Hep B Vaccine Increases MS Risk?

September 14, 2004

This is from another list. I looked at nvic.org and didn't see anything on this

report yet. Anyone else seen similar reports?

Dale

http://www.medscape.com/viewarticle/489057

Hepatitis B Vaccination Increases Multiple Sclerosis Risk

Laurie Barclay, MD

Sept. 13, 2004

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.

The National Multiple Sclerosis Society supported this study.

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. "

Neurology. 2004;63:772-773, 838-842

Reviewed by Gary D. Vogin, MD

------------------------------

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

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.

Discussion.

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.

Laurie Barclay, MD

Sept. 13, 2004

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.

The National Multiple Sclerosis Society supported this study.

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. "

Neurology. 2004;63:772-773, 838-842

Reviewed by Gary D. Vogin, MD

------------------------------

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

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.

Discussion.

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.

September 15, 2004

Well, I am glad that this was posted although I must say I'm very upset by

what I read. Just this past week my brother's wife's mom died from MS and my

children's father's sister has advanced MS. We are already having to accept that

one grandson is autistic and that may or may not have been caused from a

reaction to vaccines given to him as an infant. And now a new worry.

Thank you for posting this ! It is important even though it is upsetting.

Hugs,

Sally