Autism Independent UK (SFTAH)

(Sent on this date)
September 29, 1997
Department of Health & Human Services
Food and Drug Administration
Rockville, MD 20857

I am a research scientist and medical student professor who has worked in the areas of autoimmunity and vaccine development for over twenty years (the past 15 years at Baylor College of Medicine in Houston). I was honored three years ago by the National Institutes of Health as the "First Margaret Pittman" lecturer for my pioneering work in contraceptive vaccines. This was a most special time for me because I understand what the impact of vaccines has had ( and will continue to have) on our society. My continued work in this area of vaccine development continues to be a major commitment because I have worked extensively with the AID and WHO programs and have a life long commitment to working to understand, and hopefully, help solve world population and disease problems.
I am writing to you, however, in reference to the adverse effects of the Hepatitis B vaccine because within the past three years, I have had two individuals working in my laboratory who have developed severe and apparently permanent adverse reactions clearly as a result of being forced to take the Hepatitis B vaccine. Both of these individuals were extremely brilliant, 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, multiple sclerosis like symptoms, and now, affirmatively diagnosed with POTS (an autoimmune cardiovascular neurological problem). His problems have been attributed to the Hepatitis B vaccine by 5 different specialists of unquestionable medical expertise (including MD/PhD's in major medical schools).
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. Personal communications are that her eye-sight is continuing to deteriorate (now in both eyes). Because she is in medical school she has been (understandably so) afraid to pursue her medical problems in the event that they might effect her medial career.
Because of my extensive work in vaccine development I am extremely 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 of this vaccine (which are clearly related to the nature of the virus itself) may be much more significant than generally known (or admitted). I have recently been in contact with physicians from several countries, who have long since described the same problems, (in white Caucasian populations), although it is clear that their observations have been, for the most part ignored. I have had visits in the past month with physicians in England and France who have serious concerns about their large numbers of patients who they believe have been effected by this vaccine. As in my experience, the effect on white Caucasians (clearly an HLA genetic linkage) is dramatic. In all of my queries, it is not clear to me, (or others who have been investigating this), that there was adequate long term follow-up information collected in the clinical trial data (especially with respect to the white Caucasian population) in which many of these effects might have been observed. In any event, even the vaccine inserts giving reported side effects, which I have found 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 discussed these issues with an international team of experts to prepare a grant proposal to investigate the scientific basis for these adverse reactions which are identical to those reactions from individuals having the virus itself. It is very apparent 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 wish to determine the long term prognosis for patients having such adverse reactions. Because I have an immunology and biochemistry laboratory we have already 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. Although our initial proposal was not funded, due mainly to criticisms of lack of patient populations with clearly defined adverse responses to the vaccine, I have since collected large numbers of reports of patients (with legitimate physician diagnoses) who wish to be involved in this study which we are including in our revised proposal. We also have preliminary evidence of a patient with a major auto antibody response to a human brain protein. We will, therefore, continue to seek funding from private as well as federal sources to carry out these studies.
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 December 26, 1996, New York Time's article on molecular mimicry which discusses theories for 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 a 4 year period from 1992 to 1996 (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.) Clearly, these reactions are HLA linked which may provide us with the basis to evaluate which individuals might have adverse reactions to this vaccine and who might be non-responders and therefore not be protected by this vaccine. I have no doubt that the pharmaceutical companies are working on this because it is obvious from the published literature that these are major issues. In the meantime, how many individuals might be adversely effected before this research has been completed?
I have now been in direct contact with dozens of severely ill patients (as well as with physicians who have hundreds more patients) clearly having adverse reactions to the hepatitis B vaccine and I feel that it is critical to investigate the early onset effects as well as subsequent development of autoimmune adverse reactions in the hope that we might find more directed treatments to avert the long term effects of those already afflicted with these problems. I believe this is possible in view of new technologies for treatment of autoimmune diseases which are targeted to the identification of specific auto antibodies to defined epitopes.
No one, especially myself, would ever assert that the hepatitis B virus is not causing serious health problems in the U.S. as well as abroad. The questions that remain to be answered: Is the Hepatitis B virus (in its elegance of evolution and survival) a master of molecular mimicry which has produced its surface protein (the one used in the vaccine) to weaken the immune system (i.e. inducing autoimmune disease)? and as (or more) importantly; Can this vaccine be modified to avoid these immune reactions or is this a virus which needs to be controlled or eradicated by early treatment or other methods? If this vaccine, by nature of the peptide (native or produced from a cDNA as a recombinant protein), has the ability to adversely effect the immune system and turns out to have severe adverse reactions in some populations, then the public reaction to ALL vaccines, including those that clearly DON'T have adverse reactions may be doomed in the public's eye. That includes new vaccines to new, and clearly major population threatening viruses as well as to such newly designed vaccines which might be critical for controlling world population. Thanks to the success of the Human Genome Project and advances in computer programs it may be possible to evaluate potential molecular structure to predict these problems in advance.
If those of use who are looking into these adverse effects of the Hepatitis B vaccine could have access to clinical samples reported to the FDA for our research (at complete confidentiality) from patients claiming adverse reactions to the hepatitis B vaccine who are willing to participate in these studies it would be most critical. Any assistance we can obtain on this study would be greatly appreciated. I can assure you that my commitment to this project, both personal and professional, has become a major priority. I understand your position in this issue and I would like to see that there is some positive outlook for these severely devastated patients having these adverse reactions.............

