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We are trying to identify more patients with autoimmune
disorders that might be related to the hepatitis B vaccine in order to find a
better way to prevent, diagnose, and treat such reactions. Since it is clearly
established that this vaccine (or the virus infection itself) may cause MS like
symptoms, your information could be a great help for our ongoing research.
Thank you for your consideration.
Bonnie Dunbar
January 3, 1997
Dr. Joyce C. Lashof, M.D.
Committee Chair
Presidential Advisory Committee on Gulf War Veterans
Illness 1411 K St. N.W.
Suite 1000
Wash. D.C. 20005-3404
Dear Dr. Lashof:
Within the past two years, I have had two colleagues who
have developed severe and apparently permanent adverse reactions as a result of
being forced to take the Hepatitis B vaccine. Both of these individuals were
extremely healthy and very athletic before this vaccine and have had severe,
debilitating autoimmune side effects from this vaccine. I know the complete
history of one, Dr. Bohn Dunbar, who is my brother who had serious rashes,
joint pain, chronic fatigue and now other degenerative disorders including
lupus like syndrome and multiple sclerosis like symptoms. My other medical
student went partially blind following her first booster injection and
virtually completely blind in one eye following the second with hospitalization
for several weeks. Following two years of consulting with specialists it has
been concurred that Bohn’s “syndomes” are due to adverse reactions to the
hepatitis B vaccine.
I have worked in autoimmunity and vaccine development for
over twenty years (the past 15 years at Baylor College of Medicine in Houston).
I was honored two years ago by the National Institutes of Health as the first
Margaret Pittman lecturer for my pioneering work in contraceptive vaccines. I
am therefore very sensitive to the balance of risk vs. benefits in vaccine development.
Because of my expertise in this area, it became apparent to me that these two
active, healthy individuals working in my laboratory at the same time developed
“autoimmune” syndromes at the same prolonged immunological time frame following
their booster injections to the hepatitis B vaccine. After carrying out
extensive literature research on this vaccine, it is apparent that the serious
adverse side effects may be much more significant than generally known. Because
it is not clear that adequate long term follow-up information was collected in
the clinical trial data, many of these effects might not have been observed.
Even the vaccine insert which most physicians do not show or discuss with their
patients are ominous.
As the result of extensive literature research as well as
our advanced knowledge in the mechanisms of autoimmune disease and hepatitis B
infection, I have put together an international team of experts to prepare a
grant proposal to establish the scientific basis for these adverse reactions.
It is clear that there are major histocompatability genetic linkages among
patients who are having the severe reactions (as opposed to those who do not
respond to this vaccine at all!). We are also trying to determine the long term
prognosis for patients having such adverse reactions. Because I have an
immunology and biochemistry laboratory we collected blood samples throughout
the period of these adverse reactions therefore we have a unique pool of serum
to begin to scientifically pinpoint the reasons for the adverse reactions.
It is apparent that the hepatitis B virus (and vaccine
developed from the hepatitis B surface antigen) is very unique from many other
viruses and vaccines and new theories and experiments (i.e. molecular mimicry
and anti-idiotypic antibodies) have been developed which could explain reasons
for autoimmune reactions caused by this virus or the viral protein used in the
vaccine. (I feel the New York Time’s article this week on molecular mimicry and
viruses causing autoimmune diseases is right on point!)
The fact that there are dozens of publications on the
correlation of this virus as well as the vaccine with autoimmune and other connective
disease disorders provides strong evidence for the correlation of this viral
antigen causing autoimmune diseases. I have obtained the FDA adverse reaction
list of over 8000 individuals with reported adverse reactions for the past 4
years (Merck vaccine only, does not include the Smith Kline vaccine which I
have been told includes another 15,000 or more). The vast majority of adults
who have these same symptoms including rash, joint pain, chronic fatigue,
neurological disorders, neuritis, rheumatoid arthritis, lupus like syndrome and
multiple sclerosis like syndrome. (It has been reported by the head of the FDA
that these reports indicate only about one tenth of the total numbers of
adverse reactions.) Furthermore, a report was presented at the National
Rheumatology meeting last year entitled “An epidemic of rheumatoid arthritis
caused by the Hepatitis B vaccine,”demonstrating the correlation between severe
adverse effects and MHC genes. It is now apparent to me that it may be
essential that more studies be carried out to evaluate patients with severe
adverse effects before this vaccine is used universally, especially in infants
who would not be at high risk for becoming infected with this virus. If we are
successful in our studies, we should be able to develop methods to predict
which individuals might be susceptible to adverse reactions.
At one point a neurologist specialist stated in front of
myself and Bohn that “We are having the same problem with your (Bohn’s)
diagnosis as we have with vets with Gulf War Syndrome who have the identical
symptoms as yours—but there are no definite tests.” In reading various reports
on the Gulf War Veterans illnesses, it appears that many of these symptoms are
those which are related to the large numbers of adverse reactions reported for the
hepatitis B vaccine. It is not clear to me, however, that this vaccine was
carefully evaluated as a potential cause of some of these reactions.
Although we have already identified numerous patients for
our initial studies and contacts, it would be a great benefit to this investigation
if you had identified a subset of any veterans having had the vaccine who
exhibit these symptoms. Any information you could provide me would be a great
help.
My work address is:
Dr. Bonnie S. Dunbar, PhD
Professor
Department of Cell Biology Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030
Fax 713-798-7341
email bdunbar@bcm.tmc.edu
or
Thank you very much for your consideration.
Sincerely,
Bonnie Dunbar
Hepatitis B and the Vaccine
Report modified from that prepared by Dr. Sheri Skinner to
Baylor College
of Medicine Safety Committee 10/7/97
The 1994 WORLD numbers are:
·
World population as determined by the World
Health Organization (W.H.O.) (1)
................................................ »
5,000,000,000 people
·
People in the world who have come into contact
with the hepatitis B virus (1)
........................................................ »
2,000,000,000
people
·
People in the world who die each year from
complications of the hepatitis B virus (2)
.........................................» 1-1,500,000 people
The 1994 U.S.A. numbers are:
·
U.S. Population(3)
..........................................................................»
261,000,000 people
·
Cases of hepatitis B virus in the U.S.A.
reported each year to the Centers for Disease
Control (CDC) (4)
............................................................................
.......» 25,000 cases/yr
If corrected for estimated under-reporting (x4) and for
asymptomatic infections (x3), the estimated actual number
is closer to(4)
............................................................................
.» 300,000 cases/yr
For HEALTH CARE WORKERS:
·
Of all reported U.S. cases, only 4-5% were due to
occupational exposure of health care workers, and this was before the hepatitis
B vaccines and before the protective “work practice controls” were in place.(5)
·
Studies suggest that hepatitis B-infected health care
workers seem to be virtually no threat to their patients. Gitnick reports that
in a number of studies, such workers were followed to collect evidence of
spread of infection to patients. None was found. (6)
2. How do adults respond to the hepatitis B virus?
·
Approximately 50% have low viral growth and an early
immune system response, and therefore develop no symptoms, resolve (defeat) the
virus, and have lifelong immunity to it. (7,10)
·
About 30% more experience what they think is the flu,
also go undiagnosed, resolve the virus and develop lifelong immunity. (10)
·
Approximately 20% have higher viral growth and a later
immune response, so they get sick enough to be diagnosed as having hepatitis B.
The vast majority resolve the virus and have lifelong immunity.(7,10) They
rarely (< 5%of them) become chronic carriers of the virus.(9)
·
About two tenths of 1% get sick, don’t defeat the
virus, and die of liver complications. (7)
·
Approximately 1-5% of adults (9,10) become so-called “healthy
carriers”, having no symptoms, but being capable of spreading the virus. Most
of these people will reach the end of their lives with little or no damage done
to their livers by the virus living there. (11,12) However, about a quarter of
these carriers are in danger of developing life threatening liver disease
decades later in life. (7,8) Bader (10) points out that “It is widely taught
that 5-10% of patients...advance to the carrier state.” but that this figure “should
not be taught at all; instead a notation of the fact should be made that
chronicity varies widely depending upon a number of defined and undefined
factors.” These factors include age at infection, gender, race, general health,
and the functioning of your immune system.
IN SUMMARY:
Of the adults who are infected with the virus, almost 95%
will recover, most with no symptoms at all and all with lifelong immunity to
the virus. Fewer than 5% will live essentially symptom-free with declining but
continuous infectiousness. About one fourth of this 5% will face life
threatening liver complications decades later. About two tenths of one percent
of all infected adults will die soon after becoming infected with the virus.
With today’s protective workplace procedures required here at Baylor, fewer
than 5% of those developing symptoms will have become infected through
occupational exposure.
3. WORST CASE SCENARIO: What’s it like to have Hepatitis B
virus? or to have an autoimmune disorder?
The Illness
Symptoms & Duration
Infectiousness
Hepatitis B
·
acute form(6,11)
Worst acute form: nausea, vomiting, low grade fever,
constant fatigue, may develop jaundice which fades along with symptoms over
approx. 4 weeks. Must stay home to recover for few months.
