Hepatitis B Vaccination Increases Multiple Sclerosis Risk

Hepatitis B virus (HBV) vaccination increases the risk of developing multiple sclerosis (MS), according to the results of a nested, case-control study published in the Sept. 14 issue of Neurology.

"Our analyses include 163 cases of MS and 1,604 controls," lead author Miguel A. Hernán, MD, DrPH, from the Harvard School of Public Health in Boston, Massachusetts, says in a news release. "We estimated that immunization against hepatitis B was associated with a threefold increase in the incidence of MS within the three years following vaccination."

More than 140 countries have followed the World Health Organization recommendation to integrate the HBV vaccine into national immunization programs. In 1996, the French government suspended routine immunization of pre-adolescents in schools because about 200 cases of MS and other central nervous system demyelinating disorders were reported after HBV vaccination. However, studies evaluating the potential link between HBV vaccination and increased risk of MS have been inconclusive.

Using the General Practice Research Database (GPRD) in the U.K., the investigators identified patients with a first MS diagnosis recorded between January 1993 and December 2000. Cases were patients with the diagnosis of MS confirmed by examination of medical records, and with at least three years of continuous recording in the GPRD before their date of first symptoms (index date). Each of the 163 cases was matched with up to 10 randomly selected controls (n = 1,604), matched for age, sex, practice, and date of joining the practice.

Compared with patients who were not vaccinated, the odds ratio of developing MS in patients who received the HBV vaccination within three years before the index date was 3.1 (95% confidence interval, 1.5 - 6.3). Tetanus and influenza vaccinations were not associated with increased risk of MS.

"Our study cannot distinguish whether the vaccine hastens the onset of MS in persons destined to develop the disease years later, or whether it causes new cases of MS in susceptible individuals," Dr. Hernán says. "It is also important to stress that 93% of the MS cases in our study had not been vaccinated."

Study limitations include potential confounding. The investigators note that any considerations regarding the administration of HBV vaccine must reflect the large benefits derived from the prevention of a common and potentially lethal infection, and they recommend additional research to elucidate the association between HBV vaccine and MS.

In an accompanying editorial, Robert T. Naismith, MD, and Anne H. Cross, MD, from Washington University in Saint Louis, Missouri, describe the "bumpy" road to universal immunization against HBV and praise the sound methodology of this study. However, they note that the selection process for cases, which was thought to be necessary to properly perform the study, might have led to some unrecognized bias.

"No data are presented to change the current Level C recommendation from the Immunization Panel of the MS Council for Clinical Practice Guidelines, which was approved by the AAN," the editorialists write. "This committee determined that the HBV [vaccine] had not been found to be detrimental in those with established MS, and recommended that patients follow the Centers for Disease Control immunization guidelines.... The indisputable benefit that the HBV [vaccine] provides against an infection that kills 5,000 per year in the United States must be weighed against any uncommon risks that remain in dispute."

Hernan MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study. Neurology 2004 Sep 14;63(5):838-842.

Department of Epidemiology (Dr. Hernan), Harvard School of Public Health, Boston; Boston Collaborative Drug Surveillance Program (Drs. Susan S. Jick and Hershel Jick), Boston University, Lexington, MA; and Department of Neurology (Dr. Olek), College of Medicine, University of California, Irvine. Email: miguel_hernan@post.harvard.edu

Abstract: Background: A potential link between the recombinant hepatitis B vaccine and an increased risk of multiple sclerosis (MS) has been evaluated in several studies, but some of them have substantial methodologic limitations.

Methods: The authors conducted a nested case-control study within the General Practice Research Database (GPRD) in the United Kingdom. The authors identified patients who had a first MS diagnosis recorded in the GPRD between January 1993 and December 2000. Cases were patients with a diagnosis of MS confirmed through examination of medical records, and with at least 3 years of continuous recording in the GPRD before their date of first symptoms (index date). Up to 10 controls per case were randomly selected, matched on age, sex, practice, and date of joining the practice. Information on receipt of immunizations was obtained from the computer records.

Results: The analyses include 163 cases of MS and 1,604 controls. The OR of MS for vaccination within 3 years before the index date compared to no vaccination was 3.1 (95% CI 1.5, 6.3). No increased risk of MS was associated with tetanus and influenza vaccinations.