Report modified from that prepared by Dr. ????? ?????? 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 Medicine (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 TABLES)

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" (i.e.: 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 regarding 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 Control of Hepatitis B as a Community Health Risk", Nov., 1993. In: Vaccine, 13, Supply #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, Supply #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 Control of Hepatitis B as a Community 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 Medicine, 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;,br> 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
References:

Anonymous (1990) Hepatitis B vaccines: reported 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) Fluctuant perception hearing loss after hepatitis B vaccine. [French] Annales d'Oto-Laryng. et de Chirur. Cervico-Faciale 113 (6), 359-361.
Brezin, A., Lautier-Frau, M., Hamedani, M., Rogeaux, O. and Hoang, P.L. (1993) Visual loss and eosinophilia after recombinant hepatitis B vaccine. Lancet 342, 563-564.
Carmeli, Y., De-Medina, T.(1993) Serious hepatitis B vaccine adverse reactions, are they immune-mediated?. Vaccine. 11(13):1358-1359.
Classen, J.B. (1996) Childhood immunisation and diabetes mellitus. (letter) N. Zealand Med. J. 109(1022):195.
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 by hepatitis B vaccine. Lancet. 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. 301(6747):345.
Senejoux, A., Roulot, D., Belin, C., Tsakiris, L., Rautureau, J., Coste, T. (1996) Acute myelitis after immunization against hepatitis B with recombinant 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. Schatz, G.C., Handler, S.C. Kuritsky, J.N., Hiner, E.E. Bregman, D.J., et al.(1988) Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Amer. J.Epidemiology. 127(2):337-52.
Soubrier, M., Dubost, J.J., Bielsa, C., Ristori, J.M., Bussiere, J.L. (1997) Erosive polyarthritis triggered by vaccination against hepatitis B (letter) [French] Presse Medicale. 26(2); 75.
Tartaglino, L.M., Heiman-Patherson, T., Friedman, D.P. and Flanders, A.E. (1995) MR imaging in a case of postvaccination myelitis. Am J. Neuroradiol. 16, 581-582.
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 erythematosis and vaccination against hepatitis B (letter). Nephron. 62(2):236.
Vautier, G. and Carty, J.E. (1994) Acute sero-positive rheumatoid arthritis occurring after hepatitis vaccination. Brit. J. Rhematol. 33:991-998.
Waisbren, B.A. (1997) Patterns that evoke concern about 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 (c) 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 (c) 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 (c) 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 (c) 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 (c) 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 (c) 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 (c) 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 gerister (well, 2 of them have contacted me but have not yet filled out the reacton report forms), 2 of them developed chronic arthritis, 1 has polyneuritis...