Fatigue can last up to a year. Blood
chemistry returns to normal within 6
months.
Mothers pass to babies if they become infected
during the third trimester.
Blood is infectious as
long as viral
antigen is in
bloodstream: generally for 3
mos. Major danger is
to sexual partner
(20%-70% of non-immune
spouses will
catch it from their
infected mate). Less
than 1% of other
family members are
found to become infected.
Fetal infection
probably occurs in the
birth canal, or
possibly through the
placenta. Breast milk
is an unlikely
source.
Hepatitis B
·
chronic
form(6,9,11)
Most do not have symptoms, but virus has not been
cleared from blood after 6 months following exposure. Ten to thirty or more
years later, about a quarter of these people will develop life threatening cirrhosis
or even more rarely, liver cancer.
Blood remains
infectious until age 35 or
so when it becomes
“relatively
noninfectious” but still must be careful.
Autoimmune
disorders(13)
Depends upon systems affected.
Inflammation of blood vessels
(vasculitis), joints (arthritis) can cause
disabling pain. Attack on the tissue of the
nerves can cause blindness (optic
neuritis), motor function impairment
(multiple sclerosis, Guillain-Barre, other neuropathies),
problems with thinking and memory. Other symptoms include temperature control
problems, disabling fatigue, eventual failure of attacked organs (diabetes).
All such disorders are frequently permanent, although there may be periods of
remission in some.
Not infectious
4. What about the medical organizations that “recommend”
the vaccine?
The following individuals were contacted by phone in the
last month and asked whether their organization recommended any vaccines. They
all said NO. They recommend vaccination procedures, since they must decide what
populations are at risk, and how best to cover those populations. They neither
test nor assert the safety or efficacy of any specific vaccine. When asked what
authority(ies)they depended upon to determine vaccine safety, they responded as
indicated below.
Organization and spokesperson
Their authority on safety American College of Preventive
Mecicine (ACPM)
H.K. Keimowitz, Exec. Director
(202) 466-2044
CDC, National Coalition for Adult
Immunization
American Medical Association (AMA)
Mr. Liznicki for Dr. J. Allen, M.D.
(312) 464-4520
CDC, FDA
American Academy of Family Physicians
(AAFP)
Robert Graham, M.D., Exec. V.P.
(816) 333-9700
Substance is on the market, therefore
must
have passed FDA inspection American College of Physicians
(ACP)
Substance is on the market
G. Thomason, Scientific Policy Office
(215) 351-2400, X-2847
5. Why should we not take the word of the FDA concerning
the necessity of the vaccine when it is good enough for the CDC and for all
these organizations?
A. The FDA based its decisions upon clinical trials and
upon post marketing surveillance studies in which patients and their doctors
were asked to report any adverse effects they noticed within 4-5 days after
each injection [4 days for Smith/Kline and 5 days for Merck].(14,15,16) The
problems being reported in increasing numbers as occurring after hepatitis B
vaccination appear to be autoimmune in origin. Such problems take weeks to
months to produce noticeable symptoms, and cannot be spotted in a 4-5 day
observation period.
B. In 1992, a study was begun by the Institute of Medicine
of the National Academy of Sciences to look at all reports of adverse effects
that might have been caused by a number of vaccines including the hepatitis B
vaccine. They did this because they were so directed by Congress through the
Dept. of Health and Human Services . This was because of increasing fears voiced
, mainly by parents, about the health of their children after vaccination.
The National Academy of Sciences published their findings
concerning the hepatitis B vaccine in 1994 (11) . The results are reproduced
here.
(INSERT TALBLES)
The Academy notes that:
·
Sensitivity to the recombinant vaccine was rarely seen,
and then mostly took the form of a temporarily sore arm.
Ten to fifteen percent experienced fatigue, headache,
fever, etc. No follow-up to these symptoms or what might follow them was ever
done.(16)
·
They report that “the trials are notable for the
absence of any serious adverse reactions”, but that “the studies were not
designed to assess serious, rare adverse events; the total number of recipients
is too small and the follow-up generally too short to detect rare or delayed
serious adverse reactions.” (16)
·
They report that “None of the clinical trials reviewed
by the committee contained information regarding hepatitis B vaccine and
....central demyelinating diseases” (ie:
Guillian-Barre syndrome, multiple sclerosis, transverse
myelitis, optic neuritis, etc.). “Evidence is inadequate to accept or reject a
causal relation between the hepatitis B vaccine and (the above demyelinating
syndromes). Nevertheless, the number of reports questioning the relation
between one or the other of these disorders of similar character suggests the
need for systematic research.”
(16)
They report that “No controlled clinical trials reviewed
by this committee contained information reguarding hepatitis B vaccine and
arthritis.” However, “The possibility that the hepatitis B vaccine can cause an
exacerbation of rheumatoid arthritis should be carefully evaluated in a population-based
study.” (16)
They note that “Antigenic stimulation of any type in such
people” (genetically susceptible to autoimmune disease) might precipitate
either an exacerbation or even the first clinically evident attack of disease
exacerbation.” (16)
C. Since the Academy’s report,
·
None of the recommended studies have been funded by any
of the drug companies, and none have been reported in the literature. (17,18)
·
Clinical studies (by laboratories not associated with
the drug companies)
investigating links between the vaccine and
rheumatoid arthritis are underway. (19, 20, 23)
·
Epidemiological studies specifically aimed at testing
the existence of a relationship between the vaccine and the development or
exacerbation of autoimmune disorders are being planned. (19)
·
In France, there is increasing concern among both
doctors and lay people about recent reports of multiple sclerosis and other neurological
disorders appearing in vaccinated patients. Recently, 150 doctors appealed to
the French Academy of Sciences to commission a study by investigators with no
connections to manufacturers of the vaccine. The Academy endorsed the call for
a survey (21,22). Meanwhile, doctors in France are under a gag order not to talk
to the press. (19)
Scientists planning and carrying out such studies (both in
the U.S. and abroad) report receiving 2 and 3 communications per day (email,
fax, letter, phone) from patients and medical personnel asking to contribute
their own or their patients’ data to the studies. (19,23)
Literature Cited
1. Kane, M.A. [WHO, Geneva, Switzerland] Global programme
for control of hepatitis B infection. In: Viral Hepatitis Prevention Board’s “Proceedings
of the International Congress: Action Towards Conrol of Hepatitis B as a
Commuinity Health Risk”, Nov., 1993. In: Vaccine, 13, Suppl #1, 1995, pp.
S47-S49.
2. Kane, M.A. [WHO, Geneva, Switzerland] Progress on the
control of hepatitis B infection through immunisation. In “Viral Hepatitis
Management. Standards for the Future.” Proceedings of a symposium held in
Cannes, France, May 1992. In Gut, 34, Suppl #2, pp. S10-S12, 1993.
3. Statistical Abstracts of the United States, 1996
Edition.
4. Alter, M.J. , et al (1994) The epidemiology of viral
hepatitis in the United States. , Viral Hepatitis, 23 (3), 437-579.
[originally from Cohen, B., et al (1987) Dig. Dis. Sci.,
32, 1428-1430.]
4. Meheus, A. (1995) Risk of hepatitis B in adolescence
and young adulthood. In: Viral Hepatitis Prevention Board’s “Proceedings of the
International Congress: Action Towards Conrol of Hepatitis B as a Commuinity
Health Risk”, Nov., 1993. In: Vaccine,
13, Suppl #1, 1995, pp. S31-34.
5. Alter, M.J. et al (1994) The epidemiology of viral
hepatitis in the United States. Viral Hepatitis, 23 (3), 437-579. [Originally from
Cohen, B., et al. (1987) Dig. Dis. Sci., 32, 1428-1430.]
6. Gitnick, G. (ed), (1994) “Principles and Practice of
Gastroenterology and Hepatology” Second Edition, Appleton & Lange, Norwalk,
Ct. , pp784-795.
7. Crawford, James M., M.D., Ph.D., Director, Program in
Gastrointestinal Pathology, Yale University School of Medicine (1997) (Personal
Communication) and Crawford, James M. (1994) The liver and the biliary tract,
In: “Robbins Pathologic Basis of Disease”, 5th edition, Cotran,
R.S., Kumar, V., Robbins, S.L. and Schoen, F.J. (eds), W.B. Saunders Co.,
Phila., PA. pp.844-845. [Text used by BCM medical students]
8. Sherlock, S. (1990) Hepatitis B: the disease. :
Proceedings of the International Conference on Prospects for Eradication of Hepatitis
B Virus. In: Vaccine, 8 (Suppl), S-6 - S-10.
9. Hyams, K.C. (1995) Risks of chronicity following acute
hepatitis B virus infection: A review. Clin. Infect. Dis. 20, 992-1000.
10. Bader, T.F. (1995) “Viral Hepatitis: Practical
Evaluation and Treatment”, Hogrefe & Huber Pub., Seattle, WA., pp. 52-78.
11. Sherlock, S. and Dooley, J. (1997) “Diseases of the
Liver and Biliary System”, Tenth edition, Blackwell Science, London, U.K., pp.
267-279, 315-334.
