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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.

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Hepatitis B Vaccines: Safety and Side-Effect Profile

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  1. 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

  2. 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

  3. Disease Total Vaccinated Yes No 160,000 40,000 16 159,984 Not vaccinated 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?

  4. 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?

  5. France: suggestion of a link between hep B vaccine and MS because of case reports of onset or exacerbation of demyelination

  6. 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

  7. 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

  8. 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 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

  9. 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

  10. 3 Hypotheses That Could Explain Demyelinating Disease Following Hep B Vaccination 1. Coincidence Intensive vaccination 2. Triggering 3. True causal relationship

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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)

  16. 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

  17. 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)

  18. 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)

  19. 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

  20. 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)

  21. 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? • …..

  22. 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)

  23. 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

  24. 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

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