9...I developed ME/CRFS, in March 1994, after a course of Hepatitis B vaccinations, which wre required for my work. Since, I have been too ill to work again and really believe that it was the vaccination that is to blame.

10...Until 1988 I was very health and worked in xxxxxxx Infirmary as a Senior Physiological Measurement Technician. In 19988 all staff in my department were given Hepatitis B vaccinations as we were seen to be at risk. I had three injections on 22.4.88, 20.5.88, and 14.10.88. During the last six months of the year I became aware of being extremely exhausted, constantly cold, feeling nauseous and sleeping excessively. I tried to carry on as normal thinking that I had just been overdoing things. I suffered from frequent colds, sore throats, headaches, teeth abscesses, boils, etc. Oftern my colleague at work would ask me if I felt okay because I looked very grey and unwell. By Christmas and New Year when I had some annual leave, I was going to bed at 11 PM and not waking up until 4 PM the following day. I returned to work after New Year not feeling rested at all.
In January 1989 I developed the wortst illness that I can remember since I had measles as a child. I had a terrible temperature, very bad headaches and felt nauseous constantly. I assumed it was flu, and returned to work after a week. As I continued to feel extremely unwell I had more time off sick, and returned to work after a week. As I continued to feel extremely unwell I had more time off sick and after returning yet again I went off sick again. I lost my job when I had been off sick for a year and at that point I consulted a trade union lawyer. After being examined by a consultant the lawyers received a medical report indicating that I was suffereing from a post viral fatigue syndrom and "the symptoms related to any viral infection are almost certainly not related to the Hepatitis B vaccination as there is no known association with illness of this type." However over the last few years there seem to ba a growing body of evidence to suggest that there is in fact a link. Although I have now got another job I still do not feel 100% recovered and I am still keen to pursue this, as this illness has a devastating effect on my life.

11...I am a qualified nurse and had recently moved to xxxxxxxx.. I joined the nurse bank in the local hospital and was required to ha ve a course of Hep B vaccinations.
My first vaccination was in 1990 around the autumn time and I remember being ill enough to be in bed for a week with what the doctor said was a flu-like virus. I recovered from that episode but was "put off" enough not to repeat the vaccinations and did not complete my course.
On acceptiving a new post within the same hospital in 1993 was advised to try again the vaccinations and did not complete my course.
My first was on 21.5.93 and I continued until 13th Jan. 1994. Following a blood test on 15.4.94 which showed a poor response, two boosters in 1994 followed. Folling another blood test in December 1994 I was told I was not immune to Hep B and was given instructions as to the procedure should I come into contact with Hep B via patients on needle-stick injury.
During this time I had had various periods of sick-time, with the doctors calling it post-viral syndroms after various tests proving negative. Last May, I went in desperation to a doctor in my practice whom I know from work and knew he was sympathetic. He looked back over my record and the varous test that had been unconclusive and diagnosed Fibromyalgia (M. E.) I continued to try and work but with episodes of sicktime becoming closer together I am now on long-term sick leave. Since my first diagnosis in May I have developed more symptoms of M.E. and am now exhausted and unable to do many of the activities I use to.

