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 incomplete picture

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

16 159,984

4 39,996

160,000

40,000

Disease Total

Vaccinated

Notvaccinated

Yes No

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 France1982 Recommendation for health care workers and high risk groups

1991 Compulsory for health care workers

1994-95 Universal vaccinationInfantsAdolescents: school-based

1998 Over 25 million vaccinated

1999 34 to 45% of population vaccinated18 millions adults 9 millions children 15 year 1.8 millions children 2 year

History of Hepatitis B Vaccine Safety Issue in France

1991Case 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

ButUniversal infant immunization programs continuedVaccine still recommended for adults at increased riskContinued support for adolescent vaccination through primary care physician

BENEFIT: fulminant hep B

3 to 29 casescirrhosis & PLC12 to 147 cases

RISK*:

1 or 2 cases of

demyelinating disease

*Hypothesis: RR = 1.4 (not statistically significant); period of time 30 yearsLévy-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 FranceFebruary 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., publishedNeurology 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)

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.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?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)

ConclusionsNo data to suggest a link with MS

Most plausible explanation for MS reported following hep B vaccination is coincidenceWeak risk cannot be rejected nor the existence of subpopulations with specific sensitivity. Impossible to demonstrate an absence of correlationExclusion of an elevated risk of MS or other autoimmune diseasesMS 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_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