12. Dragosics, B., Ferenci, P., Hitchman, E. et al. (1987)
Long-term follow-up study of asymptomatic HBsAg-positive voluntary blood donors
in Austria: a clinical and histologic evaluation of 242 cases. Hepatol. 7, 302.
13. Abbas, A.K., Lichtman, A.H. and J.S. Pober (1994) “Cellular
and Molecular Immunology” (second edition), W.B.
Saunders Co., London, U.K. pp.382-392. [Text used by BCM
medical students]
14. Physician’s Desk Reference, 1997 and flyer enclosed
with Merck
Recombivax vaccine
15. Physician’s Desk Reference, 1997 and flyer enclosed
with Smith/Kline
Beecham Engerix vaccine
16. Stratton, K.R., Howe, C.R., Johnston, R.B. (eds) for
Institute of Medicine, (1994) “Adverse Events Associated with Childhood
Vaccines: Evidence Bearing on Causality”, National Academy Press, Washington,
D.C.
17. Computer searches of the literature from 1966 to
present.
18. Dr. Richard T. Johnson, Dept. Neurology, Johns Hopkins
University (personal communication).
19. Dr. Bonnie S. Dunbar, Dept. Cell Biology , Baylor
College of Medicine (personal communication).
20. Pope, J. E., Stevens, A. , Howson, W. and Bell, D.A.
(1998) The development of rheumatoid arthritis following recombinant hepatitis
B vaccination. (in preparation).
21. GPV’s Expanded Programme on Immunization (1997)
Immunization news.
Vaccine and Immu. News, (4), June, p.8.
22. Appeal listing concerns of physicians addressed to
presidents of the Academie des Sciences, Academie de Medecine, and Academie de
Pharmacie , Sept. 18, 1996; Reply by Institute de France, Academie des
Sciences, Dec. 10, 1996; Reply by Academie Nationale de Medecine, Feb. 4, 1997.
23. Dr. C. Shepherd, Medical Director, Myalgic
Encephalomyelitis Assoc. , Gloucestershire, U.K. (personal communication)
Reports of Adverse Reactions of Hepatitis B
Vaccine
(Not including over 30,000 FDA Adverse Reactions
Reports)
(Updated from NIH GRANT PROPOSAL).
Adverse Reaction/Diagnosis
Reference
Systemic “Lupoid hepatitis”, lupus
erythematosus
Tudela and Bonal, 1992;
Mamoux and Dumont, 1994;
Guiserix, 1996 Arthritis (polyarthritis, rheumatoid
arthritis)
Rogerson and Nye, 1990;
Vautier and Carty; 1994;
Gross et al., 1995;
Pope et al., 1995;
Pope et al, 1997 (in preparation);
Biasi, 1987-1993.
Hassan and Oldham 1994
Rheumatic Review, 1994;
Soubrier et al, 1997 Vascular Disorders (vasculitis,
polyarteritis, erythema nodosum, cryoglobulinemia, uveitis)
DiGuisto and Bernhard. (1986);
Fried et al, 1987;
Goolsby, 1989;
Cockwell et al., 1990;
Rogerson and Nye, 1990;
Mathieu et al., 1996;
Carmeli and De-Medina, 1993;
Mathieu and Krivitsky, 1996;
Graniel et al, 1997.
Guillain Barre Syndrome
Shaw et al., 1988
Demyelinating disorders (optic neuritis, Bell’s
Palsy, demyelinating neouropathy, multiple
sclerosis etc.)
Ribera and Dukta, 1983;
Shaw et al., 1988;
Herroelen et al., 1991;
Nadler (1993);
Devin et al., 1996;
Dunbar et al., (unpublished observations);
Senejoux et al., 1996;
Baglivo et al., 1996;
Bonfils et al, 1996;
Manna et al., 1996;
Kaplanski et al., 1995;
Marsaudon and Barrault, 1996;
Berkman et al., 1996;
Waisbren, 1997;
W.H.O., 1990;
Brezin, et al, 1993
Diabetes mellitus
Poutasi, 1996;
Classen, 1996
Chronic Fatigue
Salit (1993);
Delage et al., 1993
Other
Germanaus et al., 1995;
Noble et al., 1997;
Senejoux et al, 1996;
Macario et al, 1995;
Biron et al, 1988;l
Trevisani et al, 1993;
Tartaglino et al, 1995
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reactions. W.H.O.
Adverse Drug Reaction
Bulletin. August, 1990.
Baglivo, E., Safran, A.B., Borruat, F.X. (1996)
Multiple
evanescent white dot syndrome after
hepatitis B vaccine. Am. J. Opthamology.
122(3):431-432.
Berkman, N., Benzarti, T., Dhaoui, R. and Mouly, P.
(1996) Bilateral
neuro-papillitis after hepatatis B
vaccination. (letter) Presse Medicale 25(28); 1301.
Biasi, D., Carletto, A., Caramaschi, P., Frigo, A.,
Pacor, M.L.
Bezzi, D., and Bambara,L.M.
(1994) Rheumatological manifestations following
hepatitis B
vaccination. Recent Progress in
Medicine. 85(9):438-440.
Biasi, D., DeSandre, G., Bambara, L.M., Carletto, A.,
Caramaschi, P., Zanoni, G., Tridente,G.
(1993) A new case of reactive arthritis after hepatitis B vaccination.
Clinical and Exper. Rheumatol.
11(2):215.
Biron, P., Montpetit, P., Infante-Rivard, C. and Lery, L.
(1988) Myasthenia gravis after general anaesthesia and hepatitis B vaccine.
Arch. Intern. Med., 148, 2685.
Bonfils, P., Biocabe, B., Potard, L.G. and Aidan, D.
(1996)
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359-361.
Brezin, A., Lautier-Frau, M., Hamedani, M., Rogeaux, O.
and Hoang, P.L. (1993) Visual loss and
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Carmeli, Y., De-Medina, T.(1993) Serious hepatitis B
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Classen, J.B. (1996) Childhood immunisation and diabetes mellitus.
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Cockwell , P., Allen, M.B., Page, R.(1990) Vasculitis
related to
hepatitis B vaccine. BMJ
301(6763):1281.
Delage, G., Salit, I., Pennie, R., Alary, M. Duval, B.
and Ward,
B. (1993) Canadian Communicable
Disease Report 19:25-28.
Devin, F., Roques, G., Disdier, P., Rodor, F.,
Weiller, P.J.
(1996) Occlusion of central vein after
hepatitis B vaccination. (letter) Lancet. 347(9015):
1626.
Digiusto, C.A., Bernhard, J.D. (1986) Erythema
nodosum provoked
2(8514):1042.
Fried, M. , Conen, D., Conzelmann, M., Steinemann, E. (1987)
Uveitis after hepatitis B vaccination. Lancet 2 (8559), 631-632.
Germanaud, J., Causse, X., Trinh, D.H., Pfau-Fandard,
B., Trepo,
C. (1995) A case of severe
cytolysis after hepatitis B vaccination. Am. J. Med.
98(3):254-256.
Goolsby, L.P.G. (1989) Erythema nodosum after Recombivax
HB hepatitis B vaccine. N.Engl. J.
Med. 321:1198-1199.
Granel, B., Disdier, P., Devin, F., Swiader, L., Riss,
J.M., Coupier,
L., Harle, J.R., Jouglard, J., and Weiller,
P.JK. (1997) Occlusion of the central retinal vein
after vaccination
against viral Hepatitis B with recombinant
vaccines. 4 cases [French] Presse Medicale. 26(2);
62-65.
Gross, K., Combe, C., Kruger, K., and
Schattenkirchner, M. (1995)
Arthritis after hepatitis B
vaccination. Scandinavian J. Rheumatol. 24(1):50-2.
Guiserix, J. (1996) Systemic lupus erythematosis following
hepatitis B vaccine. (letter) Nephron 74(2); 441.
Herroelen, L., DeKeyser, J. and Ebinger, G. (1991) Central
nervous system demyelination after immunization with recombinant hepatitis B
vaccine. Lancet 338, 1174-1175.
Kaplanski, G., Retournaz, F., Durand, J. and Soubeyrand,
J. (1995) Central nervous system demyelination after vaccination against Hepatitis
B and HLA haplotype. (letter) J. Neurol. Neurosurg. and Psychiat. 58 (6),
758-759.
Macario, F., Freitas, L., Correia, J., Campos, M. and
Marques, A. (1995) Nephrotic syndrome after recombinant Hepatitis B vaccine.
(letter) Clinical Nephrology 43(5); 349.
Mamoux, V., Dumont, C. (1994) Lupus erythematosus
disseminatus and vaccination against hepatitis B virus (letter) [French], Archive
de Pediatrie. 1(3): 307-8.
Manna, R., De Santis, A., Oliviero, A., Carnevale, A.,
Caputo, s., Pahor, M., Laudisio,A., Gasbarrini, G. (1996)
Leukoencephalitis after recombinant hepatitis B vaccine.
(letter)
J.Hepatology, 24(6); 764-765.
Marsaudon, E. and Barrault, M.F. (1996) Meningeal reaction
after vaccination against hepatitis B. (letter) Presse Medicale 25(32);
1561-1562.