12...I am 33 years old and I use to work for social services (adults with learning difficulties). I was advised from work to have this vaccine.
I started my course of injections in May 1994. I became ill after having the second vaccine, feeling sick, hot and cold sweats. It just felt like I was comding down with flu. This passed after a couple of days. I had to take time off work. I didn't want to have the third injection, but they said I needed to complete the course. After a coupld of hours I was feeling ill again, it passed off within a couple of days.
I went back for some blood tests about four months later. The results came back and showed it hadn't worked. So was told I needed a booster, (which I had near end of 1994 and beginnig of 1995.) Within a couple of hours of having this injection I began to feel ill, feeling sick and diarrhea, hot and cold sweats feeling dizzy. Spent most of that day in bed thinking it would pass. When I tried to get up the next day it was worse. Pains in arms and legs, was sick, when I tried to get out of bed, my legs just wouldn't hold me, I felt like I was falling and spent the next few days in bed and had to take more time off work.
I went back to work and found doing my job very difficult. As I was getting tired very quickly I was always getting colds and couldn't shake them off and severe sore throats, swelling of the face and neck and then getting larangitis. I took medication which didn't help. It cleared for a few weeks and came back again the last time I had it, it lasted for 7 months. I had been off work for nearly a year.
I went back six weeks for blood tests i.e. Hep B. The results came back I had no natural immunity to the Hep B and was told to have another booster which would have been the fifth. I refused. I hate to think what this one would have done to me.
The tiredness was getting worse and walking quite difficult. So I went to my G.P. in 1995 June-July Why I was feeling like this he said, it was stress and wanted to put me on anti-depressants which I refused to take.
I keep going back to the doctor until he would do something about this. He did lots of tests but everything came back normal.
I went to see a specialist who said it was M.E. I told him about the Hep B but he just wouldn't accept this. In October 1996 I was retired on ill-health. I have been off work for over two years and have had M.D. for 3 years.
I developed M.E. after my third dose of the Hepatis B vaccine. My symptoms started after about ten days which included pins and needles and numbness in the lower limbs. Burning pains in the lower limbs. Strange pains popping all over the body and joing pains.

13...My particular encounter was with Hepatavax in 1987. Since that time, I have been plagued with exacerbation and remission of multiple and varried multiple scherosis-like symptoms. Not to give an "orphan recital" but because sometimes it is an encouragement to hear that you are not alone in your battle in the unknown territory of an unknown pathophysiology. I'll tell you the problems I've had with my version of our common "plague.>" (If this is not helpful for you,l skip to the next paragraph). The list that follows has expressed themselves in various combinations and various levels of severity over 10 years. The "flare-ups" I have, last from 2 to 4 months and are usually totally incapacitating. When they subside, I've been extrememly happy I have minimal residual problems and can resume my life and work with a few modifications.
The Proverbial list:
1. Extremem fatigue-weakness to point of prostration. Even breathing is a chore.
2. Sever let-burn, rt. sided nerve paint-esp. arm and leg.
3. Complete altered numb like feeling of entire rt. side of body, including head.
4. Hypersensitivitiy to stimuli on rt. side-hyper reflexia.
5. Occillopsia
6. Nystagmus
7.Professionally, my 7 years of education as an RN and BSN are now limited in their advantage, as I avoid fatigue, so cannot work full time and progress to high level nurse management positions. Also have had to make a career alteration as am unable to work 12 hour shifts.

14...I have been ooking for this kind of discussion about Hep. B. vaccine for about 2 years now. I would like to be able to tell you in length about the problems I have had since receiving this vaccine. I have lupus symptoms, I have never had a problem until I recieved the vacdine. I also work in the medical field and have for 12 years. I was very healthy and athletic before this vaccine. I have extremem joing pain, fatigue, rashes and a numerous amount of other symptoms right after the injection and some of the problems have remained. I have talked to VARES, no one seems to find a corralation between the vaccine and these symptoms. I would appreciate any information concerning treatments and these symptoms.

15...How much of a relatiohship is having the hep B vaccine and the hepatitis B vaccine and the progression of MS? I had the vaccine in 1994/95 and my MS has progressed rapidly since then. If my progression is due to the vaccine, can anything be done to reverse the affectgs o the vaccine? Would antiviral medication, such as famvir or aciclovir, be beneficial?

16...I am responding to the Perspective ME magazine...if they have a clear ut history of Hep B vaccination followed by ME/CFS" I believe I fite this description. Please contact me with more information.

17...My husband used to be an exyremely healthy man (ex-Forces) until he had the vaccine--I will fax you a brief history of his state of health. He was diagnosed "Rheumatoid Arthritis" although X-Rays haven't shown anything. We have been doing our own research locally and many people are experiencing problems. Two people we know have multiple sclerosis. My husband had the Energix B-Smith Kline Beecham product and their reaction was they only 10 reactions in 100,000 doses. We don't believe it. Without drugs my husband could not work-- he takes 2 Voltarol a day and 2g of sulphasalazine each day. He was a medical and dental engineer in the Royal Naval Hospital, but he has now had to accept a desk job at Andover. (40 miles from home). The journey is no help to him--he gets very fatigued, and has to go to bed at 9PM most evenings. He is in constant pain.

