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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.

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hepatitis b vaccines safety and side effect profile

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
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







16 159,984



4 39,996

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 incomplete picture

Example: population 200,000, risk of disease 1/10,000, vaccine coverage 80%

Selection bias?

safety profile
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 disordersand 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
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
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

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

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


fulminant hep B

3 to 29 cases

cirrhosis & PLC

12 to 147 cases

global negative impact
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
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
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
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
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
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
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
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
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 2-month 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
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 0.3-4.2) 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
US CDC Vaccine Safety Datalink Case-Control StudyVertsraeten 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 .51-1.37) , 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
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
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)
  • 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
Resources on the Web
  • WHOgeneral(make a search)www.who.int/m/topicgroups/information_resources/en/index.shtml
  •  Vaccines & Biologicals web site www.vaccines.who.int
  •  Immunization Safety web sitewwwstage/vaccines-surveillance/ISPP/81916169000.shtml
  •  Environmental Health web sitewww.healthcarewaste.org/
  • Safe Injection Global Network web sitewww.injectionsafety.org