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Hepatitis B Vaccines: Safety
and Side-Effect Profile
Philippe Duclos, WHO
Strengthening Immunization Systems and
Introduction of Hepatitis B Vaccine in Central
Eastern Europe and the Newly Independent
States
St Petersburg, Russian Federation, February
June 24-27, 2001
Vaccine Preparations
Highly purified preparations of HBs Ag
Prepared by harvesting HBs Ag from the
plasma of people with chronic infection or
by inserting plasmids containing the viral
gene in yeast or mammalian cells
Aluminium phosphate or aluminium
hydroxide
Sometimes thiomersal as preservative
Safety profile: important issues
Allegations or facts?
Relatively new vaccine - different age
groups
Surveillance data and/or properly controlled
studies
Surveillance, case report, case series: an
picture
Example:incomplete
population 200,000,
risk of disease 1/10,000, vaccine coverage 80%
Disease
Total
Yes
No
Vaccinated
16
159,984
160,000
Not
vaccinated
4
39,996
40,000
Safety Profile
Pain and tenderness in 15% (3%-29%) of
vaccinations and fever > 37.7°c in 1%-6%
Fever, headache, muscle aches and pain,
nausea, vomiting, loss of appetite, and
fatigue occur at same rate as in placebo
Anaphylactic reaction 1 per 600,000 doses
Cases of rheumatoid arthritis, thyroiditis,
lupus, hematological disorders and
demyelinating diseases of central nervous
system (multiple sclerosis) reported but no
causative link demonstrated
No association with Guillain Barre Syndrome
No association with diabetes
Hair loss? Other allegations?
France: suggestion of a link between
hep B vaccine and MS because of case
reports of onset or exacerbation of
demyelination
Hepatitis B Vaccination in France
1982
Recommendation for health care workers
and high risk groups
1991
Compulsory for health care workers
1994-95 Universal vaccination
Infants
Adolescents: school-based
1998
Over 25 million vaccinated
1999
34 to 45% of population vaccinated
18 millions adults
9 millions children  15 year
1.8 millions children  2 year
History of Hepatitis B Vaccine
Safety Issue in France
1991
Case reports in Lancet
1994
Official pharmacovigilance
survey
1995
« Dear Doctor Letter »
1995-98 Growing pressure on hep B
vaccination program
French Authorities Temporarily Stopped
School-Based Adolescent Hepatitis B
Vaccine Programs on October 1, 1998
But
Universal infant immunization programs
continued
Vaccine still recommended for adults at
increased risk
Continued support for adolescent
vaccination through primary care physician
BENEFIT:
fulminant hep B
3 to 29 cases
cirrhosis & PLC
12 to 147 cases
RISK*:
1 or 2 cases of
demyelinating disease
*Hypothesis: RR = 1.4 (not statistically significant); period of time 30 years
Lévy-Bruhl D. et al BEH 1999; 9:33-5
Global Negative Impact
Misquoting of French decision
Fueled by legal actions and court decisions in
France
Could have been disastrous
Several countries considered stopping hep B
vaccination
Several countries contemplated withholding
introduction of hep B vaccination
Limited impact on coverage but hard to
measure
Long term effect on image of vaccine
3 Hypotheses That Could
Explain Demyelinating Disease
Following Hep B Vaccination
1. Coincidence
Intensive vaccination
2. Triggering
3. True causal relationship
French Post-Market Surveillance
Data as of December 31, 1999
636 nervous central demyelinating diseases and
87 cases of peripheral demyelinating disease
16 MS in children <=15 years including 15 first
crisis; 0 case in < 24 months
Age and sex distribution similar to age and sex
distribution of MS in general population
Increased reporting between 1998 and 1999 due
to visibility
Observed versus expected cases unremarkable
France accounts for the vast majority of MS
reports globally
Pilot Case-Control Study (A.