Mattieu, E., Fain, O., Krivitsky, A. (1996)
Crioglobulinemia after hepatitis B vaccination. (letter) N. England J. Med. 335(5):355.
Nadler, J.P.(1993) Multiple sclerosis and hepatitis B
vaccination. (letter)
Clin. Infec. Disease. 17(5):928-929.
Noble, J.P., deGennes, C., and Bousquet, O. (1997) Skin
diseases related to Hepatitis B vaccine. (letter) [French]
Gastroenterologie Clinique et Biologique 21(1); 87
Pope, J., Bell, D.A. and Sievers, A. (1995) An epidemic of
rheumatoid arthritis linked to hepatitis B vaccination. Arthritis and Rheumatism.
38(9) 667-6816.
Poutasi, K. (1996) Immunisation and diabetes. (letter) N.
Zealand Med. J.
109(1026):283.
Rogerson, S.J. Nye, F.J.(1990) Hepatitis B vaccine
associated with erythema nodosum and polyarthritis. Brit. Med. J.
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Senejoux, A., Roulot, D., Belin, C., Tsakiris, L.,
Rautureau, J.,
Coste, T. (1996) Acute myelitis after
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vaccine (letter).
[French] Gastroenterologie Clinique et
Biologique. 20(4):401-2.
Shaw, F.E. Jr., Graham, D.J. Guess, H.A. Milstien,
J.B. Johnson, J.M.
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Soubrier, M., Dubost, J.J., Bielsa, C., Ristori, J.M.,
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Presse Medicale. 26(2); 75.
Tartaglino, L.M., Heiman-Patherson, T., Friedman, D.P. and
Flanders, A.E.
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Trevisani, F., Gattinara, G.C., Caracini, P., et al (1993)
Transverse myelitis following hepatitis B vaccination. (letter) J. Hepatol., 19, 317-318.
Tudela, P., Marti, S., Bonal, J. (1992) Systemic lupus
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Vautier, G. and Carty, J.E. (1994) Acute sero-positive
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the strategy of universal hepatitis B vaccination in the United States. (In preparation)
GRANT SUBMITTED TO NIH (Revision in Progress) I. Specific
Aims. A
considerable body of literature dating from the 1970’s
associates hepatitis B viral infection with a number of
serious autoimmune
and neurological disorders. These disorders include
arthritis,
chronic fatigue syndrome, vasculitis, arthralgia, Guillain
Barre syndrome,
multiple sclerosis and systemic lupus erythematosus. More
recently
there have been thousands of reports that similar severe
adverse reactions
arise from the hepatitis B vaccine developed against the
major
hepatitis B surface antigen (HBsAg). And there is evidence
that these
effects are related to MHC class II genes. There are also
numerous
studies demonstrating that lack of of response to the HBsAg
vaccine
(estimated to be 10% in some populations) is related to HLA
subtypes. It
has further been reported that levels of antibodies in sera
of “responders”
(including “super-responders”, estimated to be 10%) are also
HLA
related. Although this vaccine is now being routinely
administrated to
newborn infants and children, as well as adults, the
clinical evaluation of
safety for U.S. Food and Drug Administration (FDA) approval
was carried out
after only 4 to 5 days of observation following
administration of
the vaccine. Since most autoimmune syndromes would be
expected to occur
after weeks or months of administration of such an
immunogen, it
is apparent that many possible autoimmune side effects would
not have been
detected in the clinical studies. Two individuals working in
the
P.I.’s laboratory have been identified as having severe
autoimmune side effects which have been attributed to administration of the
hepatitis B vaccine. Consequently, rare serum samples were obtained from one
individual following the onset of those reactions. In addition, other Co-PI’s in
this project (Bell, Pope) have identified numerous patients with adverse reactions
and have concluded that hepatitis B vaccine triggers rheumatoid arthritis (RA)
in MHC class II genetically susceptible individuals. This group with expertise
in rheumatology, immunology and epidemiology, have initiated a study to follow
these reactions in ongoing vaccine trials. It is, therefore, proposed to study
these adverse reactions to the hepatitis B vaccine in collaboration with other
Co-PI’s with expertise in MHC genetic linkage (Hildebrand) and hepatitis B virology
(Kennedy) to determine whether such autoimmune reactions can be predicted by
identifying specific HLA subtypes. It is further proposed to identify
autoantibodies which might be common among these patients in order to determine
possible therapeutic strategies. The
P.I. has assembled this
group of investigators to systematically evaluate the autoimmune reactions to
the hepatitis B vaccine and accomplish the following aims:
SPECIFIC AIM 1. Characterize autoimmune responses in
subsets of these patients (i.e. RA or multiple symptom autoimmune demyelinating
disease) by: (a) Identifying epitopes of the HBsAg protein which are recognized
by antibodies in sera throughout the onset of autoimmune reactions and
following long term reactions (using yeast, baculovirus recombinants, native
protein, monoclonal antibodies and anti-idiotypic antibodies against HBsAg);
and (b) Characterizing cellular immune responses by identifying responsive T
cell immune responses (e.g. Helper, Cytotoxic) and MHC peptide binding sites.
SPECIFIC AIM 2. Identify and characterize
autoantibodies in sera of patients with autoimmune disorders following
administration of the vaccine to determine whether common antibodies are
generated which can be used to develop therapeutic methods by: (a) Using immunohistochemistry
to identify cell types to which autoantibodies are directed (if clinical data
is not already available); (b) Using immunoprecipitation and immunoblot
analysis with one and two-dimensional PAGE methods to identify antibodies which
recognize human proteins; and © determining whether antibodies to specific
peptides known to be important in autoimmune demyelinating disease are present which
could account for the adverse reaction.
SPECIFIC AIM 3. Determine if subsets of patients
having adverse reactions to the HBsAg vaccine have similar and predictable MHC
gene sequences using high resolution DNA sequencing of complete HLA genes in order
to: (a) Evaluate the potential for molecular mimicry as a mechanism for the
development of autoimmune disorders: (b) Develop pre-screening methods to
predict adverse responses to this vaccine.
In summary, the studies outlined in this proposal
will address our hypothesis that hepatitis B recombinant vaccine does cause
adverse autoimmune reactions in genetically susceptible individuals. They will
also provide new insights into the predictability of determining adverse side
effects of the hepatitis B vaccine in individuals at risk as related to their
histocompatability subtypes. These studies are also unique in that they will
follow the onset of human autoimmune disorders and could further identify
specific autoantibodies to “self” epitopes which could provide a mechanism for
specific immunotherapy in patients who have been adversely effected by this
vaccine or who are suffering from other autoimmune diseases.
II. Background
and Significance
A. Hepatitis B
infection and clinical status. Hepatitis B virus (HBV) is an infectious DNA
virus of the hepadnavirus family transmitted in blood, semen, or saliva through
close physical contact. Inoculation of the virus is thought to occur through
breaks in skin or mucous membranes. The virus can also be transmitted from
mother to child. (See general reviews by Stevens and Lowe, 1995; and Crawford,
1994 ). There are, however, conflicting reports as to the actual incidence of
the disease and the populations of groups, e.g. IV drug users, susceptible to
the disease in the United States (see Progress Report below). Furthermore,
because the vaccine was developed for those at high risk of disease, including
IV drug users and sexually promiscuous individuals, efforts to require administration
of the vaccine to most, if not all of the U.S. population is controversial. The
rationale for general vaccination against hepatitis B in other countries has
also been challenged (Oberg, 1996). The controversy is exacerbated by an
increased number of adverse reaction reports connected with this vaccine. The
controversy stems to a great extent from our lack of understanding of the
mechanisms of the immune response to the hepatitis B surface antigen and lack
of long term follow-up of individuals who have received the vaccine.
There is a large volume of literature available on
the HBV virus which has been reviewed in detail (Strandring et al., 1986;
Crawford, 1994;
Hollinger, 1996; See reviews in text by Ellis of the
Merck Research Laboratories, 1993). Citations are limited in this proposal to
those immediately relevant to its hypotheses and aims.
As outlined by Stevens and Lowe, infection is
estimated to be subclinical in 65% of patients but this virus has clinical
patterns of infection including:
1. Acute self-limited
hepatitis which is common among patients who recover after an illness with
jaundice, malaise, and anorexia and have lifelong immunity to the virus.
2. Fulminant acute
hepatitis which is very rare and causes massive necrosis of liver cells.
3. Chronic hepatitis
which may affect 5-10% of cases and may either progress to liver cirrhosis or
to recovery.
4. Clinically
inapparent asymptomatic infection which is a sub-clinical form of infection in
which infection may progress to chronic hepatitis or the patient may become a
carrier.
B. Hepatitis B
viral surface antigen (HBsAg) used in the vaccine.