Conclusions: These findings are consistent with the hypothesis that immunization with the recombinant hepatitis B vaccine is associated with an increased risk of MS, and challenge the idea that the relation between hepatitis B vaccination and risk of MS is well understood.

We estimated that immunization against hepatitis B was associated with a threefold increase in the incidence of MS within the 3 years following vaccination. Other common immunizations were not associated with an increased risk of MS.

Our study cannot distinguish whether the hepatitis B vaccine hastens the onset of MS in persons destined to develop the disease years later, or whether it causes new cases of MS in susceptible individuals. However, the similar age at first symptoms between vaccinated and unvaccinated cases does not support the former explanation.

Elucidating the reasons for the association between hepatitis B vaccine and MS may eventually contribute to a better understanding of the etiology of MS, but any decision concerning hepatitis B vaccination needs to take into account the large benefits derived from the prevention of a common and potentially lethal infection. It is also important to stress that 93% of the MS cases in our study had not been vaccinated.

The use of a nested case-control study minimized the bias due to inappropriate selection of controls, and the use of prospectively recorded computerized vaccination records prevented recall bias. Other types of differential misclassification of vaccination history are also unlikely because exposure information was gathered prospectively before the first symptoms of the disease. A certain degree of non-differential (random) misclassification of vaccination history is possible (e.g., a small proportion of persons might have been vaccinated without their GP's knowledge), but its practical consequence would be an attenuation of the association between vaccination and MS. As always in observational research, confounding is a theoretical explanation for the association. Our analyses are therefore matched on and adjusted for various known or suspected risk factors for MS.

The use of computerized medical records is an efficient strategy to identify individuals with a diagnosis of MS. However, our approach was to combine the use of computerized medical records to identify individuals with a diagnosis of MS with the retrieval and review of paper medical records to determine their date of first symptoms, since we found that the computer records did not provide sufficient information to determine the subjects' clinical history, including date of first MS symptoms. An accurate determination of the date of first symptoms is important because, as we observed, the probability of hepatitis B vaccination decreases after clinical onset of MS. Thus, the use of dates that are posterior to the true date of first symptoms may cause a downward bias of the OR for acute exposures such as vaccinations.

Several case-control studies have evaluated the association between hepatitis B vaccination and risk of MS or demyelination (table 4). Two French studies found about a 1.5-fold increase in the risk of a first episode of CNS demyelination during the 2 months following hepatitis B vaccination.5,6 In both studies, the date of first symptoms was ascertained by review of medical records, and dates of vaccination were obtained retrospectively by questionnaire and phone interview of the participants. Concurrently with the first reporting of results from the French studies, a preliminary assessment of the association between hepatitis B vaccination and MS in the GPRD found a 1.6-fold increase (95% CI 0.6, 4.0) in the risk of MS or demyelination during the 12 months following hepatitis B vaccination.7 MS diagnoses and dates of first symptoms were ascertained by review of computerized records only.

More recently, a case-control study in three North American health maintenance organizations (HMOs) found a nonsignificant increase in the risk of MS or optic neuritis 1 to 5 years after vaccination against hepatitis B, and no increase before 1 year or after 5 years.8 The date of first symptoms was retrieved from medical records and telephone interviews, and vaccination histories included both vaccinations recorded in HMO records and those reported in telephone interviews.

A case-control study nested in the Nurses' Health Studies did not find an increased risk of MS associated with hepatitis B vaccination in women.9 The vaccination status was obtained retrospectively and the analysis included only women who self-reported never having been vaccinated in a questionnaire, and those who self-reported having been vaccinated and for whom vaccination certificates were available. This design may cause selection bias leading to a downwardly biased OR.18-20 Perhaps more important, the date of first symptoms of the disease was retrospectively assessed by questionnaires sent to each case and the current treating neurologist or internist.

Two other studies did not find an increased risk of MS after immunization against hepatitis B. A study conducted in a database consisting of integrated pharmacy and medical claims from six HMOs in the United States found no difference in the 3-year risk of diagnosis of demyelinating diseases between subjects vaccinated and non-vaccinated for hepatitis B.10 This null finding is consistent with our null finding in the GPRD when we used date of diagnosis, rather than date of first symptoms, of MS to define the period of risk. An ecologic study compared the number of adolescents who developed MS before (1986 to 1992) and after (1992 to 1998) a school-based hepatitis B vaccination program was implemented in British Columbia, Canada.11 Nine out of 288,657 unvaccinated teenagers and 5 out of 289,651 vaccinated teenagers had first symptoms of MS, but the unvaccinated had up to 13 years of follow- up, while the vaccinated had only up to 7 years of follow-up and therefore less opportunity to be diagnosed with MS.

