childhood vaccinations
dangers and risks of vaccines in children
hepatitis b vaccine safety

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Hepatitis B Vaccine: The Risks

Several case reports raised concerns that hepatitis B (HB) immunization might be linked to new cases or reactivation of multiple sclerosis (MS) or other demyelinating diseases within a period of 2 to 3 months after vaccination.1 Articles published in the media stating a link between HB immunization and MS further fueled worry over the safety of the vaccine.

Suggestions also arose that all vaccines, including hepatitis B, could shift the immune system toward an auto-immune direction, shifting from Th1 to Th2 cytokine production, thereby encouraging the expression of auto-immune disease, including autism, among individuals rendered susceptible by other mechanisms.

There are three hypotheses that could explain the observed cases of demyelinating disorders following HB vaccine:2

  1. Coincidence: due to the large number of HB vaccine doses administered, many of them in age groups where symptoms of MS first occur.

  2. "Triggering": an increased risk of symptomatic demyelination following HB vaccine which would act as a "trigger" in individuals predisposed to develop MS or central nervous system (CNS) demyelinating diseases. These individuals would have developed demyelination with or without an altered natural history following some immunologic or other precipitating factor.

  3. A true causal relationship between HB vaccination and MS or other CNS demyelinating disease.

Evidence to support the first hypothesis includes the fact that no statistically significant association was found between hepatitis B vaccine and MS in the limited studies conducted to date. Further, the age and sex distributions of MS cases reported through spontaneous reporting systems match the recognised age and sex distribution of MS cases that preceded the use of the vaccine and are not correlated with vaccine administration.

In support of the second hypothesis of an increased risk of MS following HB vaccination seen as a precipitating factor is that some studies have shown slightly elevated odds ratios, although these were not statistically significant. Evidence inconsistent with this second hypothesis is the observation that no increased risk was found in another study. No tangible evidence was presented for the biologic plausibility of any association.

There is, to date, no evidence of a causal link between hepatitis B virus infection and CNS demyelinating disorders including multiple sclerosis. Additional epidemiological and immunological research is ongoing or planned to further examine any association between vaccination, including hepatitis B, and CNS demyelinating disease. Altogether, evidence in favour of an increased risk following vaccination is weak and does not meet the criteria for causality.

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Hepatitis B: The Disease

More than 2,000 million persons worldwide have serologic evidence of past or current hepatitis-B (HB) virus infection. More than 350 million chronic carriers of the virus are at high risk of death from cirrhosis and liver cancer, diseases which kill almost 1 million persons a year.3

In the USA, the Centers for Diseases Control and Prevention (CDC) estimated (on the basis of death certification data and specific studies) that 54% of the 32,000 deaths from chronic liver disease per annum are due to hepatitis viruses B and C infections; 4,480 of these chronic liver disease deaths are due to hepatitis B virus. Hepatocellular carcinoma deaths due to hepatitis B add another 3,000 deaths per annum. The annual costs of this infection in the USA are estimated at $658 million.

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History of the Hepatitis B Vaccine

The Hepatitis B (HB ) vaccines have been available since 1982 and more than one billion doses have been used. Approximately 100 countries, consistent with World Health Organization policy, have added HB vaccination to their routine childhood immunization programmes and most countries have, in addition, adopted a policy to vaccinate adults at increased risk.

HB vaccine is approximately 95% effective in preventing the HBV chronic carrier state. Direct reduction of liver cancer has already been documented in immunized children. The use of hepatitis B vaccine, both plasma-derived and recombinant, has resulted in dramatic reductions in the prevalence of the carrier state in many areas.4

In areas without significant perinatal transmission the carrier rate has been reduced to less than 1% from levels of 15-20%. In areas where perinatal transmission is important (e.g. China) the reduction has been to less than 2% of the vaccinated population.5 Data from Taiwan shows that hepatitis B vaccination reduces the incidence of liver cancer in children.6

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Available Data on the Safety of Hepatitis B Vaccines

1. Literature and Clinical Trials:

Safety trials have been carried out in healthy individuals of all ages as well as in those at increased risk of infection and those with impaired immunity (for example, hemodialysis patients). The recording of adverse events within trials is the responsibility of the investigator. Active surveillance is usually carried out for the first 4 to 14 days after each dose of vaccine and unsolicited recording of health events occurs for 30 days after each dose.

Serious adverse events are recorded throughout any study which may be up to 7 or 13 months in immunogenicity studies, or longer in phase III trials. Deaths and congenital abnormalities should be reported at any time if they are brought to the attention of the investigator and/or if they are thought to be vaccine related.