1. HBV and HBsAg
particles. In the late 1960’s, patients with high titers of infectious HBV were
found to have a specific antigen (Prince, 1968) (See review by Gerlich and
Bruss, 1993). This antigen was originally named Australia antigen (Blumberg et
al., 1965) and was found associated with three types of particles. These
include: (a) pleomorphic spheres (20 nm diameter); (b) filaments of variable
length (approx. 20nm diameter); and © spherical double-shelled particles
(approx. 42nm diameter) called the Dane particle (Dane et al., 1970). As
reviewed by Gerlich and Bruss, the antigen present on the outer protein shell
of the Dane particle is referred to as hepatitis B surface antigen (HBsAg) and
its antibody as anti-HBsAg.
The major protein or S protein of HBsAg consists primarily
of a 25kDa (p25) and a 30kDa glycosylated (gp 30) form (Peterson, 1981). The HBsAg
consists of four serological serotypes (adw,ayw,adr, and ayr); and serotype
specificity results from a combination of the group specific a determinant
which is present in all serotypes, and subtype contributions from two sets of
mutually exclusive determinants d/y and w/r.
Following natural infection with HBV or with immunization with HBsAg, protective
immunity has been shown to correlate with the presence of antibodies reactive with
the group-specific a determinant. (See review by McAuliffe et al., 1980). Large
numbers of detailed studies have demonstrated the complex molecular,
structural, immunogenic and antigenic nature of the molecular nature of the HBV
as well as the HBsAg. These include
post-translational modifications including glycosylation and phosphorylation of
the HBV proteins (Peterson, 1981; Albin and Robinsson, 1980). These studies
have been outlined in great detail in a review by Gerlich and Bruss (1993).
The severe autoimmune side effects addressed in this
proposal are the same or similar for (a) the hepatitis B virus, (b) the
plasma-derived vaccine, and © the recombinant vaccine derived from expression
of the cDNA in yeast. The yeast-derived vaccine has a different form of glycosylation
than the native viral protein and yet the autoimmune side effects are similar.
As a consequence, the investigators hypothesize that the peptide structure of
the protein used in the vaccine initiates the primary autoimmune adverse
responses.
C. Association
between Hepatitis B virus infection, genetic linkage, and autoimmune disease.
1. Immunogenicity and
antigenicity of viral antigens. It has long been established that viral
infections can be associated with autoimmune disease (Oldstone, 1990; Tomer and
Davies, 1993; Wucherpfennig and Strominger, 1995, Gianani and Sarvetnick,
1996). For example, it was reported as early as 1971 that anti-viral antibodies
were associated with systemic lupus erythematosus(SLE) (Hollinger et al.,
1971), and two years later it was reported that pathogenesis of demyelination
was induced by a mouse hepatitis virus (Weiner, 1973).
Mechanisms by which viruses may play a role in the
development of autoreactive immune responses include: polyclonal activation of
B and/or T cells, molecular mimicry, viral infection of immune cells, exposure
of sequestered antigens, or altered host cell expression (“neoantigen or altered
self”) in virus infected host cells (McChesney and Oldstone, 1987;
Schattner and Rager-Zisman, 1990; Barnett and Fujinami,
1992;
Barnett et al., 1993). It is also well established that T
lymphocytes recognize major histocompatability (MHC) molecules that have bound peptide
epitopes derived from the intracellular processing of antigens. The immunogenicity
of a given epitope is therefore dependent upon three major factors, including:
(a) the generation of the appropriate fragment; (b) the presence of an MHC
molecule that binds this fragment; and © the presence of T cells capable of
recognizing the complex (Panina-Bordignon et al., 1989).
A summary of representative published reports of
associations between
extrahepatic adverse reactions to hepatitis B infection is
given in Table
1. As earlier stated,
there is a substantial body of evidence demonstrating the immune-related side
effects of the hepatitis B infection. Although these reactions have generally
been considered to be due to immune complex disease similar to chronic
experimental serum sickness (Carmeli and De-Medina, 1993), the potential for
other immune mechanisms (e.g. viral molecular mimicry) has yet to be studied in
detail.
Table 1. Representative Reports of Extrahepatic
Adverse Reactions to Hepatitis B virus infection.
Adverse Reaction/Diagnosis
Reference
Systemic “Lupoid hepatitis”, Systemic lupus
erythematosus
Borisova and Krel, 1992; Chng et al., 1993 Arthritis
(polyarthritis, rheumatoid arthritis)
McCarty and Ormiste, 1973; Gocke, D., 1975; Duffy et al.,
1976;
Onion et al., 1971; Wands et al., 1975; Chistau and Helin,
1987;
Morris and Stevens, 1978; Pease and
Keat, 1985; Tsukada et al.,
1987
Vascular Disorders (Vasculitis, polyarteritis,
erythema nodosum)
Gocke, D., 1975;Sargent et al., 1976;
Duffy et al., 1976;Trepo et al.,
1974; Michalak, 1977; Maggiore, 1983;
Di Giusto and Bernhard,
1986; Tsukada et al., 1987; Rogerson
and Nye, 1990
Guillin Barre Syndrome
Neirmeijer and Gips, 1975; Penner et al., 1982Tsukada et
al., 1987;
Tabor et al., 1987
Demyelinating disorders (optic neuritis,
demyelinating neouropathy etc.)
Galli et al., 1986; Tsukada et al.,
1987; Inoue et al., 1994; Achiron,
1994
Chronic Fatigue
Berelowitz et al., 1995
Glomerulonephritis
Venkataseshan et al., 1990
2. Role of MHC genes
in autoimmune disorders.
There is substantial evidence that there are strong
associations between autoimmune disorders and MHC molecules (See reviews by
Paul, 1987;
Abbas, 1994). In systemic lupus erythematosus (SLE)
the presence of HLA-DR2 or HLA-DR3 haplotypes is associated with a relative
risk which is doubled if both are present (Mackworth-Young and Schwartz (1988). Rheumatoid arthritis (RA) is a chronic
inflammatory polyarthritis which has a strong association with MHC Class II
molecules, although the concordance of disease occurs at only 15% in
monozygotic twins suggesting that environmental factors may also play a role in
the onset of disease in genetically susceptible individuals (Silman et al.,
1993). Of patients having type I diabetes, about 95% have HLA-DR3 or DR4
haplotypes or both as compared to 40% of the general population (Rotter et al.,
1983).
It has also been shown that cytotoxic T lympocytes
recognize an HLA-A2-restricted epitope within the hepatitis B virus
nucleocapsid antigen (Penna et al., 1991). More recently it has been shown that
MHC class I-restricted responses as well as class II restricted responses may
also be involved in the pathogenesis of demyelinating disorders (Pelfrey et
al., 1993; Tsuchida et al., 1994). In multiple sclerosis, myelin proteins are thought
to be the targets for autoreactive T-cell responses. In studies by Tsuchida et
al. (1994) it was found that self peptides derived from human myelin proteins
(including sequences from human myelin basic protein, proteolipid protein,
myelin associated glycoprotein and myelin oligodendrocyte glycoprotein) bind to
and form stable complexes with HLA-A2. These studies are important because they
demonstrate that self peptides from human myelin proteins can induce
autoreactive CD8 cytoxic lymphocytes and that these lymphocytes produce
cytokines thought to be important in mediating demyelinating diseases.
3. Role of MHC genes
in immune response to HBsAg of virus and vaccine.
It has long been known that there is a genetic
correlation of the immune response with respect to the hepatitis B surface
antigen (Milich et al., 1982, 1983). It has been clearly documented that the
human antibody response to the hepatitis B surface antigen (HBsAg) vaccine is
associated with the major histocompatability complex (MHC) and is inherited in
a dominant fashion (Craven et al., 1985; Kramer et al., 1988; Alper et al., 1989;
Varla-Leftherioti et al., 1990; Kruskall et al., 1992). It has further been
reported that 5 to 10% of healthy individuals fail to respond (“non-responders”)
to the plasma-derived HBV vaccine (Weissman et al., 1988, Kramer et al., 1988).
Because the plasma derived vaccine contains a distinct glycosylation pattern
from that of the yeast-produced vaccine, these investigators carried out
studies to evaluate whether the recombinant, yeast- produced vaccine would
produce antibody titers in the non-responder population. These studies
demonstrated that the recombinant hepatitis B vaccine (Recombivax HB) in
non-responders to the plasma derived vaccine and that HLA subtyping showed a
high prevalence of DR7, B8, and the combinations of DR3, DR4 and DR7.
Additional studies by Margot et al. (1992) indicate
that: (a) the response to the HBsAg vaccine is MHC-linked and inherited in a
dominant fashion, (b) that an abnormal or missing immune response (Ir) gene for
HBsAg is a characteristic of most examples of the extended haplotype (HLA-B8,
SCO1, DR3), and © other haplotypes also have abnormal or missing Ir genes for
HBsAg.
Sktachowski, et al., (1995) have also shown that that
responder groups can be divided into two subgroups: low responders and high responders.
In these studies marked differences were observed between responders and
non-responders in the occurrence of carriers of different MHC class I, II and
III alleles. High responders were found to have different haplotypes than low
responders. These findings indicate that amounts of antibody to HBsAg is
genetically influenced even in patients demonstrating adequate antibody
response.