18...I began nurse training in August 1990 and was advised to have the course of 3 Hep B vaccinations. About 10 minutes after the first injection I collapsed and was unwell for 5 weeks. I had all M.E. like symptoms (exhaustion, muxcle pain, and fatigue, joint pain, co-ordination and balance problems, memor loss, etc). However, the hospital's Occupational Health department told me that no one was ever ill after the vaccnations.
After restarting training I was advised to finish the course of injections, and eventually had the second one in February 1 991. I didn't pass out, but started feeling light-headed within an hour. After 24 hours I developed balance problems, and soon all the sumprotms I's experienced after the first injection returned. I first had the possibility of having M.E. metnioned after 3 months. and had the diagnosis confirmed after 10 months, following various tests, examinations, etc. My employers were not sympathetic and I eventually had my employment terminated due to ill-health.
I have now been ill with M.E. for over 6.5 yrears with no real improvement, although one or two problems have been helped by homeopathic treatmetn. I am unable to work at all, and have to spend a lot of time resting.

19...I have a condition called "acute transverse myelitis" which hit me when I was 28 years old. I am nearly 32 y.o. now. Basically this condition is inflammation of the spinal cord. It is a very rare disease of the spinal cord--neurological disease, causing dehabiliting symptoms associated with the loss of spinal cord segment.
I had a Hep B vaccine - Sept. 1993 and was struck down June 17, 1994.

20...I myself a Midwife have had one Hepatitis B vaccination in January 1995 on which I took a bad reaction. I felt my arm cold and tingly at the injection site. I flushed up, I was aware of not being able to move the left side of my body, then I had an out of body experience. I heard every word of the staff who paniced at this point, and heard one nurse telling the other to locate the doctor who was at the shop for a pint of milk. I heard them discuss my breathing my muscular actitivy and lack of pulse. I heard them calling me back and felt myself jolt in the chair to which the doctor felt a pulse in my neck. I did not require Adrenaline by this stage. I was told by the staff never to come back to the department for more vaccines as I gave them such a fright and that I was lucky to be alive. I was sent homr unescorted, but the evening of the incident and the following morning I received calls from the department saying I had an anaphylactic reaction, then I was told I was like someone who had tetany. On the evening of the vaccine I felt very tired but due to the out of body experience I felt a sense of calmness.
The next morning my muscles were painful, I felt extremely tired, and I had pain in my sternum. After telephone conversation I realized the seriousness of the incident, especially when I was told the department did not hae a Brookes airway, and were too far away from the rest of the hospital to get help. They had redesigned the forms for the staff as there had been no spaces for next of kins and they had now ordered up a Brookes airway from the pharmacy and if I was a domestic or nursing auxillary she would not be telling me this.
Weeks after the incident, one nurse told me I was an actress and I should gain an Oscar for my performance. At this I was infuriated, I told my GP an I telephond my trade union representative for advice. The matter was taken to the suppodely investigated and found that there was indeed now adequate equipmen in the department. I did not take the case to a lawyer for fear of losing my job.
I have had several viral illnesses, flu like illnesses, muscular paings, tiredness, and general lethargy since this day.
I have no support fom the Occupational Healthy Department probably frightned of opening up the case due to litigation, no support from the Management as I am classed as a trouble maker as I approached the Union. Last October my symptoms came to a head. I wanted to sleep all the time, I felt very lethargic muscular pains, swollen glands, sore throat, and nauseatd. My GP took bloods which showed a significantly positive Monospot.
The Monospot test remained positive until February 1997. Since this time I have had poor mobility and the symptoms remain. My GP said I have got Post Viral Syndrome. I am attending a Consultant Physician who has done viral studies, which were negative and I have been sent for an MRI scan to eliminat M.S.
As I have ben off work for approximately one year, the Management are now in the process of terminating my contraction. As I am on long term sick and also a NON RESPONDER to Hepatitis B my future in Nursing and Midwifering has just about come to a close. I feel very isolated with my case and sad I did not receive adequate support from the Health Service.