Alpérovitch, Fédération de Neurologie,
Pr. O. Lyon-Caen Hôpital Pitié
Salpêtrière, 1997)
121 cases and 121 controls
OR 1.8 (95%CI .5-6) for 2 months interval
OR 1.7 (95%CI .8-3.7) for all intervals
Multi-Centre Case-Control
Study (E. Touze, France, 1998)
242 cases and 407 controls
OR 1.4 (95%CI .4-4.5) for 2 months,
valid vaccination
OR 1.8 (95%CI .7-4.6) for 2 months, all
subjects
UK General Practitioners
Research Database Study (M
Sturkenboom et al., 1998)
Population based matched case-control
study (6 controls per case)- 343 MS and
138 CDD
OR 1.4 (95%CI .8-2.4) 2 months interval
OR 1.5 (95%CI .6-3.9) 12 months interval
Survey of 735 Patients Seen
at MS Clinic, Coustans et al.,
Rennes France
February 97 to August 98, 24
vaccinated patients with MS
diagnosed prior to hep B vaccination
Mean annual rate of relapse was .62
in 24 months prior to vaccination and
.5 after (NS)
Retrospective US Cohort Study
(F. Zipp et al., published )
Healthcare database from 88 to 95,
134,698 individuals (27,229 vaccinated)
No elevated risk at any time point
monitored and for age-dependent risk
Canadian Retrospective Cohort Study (D.
Sadovnick and D. Scheifele,
published)
Vaccination of 11-12 year old students Oct
1992
Onset of MS among adolescents age 11-17
years. Data from British Columbia’s
Children’s Hospital and provincial MS
clinic
9 cases prevaccination period - Jan 1986
through Sep 1992 (288,657 children) and 5
in post vaccination - Oct 1992 through Sep
1998 (289,651 children with 92.3%
vaccinated)
Vaccimus Cross-Over Study in
MS patients, Pr. Confavreux et
al., published
Neurology departments of the EDMUS
network, all 643 patients with MS
Compare exposure to vaccination in the 2month period before a relapse with that of
four 2-month control periods
RR of relapse was 0.67 (95%CI 0.2-2.17)
Nurse Health Study (NHS)
(Harvard University, A.
Ascheiro et al., published)
Nested case-control in two cohorts of
nurses NHS (121,700 women) and NHSII
(116,671 women)
192 cases and 645 matched controls
RR (within 24 months) of MS for
vaccinated women was 0.7 (95%CI 0.3-1.7)
using healthy controls and 1.0 (95%CI 0.34.2) using breast cancer controls
Confirmed the existence of recall bias with
self reported dates of vaccination
US CDC Vaccine Safety
Datalink Case-Control Study
Vertsraeten et al.
Health Maintenance Organizations large
linked databases
445 cases (18-49 years, MS or optic
neuritis cases first diagnosed in 1995 to
99), up to 3 matched controls
OR never/ever vaccinated: .83 (95%CI .511.37) , OR < 1 year before onset .77 (95%CI
.32, 1.85). 1-5 years before onset 1.08
(.56,2.09), > 5 years before onset .61
(.25,1.49)
Why Slightly Discordant
Results, Particularly with Early
Studies?
Biases (recall bias) and confounding
effect?
Differences in “at risk” period used?
French effect?
Lack of power?
Different vaccines?
…..
Biologic Plausibility: Link between
Hepatitis B and MS?
Worldwide geographic distribution of
cases of MS and hep B quite distinct
No published report describing onset or
exacerbation of MS following hep B
infection
Molecular mimicry? No known homology
between the HBs antigen and human
myelin protein
Testing immunological cross reactivity 
negative results (R. Liblau)
Conclusions
No data to suggest a link with MS
Most plausible explanation for MS reported
following hep B vaccination is coincidence
Weak risk cannot be rejected nor the existence of
subpopulations with specific sensitivity.
Impossible to demonstrate an absence of
correlation
Exclusion of an elevated risk of MS or other
autoimmune diseases
MS risk in worst case-scenario (<.3/100,000
preadolescents, <1/100,000 adults)
Excellent safety profile of hep B
vaccine
Resources on the Web
WHO general (make a search)
www.who.int/m/topicgroups/information_r
esources/en/index.shtml
 Vaccines & Biologicals web site
www.vaccines.who.int
 Immunization Safety web site
wwwstage/vaccinessurveillance/ISPP/81916169000.shtml
 Environmental Health web site
www.healthcarewaste.org/
Safe Injection Global Network web site
www.injectionsafety.org