Many of these studies have been summarized by Abbas
(1994). His work indicates that Caucasians who are homozygous for an extended
HLA haplotype containing HLA B8, DR3, Dqw2a are low responders to the HBsAg. In
this review he proposed that individuals who are heterozygous for this locus
are high responders presumably because the other alleles contain one or more
HLA genes that confer responsiveness. Abbas et al therefore concludes that HLA
typing may prove to be valuable for predicting the success of this vaccine
(Abbas et al., 1994) . This proposal therefore hypothesizes that HLA typing may
also prove to be valuable for predicting the failure of the vaccine, including
non-response or autoimmune side effects.
D. Association of
the hepatitis B surface antigen vaccine and autoimmune syndromes.
Although there have been numerous reports of the
efficacy of the hepatitis B plasma and recombinant vaccines (Mast and Alter,
1983;
Hollinger et al., 1986; Zahrandnik et. al., 1987;
McMahon and Wainright, 1993), these reports concentrate primarily on antibody
titers (e.g. responders and
non-responders); and no long term follow-up has been reported. The clinical
trials reported in the drug inserts cite 4 or 5 day follow-ups, which could be
expected to be too short an observation period to obseve long term autoimmune
responses. Table 2 includes a representation of published reports of such
adverse reactions although it does not include summation of the tens of
thousands of reactions reported to the FDA Adverse Reaction Reporting System.
We have included 12 pages representative of 900 total pages of those reaction reports
(Merck vaccine only)(See Appendix 1). Note: one listing is a report by a
registered nurse of 15 incidences of multiple schlerosis; she inquires whether
there is any known relationship with this vaccine.
To date, the most detailed study which has
demonstrated a correlation of rheumatoid arthritis (RA) with the hepatitis B
vaccine and a relationship to HLA subtypes is that of the two Co-P.I.s of this
project . RA is not listed as a
potential side effect for this vaccine in the Physician Desk Reference or
package insert for the Energix (Smith Kline) vaccine. This study is summarized
in the Progress Report and is provided in complete form in Appendix 2.
Table 2. Reports of Adverse Reactions of Hepatitis B
Vaccine (does not include the FDA Adverse Reactions Reports).
Adverse Reaction/Diagnosis
Reference
Systemic “Lupoid hepatitis”, Lupus
erythematosus
See Appendix 2; Tudela and Bonal,
1992; Mamoux and Dumont,
1994;
Arthritis (polyarthritis, rheumatoid arthritis)
Rogerson and Nye, 1990; Vautier and Carty; 1993; Gross et
al., 1995;
Pope et al., 1995; (see Appendix 2 and 3); Biasi,
1987-1993.
Vascular Disorders (Vasculitis, polyarteritis,
erythema nodosum, cryoglobulinemia)
DiGuisto and Bernhard. (1986);
Goolsby, 1989; Cockwell et al., 1990;
Rogerson and Nye, 1990; Mathieu et
al., 1996; Caarmeli and De-Medina,
1993; Isla, 1993; Mathieu and Krivitsky, 1996.
Guillain Barre Syndrome
Shaw et al., 1988
Demyelinating disorders (optic neuritis, Bells
Palsy, demyelinating neouropathy, multiple
schlerosis etc.)
Ribera and Dukta, 1983; Shaw et
al., 1988; Herroelen et al., 1991; Nadler
(1993); Devin et al., 1996; Dunbar et al., (unpublished
observations);
Senejoux et al., 1996; See Appendix 2; Baglivo et al.,
1996;.
Diabetes mellitus
Poutasi, 1996; Classen, 1996
Chronic Fatigue
I. Salit (1993);
Delage et al., 1993
Other
Germanaus et al., 1995
The majority, if not all, of these reported side effects
of the recombinant hepatitis B vaccine are the same as or similar to those
reported as extrahepatic manifestations of the virus infection itself. These
severe adverse side effects are also associated with autoimmune responses. Some of these reported adverse reactions
have been dismissed (e.g. Canadian Laboratory Centre for Disease Control
report, Delage et al., 1992) because (a) there was no clear pattern of the
onset of symptoms and (b) there was no biological evidence to support the
occurences of adverse reactions (i.e. no circulating virus). In view of
substantial new information that autoimmune disease can be induced by viral
molecular mimicry, anti-idiotypic antibodies, or anti-phospholipid antibodies
(see discussion below), it is apparent that the dismissal of these reactions as
a result of vaccination might well have been premature.
In the text “Adverse Events of Childhood Vaccines”, (1993)
Hauser et al. (1987), state: “The
antibodies produced after infection with hepatitis B virus or after
administration of plasma derived vaccine or recombinant vaccine are alike in
terms of their ability to elicit protective determinants that are active
against all subtypes of the virus...” and that “the results of the trials of
recombinant vaccine are much the same as those of trials of the plasma-derived
vaccine”. They further stated that the studies were not designed to assess
serious, rare adverse events, the total number of recipients were too small and
the follow-up generally too short to detect rare or delayed, serious, adverse
reactions. Finally it was pointed out that “overall the number of examples of
adverse neurologic outcomes following receipt of hepatitis B vaccine are of
concern, particularly those resulting in demyelinating neurologic disease”.
In view of these observations and the more recent
observations outlined in Table 2, it is medically crucial to evaluate the
nature of the autoimmune reactions (i.e. risks) associated with the hepatitis B
vaccine and to determine if individuals who will have these adverse reactions can
be identified in advance of receiving the vaccine.
E. Possible molecular
mechanisms for adverse reactions to the hepatitis B vaccine.
1. Molecular
mimicry: There has long been an awareness that viruses have developed evasion
strategies by which they can successfully circumvent immune detection and/or
effect. There have been recent studies of the molecular mechanisms that viruses
use to circumvent the immune system (Lidbury, 1994). Molecular mimicry, which
is one of the proposed mechanisms, has been characterized as the presence of
one or more common epitopes, either linear or conformational, shared by host
and microbial determinants (Dyrberg and Oldstone, 1986; Olesak, 1994).
The theory that molecular mimicry between viral and
self antigens could, in some instances, initiate autoimmunity has gained
increased acceptance in the past few years (Fujinami and Oldstone, 1985; Jahnke
et al., 1985; Fujinami, 1988; Olesak, 1994; Wucherpfennig and Strominger, 1995;
Gianani and Sarvetnick, 1996; Baughan et al., 1995). One study has provided
evidence that while only one peptide could have been identified as a molecular
mimic by sequence alignment, seven viral and one bacterial peptide efficiently
activated T cell responses in cells isolated from patients with multiple
sclerosis (Wucherpfennig and Strominger, 1995). These authors conclude that the
diverse nature of the molecular mimicry peptides and the ubiquitous presence of
some of these pathogens make it difficult to establish a direct epidemiological
link between these viral infections and the occurrence of multiple sclerosis. These authors also conclude that: “Genetic
modifications of viral vaccines that eliminate proven mimicry epitopes could
make viral vaccines safer and reduce the frequency of post-vaccinal
encephalomyelitis”.
With respect to the hepatitis B virus, it has been
shown by Fujinami and Oldstone (1985) that when computer aided analysis
identified peptide sequences shared between the viral protein and myelin basic
protein (MBP), these peptides could stimulate a T cell proliferative response directed
to MBP and result in autoimmune central nervous system disease in rabbits. In
fact, this study of the hepatitis B protein was used as the basis for the
molecular mimicry model of autoimmune disease (Barnett et al., 1993).
It has also been shown that the conformational nature
of peptides may be important for conferring molecular mimicry (Madden et al.,
1993). It is clear that detailed molecular and biochemical analyses need to be
carried out to identify specific peptides which might be acting as molecular mimics.
The advances in computer technology and data bases now provide the tools
necessary to design experiments to evaluate these hypotheses directly.
2. Anti-idiotypic
antibodies. Anti-idotypic antibodies are associated with autoimmune disorders
including myasthenia gravis, diabetes, systemic lupus and Grave’s disease
(Nasu, et al., 1982; Rauch et al., 1985;
Dwyer et al., 1983,1987; Sikorska, 1986; Schoelson et
al., 1986), as has been demonstrated directly in experimental animal models
(Shoenfeld, 1994;
Blank et al., 1995). It has been proposed from these
results that in some autoimmune diseases, especially in those in which the
presumed autoantigen is not immunogenic (e.g. DNA, cardiolipin), that
antibodies against the infecting agent may carry a pathogenic idiotype of a
specific autoantibody (Schoenfeld, 1994). The latter author has further hypothesized
that, if a subject is prone to autoimmunity (e.g. genetic, hormonal), the
pathogenic idiotype will progress in dysregulating the immune system resulting
in a clinically overt autoimmune disease.
