Reports of Adverse Reactions of Hepatitis B Vaccine
(Not including over 30,000 FDA Adverse Reactions Reports)
(Updated from NIH GRANT PROPOSAL).

Adverse Reaction/Diagnosis

Reference

Systemic "Lupoid hepatitis", lupus erythematosus Tudela and Bonal, 1992;
Mamoux and Dumont, 1994;
Guiserix, 1996;
Arthritis (polyarthritis, rheumatoid arthritis)   Rogerson and Nye, 1990;
Vautier and Carty; 1994;
Gross et al., 1995;
Pope et al., 1995;
Pope et al, 1997 (in preparation);
Biasi, 1987-1993;
Hassan and Oldham 1994;
Rheumatic Review, 1994;
Soubrier et al, 1997;
Vascular Disorders (vasculitis, polyarteritis, erythema nodosum, cryoglobulinemia, uveitis)   DiGuisto and Bernhard. (1986);
Fried et al, 1987;
Goolsby, 1989;
Cockwell et al., 1990;
Rogerson and Nye, 1990;
Mathieu et al., 1996;
Carmeli and De-Medina, 1993;
Mathieu and Krivitsky, 1996;
Graniel et al, 1997;
Guillain Barre Syndrome    Shaw et al., 1988;
Demyelinating disorders (optic neuritis, Bell's Palsy, demyelinating neouropathy, multiple sclerosis etc.) Ribera and Dukta, 1983;
Shaw et al., 1988;
Herroelen et al., 1991;
Nadler (1993);
Devin et al., 1996;
Dunbar et al., (unpublished observations);

Senejoux et al., 1996;
Baglivo et al., 1996;
Bonfils et al, 1996;
Manna et al., 1996;
Kaplanski et al., 1995;
Marsaudon and Barrault, 1996;
Berkman et al., 1996;
Waisbren, 1997;
W.H.O., 1990;
Brezin, et al, 1993;
Diabetes mellitus Poutasi, 1996;
Classen, 1996;
Chronic Fatigue Salit (1993);
Delage et al., 1993;
Other: Germanaus et al., 1995;
Noble et al., 1997;
Senejoux et al, 1996;
Macario et al, 1995;
Biron et al, 1988; l
Trevisani et al, 1993;
Tartaglino et al, 1995

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 hepatitis 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 () 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 and hepatitis B virology 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:

1. 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


2. 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:

1. Using immunohistochemistry to identify cell types to which autoantibodies are directed (if clinical data is not already available);



2. Using immunoprecipitation and immunoblot analysis with one and two-dimensional PAGE methods to identify antibodies which recognize human proteins; and



3. 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:

1. Evaluate the potential for molecular mimicry as a mechanism for the development of autoimmune disorders:



2. 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 sub-clinical 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:

1. pleomorphic spheres (20 nm diameter);


2. filaments of variable length (approx. 20 nm diameter); and


3. spherical double-shelled particles (approx. 42 nm 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

1. the hepatitis B virus,


2. the plasma-derived vaccine, and


3. 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 auto-reactive 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:

1. the generation of the appropriate fragment;


2. the presence of an MHC molecule that binds this fragment; and


3. 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.

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