20...I have worked as a Clinical Neuropsychologist for almost twenty years. During the last seven years I have resided in Florida and worked as a Clinical Physchologist for the Department of Health and Rehabilitative Services xxxxxxxxxxxxxxxxxxxxxx. On December 31, 1996, I received my first Hep B shot. On January 16, 1997 (more or less 2 weeks after) I developed my sumptoms. As I was driging towards work early in the morning I felt what could be best described as an electrical discharge running throughout the left side of my body, I experienced increased palpitations, chest pain, elevated blood pressure and a generalized state of anxiety. I drove myself to the emergency room of the hospital. They completed an EKG, and although my heart was responding "strangely" I was not having a heart attack. Following this I was rushed via ambulance to Tallahassee, they ran all possible tests and everything came out normal. During this whole time, I was experiencing difficulties breathing and swallowing. The doctors could not find anything wrong with me. I insisted there was something wrong, they tried to tell me I was "depressed". I insisted I was not, finally I went to a neurologist, to my request an MRI was completed. The results of the initial MRI indicated a demyelination process going on. but is was not consclusive. I had many but not the classical symptoms of MS. The neurologist acknoledge to me later that he thought I was just "depresssed" and that nothing would show in the MRI, those were his thoughts. He has not been able to explain why do have this difficulties in breathing and swallowing. They are persistant difficulties and now they also include fatigue, pain in the lower joints, as wll as pain in the whole body. Although I am being treateed as though I have "MS" the diagnosis is not conclusive. I am currently taking Avonex once per week (shot) and Baclofen PRN. Prior to this event, I have been a very healthy person. I have been very active and some people thought that I could be best described as hyperactive. I have had no major health problems. I have had no indications of neurological involvemet. In reality, I was okay until I had my first Hep B shot. What is my situation now, a battle against pain, fatigue and constant difficulties.

21...I am an American working in Pakistan with the United Nations. The 17 year old daughter of one of my staff has experienced a severe reatons to Hepatitisu B vaccination. Can you advice of instituteions, groups or individuals with specdial knowledtge or experience relevant to such a case?

22...My brother was a completely active (inexhaustible) and healthy male who had several advanced degress in science when he came to work in my laboratory. He had a mild reaction after the first injection of the Hepatitis B vaccine and a severe reaction which has progressed since a few days following the second leaving him with long term serious disabilities including extreme fatique short term memory loss, vision problems, severe joint and muscle pain, sensitivity to heat and cold, facial and skin rashes, and now POTS (postural othostatic tachachardia syndrome) which is a cardiovascular problem related to viral infections. He has been officially diagnosed by 5 doctors as having a serious reaction to the hepatitis B vaccine and has been completely unable to continue his formerly active lifestyle.

23...I have observed two students (one a per-medical student and one a medical student) who have had serious reactions to the hepatitis B vaccine. One received her first injection and was sick with "flu-like" symptoms for a week. Three weeks after the second boost she was diagnosed with multiple sclerosis or optic neuritis as she had lost most of the eye sight in one of her eyes. After a few months she recovered most her eyesight but was told she had to have the third booster to get into medical school. Three weeks following this booster she had a more serious reaction, resulting in hospitalization, and now has permanent eye sight damage. The other student has just finished his third injection which was given to him while he had an upper respiratory tract infection and had serious eye "inflammation". He is currently on steroid medication and under observation.

24...I am suffering from M.E. (Myaligic Encephalomyelitis) in a particular severe and disabling form. The onset was in 1974 following an acute fever, as a result of which I was physically disabled with muscle weakness and also mentally disabled with poor memory and concentration. I have managed reasonable well over the following 18 years but unfortunately I suffered a severe relapse in 1992 and 1994. This was due to the fact that I was first immunized in 1992 for Hepatitis B and again with a booster in 1994. I have only recently been diagnosed as suffering from M.E. and I have since discovered that this relapse from the vaccine is characteristic of the condition.