Autoantibodies that are anti-idiotypic to anti-viral
antibodies have also been observed (Plotz, 1983). Furthermore, anti-idiotypic
reagents that bear an internal image capable of mimicing the hepatitis B
surface antigen have been used to induce an antibody response to HBsAg in both rabbits
and chimpanzees (Kennedy et al., 1986). Also in vivo injections of anti-idiotypic
antibodies have been used to prime the immune response of mice to HBsAg
(Kennedy et al., 1984). Given the correlation of anti-idiotypic antibodies with
antigens known to be associated with molecular mimicry, the probability that
such antibodies are involved in the adverse reactions associated with hepatitis
B vaccination appears high and needs to be addressed in detail as is proposed
in this study.
c. Anti-phospholipid antibodies. Recently,
anti-phospholipid antibodies have been shown to be associated with clinical
syndromes such as SEL and thrombosis (Puurunen et al., 1996), recurrent
abortion and thrombocytopenia. Other reports include a relationship to multiple
sclerosis (Sugiyama and Yamamoto, 1996). It has been shown recently that there
is an increased incidence of anti-cardiolipin antibodies in patients having
autoimmune thyroid diseases, although these autoantibodies are thought to
represent a non-specific marker of immune dysregulation. Other studies have described autoimmune
phenomena in which anti-phospholipid antibodies are associated with “anti-phospholipid
syndrome” (Lekarstvi, 1994), and there has been a report of a patient with mixed
types of chronic active hepatitis and primary bilary cirrhosis having this
syndrome (Saeki et al., 1993). In addition, it has been shown that
anti-phospholipid antibodies in women with recurrent fetal loss correlate to
clinical and serological characteristics of SLE (Bagger et al., 1993, Zurgil et
al., 1993). One of the patients who will be participating in this study had
recurrent miscarriages following the onset of adverse reactions to the
hepatitis B vaccine and had noted anti-cardiolipin antibodies (See Appendix 2)
A proposed mechanism for anti-phospholipid antibodies involved in autoimmune
diseases has been derived from observations that heparin sulfate is a high
affinity antigen of pathological significance for anti-DNA and anti-phospholipid
antibodies. Interference due to binding
of these antibodies with components of the cell surface and heparin sulfate,
which is an extracellular matrix molecule, could play a major role in tissue
injury including the vasculature system (Shibata et al., 1993). As vascular
problems are a common adverse effect of the HBsAg, this will be an important
parameter to evaluate.
The hepatitis B surface antigen binds to a human
liver plasma membrane protein, endonexin II, a calcium dependent phospholipid
binding protein (deBruin et al., 1996). This protein has further been shown to
be associated with numerous tissue cell types. They conclude that the species
specific distribution of the HBsAg binding protein correlates with the species
tropism of hepatitis B virus infection. Because this protein is not present in
species which are not infected with this virus, the binding to this surface
molecule might be important in the mechanisms of cellular internalization of
this HBsAg. There is also a correlation of anti-phospholipid antibodies in some
patients who have been exposed to the HBsAg and the prevalence of demyelinating
autoimmune disorders. Thus it is possible that the binding of HBsAg to this phospholipid
binding protein may be related to cellular internalization during immune
processing of the peptide and may be related to some of the reported adverse
reactions.
III. Preliminary Data and
Progress Report
A. Risk vs. benefit of Hepatitis B vaccine.
For any vaccine, it is critical to evaluate the
risk/benefit ratio to determine the efficacy, safety and practicality of the
vaccine. We have initiated investigations to evaluate the risk (i.e. adverse
vaccine reactions) vs. the benefits of
this vaccine. Based on well respected published values from the major text used
in U.S. medical schools (Crawford, 1994), as well as values from the Centers
for Disease Control (CDC) of the incidence and clinical manifestations of this
disease the following estimations of vaccine efficacy have been calculated.
1. Estimation of the
risk of contracting hepatitis B in U.S. It is commonly reported by drug company
brochures and Center for Disease Control (CDC) publications (Hadler and
Margolis, 1993) that there are 200,000 to 300,000 cases of hepatitis B per year
in the United States. There are arguments on the internet attributed to the
Mobidity and Mortality Weekly Report (internet: www.i-wayco.com/niin/van/van_p5.html)
argue that the number of cases may be lower. In this reference, it is reported that
in 1992 there were 358 reports of Hepatitis B in New York City and 438 in
Upstate New York and only 13,857 cases nationwide. The broad range of estimated
cases of hepatitis B in the United States is clearly a problem in assessing the
risk of contracting hepatitis B in this country. That problem is compounded by three apparent additional problems:
(a) the fact that the majority of these cases appear confined to I-V drug users,
sexually promiscuous persons, and medical contacts; (b) the genetic predisposition
of some exposed to the hepatitis B virus to fend it off without serious
illness; and © contraction of the disease by non-responders to the vaccine
after vaccination.
Our best assesment of the risk is outlined in Table 3. As
best we can we take into account the worst and best case scenarios from the
above information and assume that every individual has the same risk (i.e.
there is no difference in risk between the normal population and high risk categories
such as drug users). This assesment is also based on the averages of clinical
populations of this disease outlined by Crawford, (1994). Clearly, the risk
would be greatly reduced if the distinction between the normal population and
high risk categories was established. Furthermore,
these numbers might vary if it was possible to assess how many non-resonders to
the vaccine contract the virus and have subsequent serious symptoms or die.
Table 3. Estimated relative risk of severe disease of
death from Hepatitis B in United States.
Worst Case
Best Case
% of
Infected
Cases per year in US
300,000 (1% of total
population
14,000 (.005% of total population).
Cases recovered
250,000+
11,520+
83%+
Healthy Carriers
15,000-30,000+
750-1400+
10%+
Fulminant hepatitis, cirrhosis and
carcinoma, and death
2500
116
0.83%
Estimated Risk of serious
illness or death
(Current US Population of
265,000,000)
0.0009%
0.000044%
2. Estimation for risk of adverse side effects of
Hepatitis B recombinant vaccine (From Physicians’ Desk Reference, 1995).
Although there are over 60 listed potential adverse reactions of “less than 1%”,
it is not clear if this is less than 1% of each of the listed effects or less
that 1% of all 60 potential reactions.
a. Recombivax HB, Merck, Inc. - quoted directly from 1997
Physician’s Desk
Reference
(PDR INSERT)
b. Energix Smith Kline Beecham - quoted directly from 1997
Physician’s Desk
Reference
(PDR INSERT)
c. Adverse Reaction Reports to Food and Drug
Administration. The P.I. has obtained from the FDA a list of adverse reactions
reported for Merck’s Recombix HB vaccine from 1990 through part of 1996. Over
7000 adverse reactions are listed. A dozen representative pages of these reports
are included in Appendix 1. It has been informally estimated that there may actually
be uprwards of 30,000 adverse reaction reports for both the Merck Recombivax
and the Smith Kline Energex vaccines. Because the FDA reports that these
adverse reactions constitute only 10% of adverse reactions, it can be assumed
that there may be tens of thousands, if not hundreds of thousands of adverse
reactions to these vaccines to date. Without direct access to the computer data
bases from which these lists are derived, it has not been possible for the P.I.
or her colleagues to obtain precise estimates of autoimmune reactions to the
two vaccines.
However, the vast majority of these severe autoimmune
reactions are known to be related to immune phenomena. These types of
devastating immune disorders require extensive long term health care. Thus even
a small percentage of effects could considerably increase the expense of health
care in the U.S. Furthermore, the devastating effect on the length and quality
of life for those adversely effected should not be ignored.
In view of these observations, there are critical
questions which need to be addressed to establish the risk/ benefit of the
current hepatitis B vaccines in the United States. These questions are
particularly important in view of recent mandates to vaccinate all children
including newborn infants. The issues include:
1. Is four or five days of observation as in the FDA
clinical trials, adequate to evaluate potential autoimmune side effects of the
recombinant hepatitis B vaccines?
2. Would the percentage of detected autoimmune reactions
to the recombinant vaccines increase if a follow-up of 30 days or longer was
carried out in vaccinated trial patients? If so, how much?
3. Would evaluation of MHC class subtypes correlate to
reported incidences of autoimmune reactions to the vaccines? If so, would it be
possible to predict which of those MHC class subtypes could be expected to have
an autoimmune reaction to the vaccine?
4. Could identification of peptides in the HBsAg, which
are responsible for adverse reaction, result in re-engineering the vaccine to
eliminate autoimmune reactions?
5. If specific immune responses are identified (e.g.
antibodies to specific self peptides), can specific autoimmune responses be
regulated (i.e. immunosupression) so
that effective treatment can be designed for those patients who have long term
serious adverse effects to the vaccine?
6. How many patients have serious illness or die of cirrhosis
or carcinoma would (or did) NOT respond to the recombinant vaccine due to MHC class
non-responsiveness and therefore would not be protected by these vaccines? Can
they be identified? If so, the alternative of immunoglobulin therapy or some
other drug therapy might be more appropriate than the misleading these patients
as to the potential of the vaccines.
B. Identification and evaluation of patients with adverse
effects to the Hepatitis B vaccine.
To date, few studies have been carried out to determine
the causes for the serious adverse effects associated with the Hepatits B
vaccine. In view of this limited information we have initiated studies to
collect serum from patients throughout the course of these adverse reactions
and to collect additional information to design studies to adequately address these
issues.
