble); P. Landrieu, Y. Mikaeloff,
M. Tardieu (Bice ˆtre); M. O. Livet (Aix en Provence);
J. Mancini, B. Chabrol (Marseilles); J. Motte, N. Bednarek,
P. Sabouraud (Reims); S. Napuri, L. Lazaro (Rennes); S. N.
Guyen (Nantes); S. Peudenier (Brest); F. Pouplard (Angers);
J. M. Pedespan (Bordeaux); S. Perelman, C. Richelme
(Nice); N. Perez (Belfort); D. Rodriguez, T. Billette de
Villemeur, M. L. Moutard, G. Ponsot (Ho ˆpital Trousseau,
Paris); M. C. Routon (Orsay); H. Testard (Annemasse),
C. Van Hulle (Rouen).
Adult neurology departments
C. Renoux (Service de neurologie et centre de coordination
EDMUS, Lyons); M. Debouverie (Nancy); F. Dubas
(Angers); G. Edan (Rennes); O. Heinzlef (Ho ˆpital Tenon);
(La Pitie ´-Salpe ´trie `re); T. Moreau (Dijon); J. Pelletier
(Marseilles); G. Saı ¨d (Bice ˆtre); P. Vermersch (Lille).
Neuroradiology departments (France): C. Adamsbaum
(Ho ˆpitalSaint-Vincent de
(Bice ˆtre); A. Tourbah (Ho ˆpital La Pitie ´ Salpetrie `re, Paris).
Clinical Epidemiology department (Canada): A. Kezouh,
S. Suissa (McGill University and Royal Victoria Hospital,
C. Lubetzki,B. Fontaine
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T able 2 Cox survival analysis of the effect of HB or tetanus vaccine exposure on relapse (second episode)
Vaccine exposure after onsetNumber of subjects
with a relapse
Crude HR* Adjusted HR*,y(95%CI)P-value
Hepatitis B (HB)
HB exposed any time (n¼33)
Time period studied after vaccination
First three months
First six months
First three years
Tetanus exposed any time (n¼165)
Time period studied after vaccination
First three months
First six months
First three years
*HR¼hazard ratio, no HB vaccine exposure is the reference group.yAdjusted on all covariates of Table1.
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