A literature search found that 350 clinical trials on the safety of hepatitis B vaccines have been conducted. From these, information is available on 230 trials involving some 18,000 subjects. In these trials, 2,000 serious adverse events were reported, of which 111 were considered by the investigators to be related to the HB vaccine. Interpretation of this data is difficult, however, because of the subjectivity involved in each trial report. Unfortunately, the sensitivity of trials for serious adverse events is also limited beyond the period of active follow up.

2. Data from the USA:

The Vaccine Adverse Event Reporting System (VAERS) [ see our section on Database of Vaccine Injury ] has been fully operational in the USA since November 1990. In 1991, one of the earliest reports to the system was from a Wisconsin physician who reported four nurses affected by demyelination subsequent to HB vaccination (from a total nursing population of 20,000). Examination of the VAERS data (1991) showed that rates of neurological disorders were ten times higher in hepatitis B vaccines than with any other vaccine. This held true for non-demyelinating symptomatology (dizzyness, paresthesiae, and vasodilatation) as well as clear demyelination.

An examination of demyelination events by time since vaccination did not show the expected peak in week 1 (as observed with influenza vaccine and Guillain BarrÈ syndrome).7,8,9 More recent safety data relating to recombinant hepatitis B vaccine in children has been published which shows no unexpected adverse events in neonates and infants given vaccine, despite the use of at least 12 million doses in these age groups.10,11,12

A review of data from VAERS on demyelinating disease for 1991-1997 showed 68 reports of multiple sclerosis. The mean age of the vaccinee was 35 (range: 15-58 years), with 77% female and 10% male (13% did not supply gender information). The median reported interval from vaccination to onset of illness was 13 days. In addition, 49 reports of optic neuritis and 26 of transverse myelitis were noted. When these events were analysed by dose of vaccine (1st, 2nd, 3rd) no pattern emerged and no conclusion could be drawn from this data. In contrast, the reports of hair loss in association with routine hepatitis B vaccination are likely to be causal ‚ particularly in view of the effect of re-challenge with the vaccine.

An analysis of a research database from the Diversified Pharmaceutical Services, a pharmacy benefits management company, was carried out in the USA. The research database was formed from six primary healthcare programmes and records reimbursement claims for both hepatitis B vaccination and medical treatment for demyelinating disorders.

A cohort analysis was performed defining a group of 27,229 who had claimed for hepatitis B vaccination and a group of 107,469 who had not claimed for hepatitis B vaccination. These groups were matched on age and sex. Analysis of rates showed rate ratios of less than one for all outcomes indicating a potential protective effect of hepatitis B vaccination. This was interpreted as potentially due to a "healthy vaccinee" effect.

Concern about the validity of both exposure and outcome measurement in this study was expressed. In addition it was not clear that person years at risk by time interval had been calculated appropriately.

3. Data from Canada:

In Canada, some 5 million doses of Hepatitis B vaccine have been delivered in vaccination programmes targeting pre-adolescents, infants and risk groups (varying by province, and over time). Between 1990 and 1998, some 2,735 adverse events were reported, 65% of these by females. The distribution of events was similar to the age distribution of vaccination. In addition, there were reports of chronic fatigue syndrome associated with the vaccine, although these reports came from a TV program. Analysis of the time relationship to vaccination showed no relationship between HB vaccination and MS.

4. Data from Italy:

Hepatitis B vaccination is obligatory in Italy, resulting in infant vaccination coverage in excess of 90%. In total, over 15 million doses of vaccine have been delivered. Compensation is available for proven vaccine induced harm and this facilitates reporting of adverse events.

In total, 504 adverse events have been reported, giving a rate of 3/100,000 doses. 19 of these involved the central nervous system (for a rate of 1/million doses), although none were multiple sclerosis. The vaccine manufacturer (SmithKline Beecham) operates an independent database. When this was searched, 5 patients with CNS events were found in Italy, one of whom had multiple sclerosis.

5. Data from Industry:

Some 630 million doses of hepatitis B vaccine have been distributed overseas, 69 million of these in France. Based on the database maintained by the companies involved, reports of multiple sclerosis (274 in number) were at a rate of 0.19/100,000 doses globally and 0.59 per 100,000 in France. Examination of the time relationship between vaccine receipt and disease onset showed no pattern to suggest causality.

6. Data from France:

An increase in reports of central nervous system demyelinating disease (CDD) possibly associated with hepatitis B vaccine at the end of 1996 led to the initiation of two epidemiological exercises in France.

First, the expected number of cases of CDD that would have occurred by chance in association with vaccination was calculated based on the underlying rate of disease and the number of doses of hepatitis B vaccine distributed in France. The observed number of cases was less than the expected. However, because of a number of uncertainties in this calculation a case control study was carried out.

Incident cases of CDD with their first episode of demyelination occurring within the last six months were recruited from hospital neurology departments. Controls also came from the same neurology departments. They were patients with other neurological conditions, some of which - for example, migraine - were chronic. They were selected by the neurologists and matched on age, sex and date of examination. Subjects with contraindications to vaccination were excluded.