The recombinant hepatitis B vaccine is a non-infectious viral vaccine derived from hepatitis B surface antigen (HBsAg) produced in genetically engineered yeast (Saccharomyces cerevisiae) cells. Although several viruses (e.g., Epstein-Barr virus) have been postulated to cause MS, the hepatitis B virus has not been prominent in the discussions of viral triggers of MS.21 It is therefore unclear how a recombinant vaccine that contains purified HbsAg, a portion of the hepatitis B virus, could trigger the immunologic processes that lead to MS. The vaccine also contains an adjuvant (aluminum hydroxyphosphate sulfate), a mercury-based preservative (thimerosal, eliminated from recent formulations), and yeast proteins (up to 5%), but these components have not been separately studied in relation to the risk of MS.

Having worked in a lab where I had to have a zillion vaccinations, I would still rather run a slight risk of a potential disease than a big chance of getting something fatal.

It is also important to stress that 93% of the MS cases in our study had not been vaccinated.

So what have they really proved here?

"Another reason none of my children have or ever will have a vaccination."

You're serious? Wow, it's a good thing your kids live around people like me.

The results here shouldn't be exagerrated.
This study only had 163 cases of MS and 1,604 controls. There have been many much larger studies that failed to prove a causal link between Hepatitis B vaccine and Multiple Sclerosis. Weight of the evidence does not support the conclusions ofthis one study.

http://www.nap.edu/books/0309084695/html/index.html
http://www.researchmatters.harvard.edu/story.php?article_id=50
http://my.webmd.com/content/article/30/1728_71212.htm

I am a 50 year old man diagnosed with MS in Aug. '03. Currently, Neurologists have no idea what causes MS or why it effects each individual that has it in different ways. Studies like this are beneficial in attempting to identify a cause/causes.

If it sheds even a glimmer of light on what may or may not cause an individual to contract this disease it is extremely important information.

While currently my MS is not debilitating I have no idea what each new day may have in store for me. If there exist things that may cause MS and these things can be avoided...avoid them at all costs.

I appreciate your recommendation but what if the risk of getting MS from a vaccination is 1 in a million and the risk of getting liver cancer from Hepatitis B is 1 in a 100,000?
Life is full of risks. It's not always easy to tell which risks can be avoided and which must be faced. Your age, gender, location, occupation, etc may cause those risks to vary so not everyone faces the same decision.

I hope your MS goes into remission and stays there. Good luck to you.

13 posted on 09/14/2004 9:21:15 AM PDT by Born Conservative (Twenty years of votes can tell you much more about a man than twenty weeks of campaign rhetoric.)

Interesting study. I suspect though that MS is caused by an interplay of immunological defects and impaired neurological repair mechanisms with a common pathogen, probably Varicella Zoster. As for this study, the Hepatitis B vaccination may act as a trigger, likely through cross-reactivity with V. Z. proteins.

I am sorry to hear about your condition. Definitely, work needs to be done. There may be a related mechanism that can be found in the interaction of the vaccines in some people's systems but the research needs to look closer at the secondary reactions and processes of the immune system as well as the other material used in the vaccination. Many reactions to vaccinations are actually to the growth media or preservatives used ie... chicken eggs and phenol. This particular article could have benefited from the authors citing something along the lines of, "Clues to possible causes of MS may be found in vaccinated patients". We don't need baseless hysteria, we need research and solid empirical evidence.

Realize its been 6 months since your post, but .........

Your comment is quite approriate.
The title misrepresents the data and the study design itself. This study establishes nothing except that young people get vaccinated.

I know a bit about vaccines and MS. I had MS long before I had the heb B vaccine and worked in the vaccine world long before I got a diagnosis. Strange life this.

Anywho, people do love to make their own conclusions based on previously held beliefs and paste them on just about anything.

And reflecting on comments of other members, WHEN the FDA approves a vaccine for MS, you and your kids should get it.

Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.