1. Correlation of onset of arthritis with the recombinant
hepatitis vaccine. Two of the Co-P.I.’s have carried out extensive studies
following 12 patients who have had long term adverse reactions resulting in
arthritis (See Appendix 2). In summary these studies show that 11/12 cases had persistent
arthritis up to 48 months. HLA class II genes expressing the Rheumatoid
Arthritis (RA) shared motif were identified in 9 of 12 patients who were
genotyped for HLA DRß1 and DQß1 alleles. These studies provide substantial
justification for carrying out further studies to determinine the risk of RA as
a consequence of hepatitis B vaccination.
2. Collection of serum samples for analysis of onset of
autoimmune syndrome. In addition to the long term studies following patients
with RA, we have identified numerous other patients whose symptoms are either demyelinating
disorders or “mixed connective tissue disorders.” We have already obtained
serum samples from some of these patients whose symptoms and onset of disease
are directly related to a time frame that is consistent which an adverse immune
reaction to this vaccine. Detailed reports from physicians have established
definite correlation with the vaccine have been obtained or will be provided
for these patients (See Appendix 2). Because one of these patients was working
in the P.I.’s laboratory during the onset of these reactions we have had
collected and have frozen monthly bleedings from 3 through 6 months after the immunization
during the onset of autoimmune adverse reactions from one of these patients
(demyelinating disease, encephylopathy, joint pain, lupus-like syndrome). In
addition, we have additional bleedings following two years at the time when
symptoms have persisted. We have not yet evaluated this serum in detail because
it is so valuable and therefore serious consideration as to the priority of
experiments will be assessed as these studies progress. These samples are
critical in that it demonstrates the potential to prospectively evaluate the
onset and evolution of autoimme disease at a relatively early stage and
provides an opportunity to determine what immunological parameters might exist
at different stages.
C. Preparation and characterization of monoclonal
antibodies and anti-idiotypic antibodies to evaluate adverse reactions to the
hepatitis B vaccine. In order to evaluate the immune response to the HBsAg, a
number of different studies have been carried out by the a Co-P.I. of this project
and his colleagues. A variety of monoclonal and anti-idiotypic antibodies to
the HBsAg have been reported in detail. (Kennedy et al., 1982; Kennedy and
Dreesman, 1983; Kennedy et al., 1983; Kennedy et al., 1986). In recent studies
direct binding and competitive inhibition enzyme immunoassays have demonstrated
that two murine monoclonal antibodies to HBsAg (A1.2 and A3.1) recognize
similar or overlapping epitopes while the A2.1 antibody recognizes a unique
HBsAg epitope. Further analysis using monoclonal and polyclonal anti-idiotypic reagents
have identifed both a private and cross-reactive idiotype, respectively on the
anti-HBs A1.2 and A3.1. ( see details in Shearer et al., Appendix 4) These
panels antibodies and reagents will be critical for characterizing the
antibodies in the serum of patients have severe reactions to the HBsAg vaccine.
D. Comparison of amino acid sequences of HBsAg with
peptides associated with demyelinating autoimmune diseases. Recent reports have
shown that (a) self peptides from human myelin proteins can induce autoreactive
CD8+ Cytotoxic T cells and that these T cells produce cytokines thought to be
important in mediating demyelinating disease (Tsuchida et al., 1994); (b)
proliferative and cytolytic CD4+ T cells from multiple sclerosis patients
recognize myelin proteolipid proteins (Pelfrey et al., 1993), and (b) that
viral peptides activate human T cell clones specific for myelin basic proteins,
and © that viral peptides can activate humant T cell clones specific for myelin
basic protein. (Wucherpfennig and
Strominger, 1995). In view of these reports, we have initiated studies to
evaluate the similarities and identitieis of peptide sequences of the HBsAg and
myelein protein peptides thought to be important in demyelinating disease.
TABLE 4 : Comparison of amino acid sequences of peptides1
derived from human myelin proteins (that are targets of autoreactice T-cell responses
and implicated in demyelinating disorders) to HBsAg.
PEPTIDE
(amino acid position)
% SIMILARITY / % IDENTITY
AMINO ACID
POSITION IN
HBsAg
2 PLP40-60
75 / 35
116-165
PLP80-88
75 / 63
83-90
PLP253-261
89 / 33
171-185
3 MAG8-16
78 / 44
11-30
MAG406-414
71 / 57
162-168
MAG509-517
89 / 44
175-190
MAG556-564
78 / 33
190-200
4 MBP110-118
100 / 67
31-45
5 MOG7-15
88 / 50
87-94
MOG133-141
75 / 25
21-28
MOG157-165
78 / 22
24-32
MOG164-172
71 / 43
203-209
MOG221-229
71 / 57
204-212
MOG240-248
75 / 25
15-24
MOG422-430
78 / 33
13-21
1 Tsuchida et al (1994); Pelfrey et al (1993). Peptides
bind to HLA-A2.
2 PLP = Proteolipid protein; 3 MAG = Myelin-associated
glycoprotein
4 MBP = Myelin basic protein; 5 MOG = Myelin
oligodendrocyte glycoprotein
These studies show that there are some HBsAg peptides
which have strikingly similar regions to the myelin proteins. Detailed studies
by Wucherpfennig and Strominger, (1995) that a single T cell receptor can recognize
quite distinct but structually related peptides from multiple pathogens. It
will, therefore, be critical in the present studies to carry out more detailed
structural analysis to identify peptide motifs as described by these
investigators.
LETTERS FROM PATIENTS WITH ADVERSE REACTIONS TO HEPATITIS
B VACCINE
(Numbers used in order to protect patient confidentiality)
1.
>From doctor’s report . “ Probable confluence of
multiple sclerosis with mild systemic lupus, known as “lupoid sclerosis”. The probable
etiology for this is her Heptavax vaccine.
2.
>From doctor’s report . “Over the 6 years I have
followed xxx. the major symptoms that she has manifested have included fatigue,
cognitive dysfunction, sleep disturbances, muscle ache, weight gain, abdominal
discomfort with nausea and diarrhea, and low grade fevers. In addtion she has
many episodes of chest discomfort and a pressure-like feeling in her chest,
resulting in shortness of breath. Associated with this has been a positive
anti-nuclear antibody with a normal sedimentation rate but elevated immune
complexes initially. Although xxx. has seen an array of excellent physicins
over the last 6 years, she really does not fit any of the American Rheumatology
Assn. Diagnostic categories.
Over this time, I have come to the same conclusion Dr.
xxxx suggested in 1991 of her symptom complex being substantially caused by the
hepatitis B vaccine. It is my opinion, with reasonable medical certainty, that
the vaccination stimulated an onoing autoimmune disease with the manifestations
outlined above.
3.
1st injection - stiff arm, fatigue started,
suffered colds. 2nd injection - stated to lose weight and general
fatigue continued. colds on a regular basis. 3rd injection - weight
loss and general fatigue continued.
4. I contracted an M.E. C.F.S type illness following the 3rd
immunisation against Hep B last April, although I have made a great
improvement, I am not yet fully recovered.
I have been diagnosed as suffereing from C.F.S., and my
employers, a local N.H.S. Trust have cited the 3rd immunization as causeing
the illness at a recent Industrial Injuries Board. The drug used was “Energix B”,
sold and manufactured by Smith Kline Beecham.
As a speech and language therapist working in the field of
learning disabilities, I was required to have the jab as part of Trust policy.
My boss, a 28 year old woman who had the jab a few weeks after me, also
developed reactive arthritis.
A blood test was taken a few months after the jab, and,
although I had the full 3 injections, I had not developed any antibodies to
Hepatitis. I was quite interested to read your notes that failure to repond to
the vaccination is related to HLA, and that this might correspond to genetic
factors in the development of auto-immune disorders.
There is a small group of health workers here who have
developed CFS/RA following vaccination.
5
My illness was diagnosed after some months as Post Viral
Syndrome. I contracted it seven days after the last of the three Hepatitis B
innoculations in September 1989. Previous to this time I was in the best of
health. I was convinced that the innoculations were the cause. I had suffered
after-effects to varying degrees from the first two jabs. I tried to convince
the Boston Community Health Authority (who had administered the innoculations) that
the vaccine was the main cause. Neither they nor the many medical specialists I
have seen would countenance that the vaccine was implicated. Their argument was
that the vaccine was man-made and not human and that the side-effects I described
were unknown.
6 I have a fairly clear history of M.E. arising after
Hepatitis B vaccination.
7
I would like to tell you the story of my sister, 25 years
old. She was a very healthy and go-ahead student before having MS symptoms and
many other diseases. Very few in France thought that the hepatitis B vaccine
could generated severe adverse effects. Yet, her strange medical story was hard
to understand without this possible interpretation, all the more because nobody
in my family had every had MS, and because the crises and disorders were so brutal
and so varied. My parents recently decided to write down in detail her medical
story you can find here. They don’t wan’t it to be published. (not included as requested).
8
There are two women who contacted me lately who both got polyneuritis (I think that’s what they said) after the Hep B vaccine and several who have chronic arthritis for the same reason. ....We also have one case which was one in Australia last November (1996) of a nursing sister who developed chronic arthritis which did not allow her to work following Hep B vaccination. She won a 6 figur award through worker’s compensation. We also had 4 adults on our geris