The vaccination status of subjects was determined by telephone interview following a letter to the subject requesting that they find their records and fixing a time for the telephone conversation. The preliminary results were presented using a variety of case sub-groups and time intervals. None of these showed statistically significant associations between HB vaccination and CDD.

There was some concern about the design of this study. In particular, the selection of controls was less than ideal, since pre-existing disease might have influenced their likelihood to be vaccinated. Community controls would have been preferable. There was some reassurance on this point since the hospital controls' vaccine experience was similar to that of the general population.

7. Studies from the UK:

Analysis of a computerized, UK-based General Practitioner database covering some 4 million people was carried out. The database included prescriptions for vaccination as well as disease codes. Individuals aged 20-60 years with episodes of central nervous system demyelinating disease (CDD) between 1/1/90 and 1/6/97 were selected from the database and matched by age, sex and practice to six controls each. Prior vaccination with hepatitis B and other vaccines were examined.

Preliminary results showed no association with multiple sclerosis, but a marginal association with acute demyelination not diagnosed as multiple sclerosis. Potential confounding and bias were carefully addressed in this study and controlled as far as was possible.

The study had the major advantage of prospective identification of exposure to vaccination and outcome. Although cases had not yet been formally validated, the diagnosis was based on hospital attendance and these records had been independently reviewed by three physicians blinded to exposure status. There was some concern about the completeness of vaccination data since vaccines given at Occupational Health departments, STD clinics and Travel clinics might not be included in the GP records. However, any misclassification would be non-differential.

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  1. Gout O, Lyon-Caen O. SclÈrose en plaques et vaccination contre le virus de l'hÈpatite B. Rev Neurol 1998; 154: 205-7; Anonymous. Lack of evidence that hepatitis B vaccine causes multiple sclerosis. Wkly Epidemiol Rec 1997; 72: 149-52.

  2. A Technical Consultation on the Safety of Hepatitis B Vaccines. Geneva, 28-30 September 1998. Report of a meeting organized by the Viral Hepatitis Prevention Board. Andy Hall and Pierre Van Damme. Viral Hepatitis Prevention Board. Centre for the Evaluation of Vaccination, WHO Collaborating Centre for Prevention and Control of Viral Hepatitis Epidemiology and Community Medicine, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

  3. Van Damme P, Kane M, Meheus A. Integration of hepatitis B into national immunization programmes. BMJ 1997; 314: 1033-36.

  4. Kane M. Status of hepatitis B immunisation programmes in 1998. Vaccine 1998; 16 (suppl.): 104-8; Kane M. Hepatitis B control through immunisation. In: Rizzetto M, Purcell R, Gerin J, and Verme G, eds. Viral Hepatitis and Liver Disease. Turin: Edizioni Minerva Medica, 1997: 638-42.

  5. Kane M. Hepatitis B control through immunisation. In: Rizzetto M, Purcell R, Gerin J, and Verme G, eds. Viral Hepatitis and Liver Disease. Turin: Edizioni Minerva Medica, 1997: 638-42.

  6. Chang MH, Chen CJ, Lai MS, Hsu HM et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997; 336: 1855-9; Hsu HM, Lu CP, Lee SC et al. Seroepidemiologic survey for hepatitis B virus infection in taiwan: the effect of hepatitis B mass immunization. J Infect Dis 1999; 179: 367-70.

  7. Langmuir AD, Bregman DJ, Kurland LT, et al. An epidemiologic and clinical evaluation of Guillain-BarrÈ syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol 1984; 119: 841-79.

  8. Ropper AH, Victor M. Influenza vaccination and the Guillain-BarrÈ syndrome. New Engl J Med 1998; 339: 1845-1846.

  9. Lasky T, Terracciano G, Magder L, et al. The Guillain-BarrÈ syndrome and the 1992-1993 and 1993-1994 influenza vaccines. New Engl J Med 1998; 339: 1797-802.

  10. Niu MT, Davis DM, Ellenberg S. Recombinant hepatitis B vaccination of neonates and infants: emerging safety data from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 1996; 15: 771-6.

  11. Mac Mahon BJ, Helminiak C, Wainwright RB, Bulkow L, Wainwright K. Frequency of adverse reactions to hepatitis B vaccine in 43,618 persons. Am J Med 1992, 92: 254-6.

  12. Shaw F, Graham D, Guess H, et al. Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Experience of the first three years. Am J Epidemiol 1988; 127: 337-52.

Written and overseen by Lewis Mehl-Madrona, M.D., Ph.D.

Program Director, Continuum Center for Health and Healing,
Beth Israel Hospital / Albert Einstein School of Medicine

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