EPIDEMIOLOGIC REPORTS * ETUDES EPIDEMIOLOGIQUES
Adverse
events after hepatitis B vaccination
P ostmarketing surveillance of adverse events after any vaccination is important to estimate the rate of occurrence of such events and to identify previously undescribed events. This permits policymakers and health care providers to improve existing vaccination recommendations and to take appropriate measures, when necessary, to reduce the incidence of adverse events. Moreover, this information may assist potential vaccine recipients to make informed decisions about vaccination. In Canada postmarketing surveillance of adverse events temporally associated with the administration of vaccines is the responsibility of the federal government's Bureau of Communicable Disease Epidemiology (BCDE), Laboratory Centre for Disease Control (LCDC), Ottawa. The main source of information on such events is voluntary reporting by health care providers to provincial or territorial authorities. (Ontario is the only province in which reporting is mandatory.) These data, in addition to information from manufacturers and other agencies, are forwarded to the BCDE. Usually there is no definite evidence to support a causal link between the administration of a vaccine and an adverse event. Consequently the reporting system is guided by criteria' based primarily on temporal associations between the specific vaccine and the adverse event and on the exclusion of other identifiable causes or antecedent factors. The inclusion criteria for the LCDC surveillance system have been well defined.' Two hepatitis B vaccines, Recombivax HB and Engerix-B, are currently licensed for use in Canada; both are yeast-derived recombinant DNA vaccines. The manufacture and distribution of Heptavax-B, a plasma-derived vaccine originally licensed for use in
Canada, ceased in 1989; however, lots distributed in 1989 continued to be used in 1990. Public interest in the safety of hepatitis B vaccination was heightened recently by recommendations of the National Advisory Committee on Immunization for universal vaccination2 and by media reports of an alleged link between hepatitis B vaccine and chronic fatigue syndrome. The BCDE found no epidemiologic evidence of an association between the vaccine and this syndrome.3 This paper summarizes BCDE data on the incidence of adverse events after hepatitis B vaccination and reviews selected published reports on the safety of the vaccines. Like the BCDE investigation a review of the literature revealed no evidence of a link between the administration of hepatitis B vaccine and chronic fatigue syndrome. In 1989 the rate of adverse events after hepatitis B vaccination reported to the BCDE was 27.7 per 100 000 doses distributed. In 1990 the rate was 20.7, and the last available rate for 1991 was 13.5. (Data for 1991 may be incomplete because of a varying lag time between an adverse event and receipt of a report.) Table I shows the number of adverse events in Canada in 1989 and 1990. The review of the literature on the postmarketing surveillance of Engerix-B administration uncovered an overall rate of 1 adverse event per 15 500 doses distributed. However, local reactions were reported to be the only events unequivocally related to the vaccine (at a rate of 1 in 85 000 doses).4 The US Centers for Disease Control (CDC), Atlanta, received reports of "vaccine-associated" illness in 118 of more than 200 000 vaccinees during a 2-year postlicensure surveillance of reactions to Heptavax-B.s Of those 118 events 56 were considered
Based on material previously reported in Canada Communicable Disease Report (a publication of the Bureau of Communicable Disease Epidemiology, Laboratory Centre for Disease Control [LCDC], Department ofNational Health and Welfare, Ottawa, Ont.) (1992; 18: 49-53) by Adwoa Bentsi-Enchill, MB, ChB, University ofOttawa and the Childhood Immunization Division, Bureau of Communicable Disease Epidemiology, LCDC. Publication in CMAJ is with permission of the author and the bureau. Reprint requests to: Dr. Philippe Duclos,
Chief, Childhood Immunization Division, Bureau of Communicable Disease Epidemiology,
Laboratory Centre for Disease Control, Tunney's Pasture, Ottawa, ON KJA OL2 OCTOBER 1, 1992
CAN MED ASSOC J 1992; 147 (7)
1023
not likely to be attributable to the vaccine, and the other 62 were described as possibly background illnesses rather than adverse reactions. In several reports the adverse events were mild or moderate only.4'6-'0 The most consistently reported local reactions were pain, swelling or induration, and erythema. General reactions included fever, malaise, fatigue or lethargy, nausea and vomiting. Other mild events, reported less frequently, included irritability, diarrhea, rash, lymphadenopathy and joint pain.8,9 l -13 The actual reported incidence rates of adverse events varied considerably (e.g., from 0.08% to 23% for pain) and generally appeared to be associated with the number of vaccine doses received or the number of vaccinees, as well as the extent to which passive reports of adverse events were investigated. The high overall rate of adverse events in one prospective study (44.7% among people given Recombivax HB and 32.0% among those given Engerix-B) was attributed to a reporting bias (the vaccinees were all health care personnel) and the rigour of instructions for reporting.7 Andre4 found that when parents reported adverse events for their infants and children vaccinated with Engerix-B the rates were lower (6% and 13% respectively) than when adults reported events for themselves (50%) in the same series. Hypersensitivity to yeast has been cited as a contraindication to yeast-derived vaccines. '4However, in one report on Engerix-B "no proven yeast
hypersensitivity reactions . . . and no significant changes in specific anti-yeast antibodies were detected after vaccination."4 In a prospective study of this vaccine one recipient had severe acute urticaria followed by psoriasis 10 days after a second dose was given; however, a similar episode had occurred several years earlier, after the patient had measles."' In a comparative study of Recombivax HB and Engerix-B a patient with no history of allergies reportedly had an urticarial reaction to a first dose of Engerix-B.'5 As for plasma-derived vaccines, the CDC,6 during a 5-year postlicensure surveillance of adverse events after vaccination with Heptavax-B, noted no reports of allergic reactions or reactions that could be related to the titres of antibodies to yeast-derived antigens during clinical trials, although yeast-derived protein constitutes up to 4% of the protein in the vaccine. An incidence rate of 1 hypersensitivity reaction per 1000 children was reported during a mass vaccination program involving 166 757 children in New Zealand;9 the types of hepatitis B vaccine were not identified. Another component of hepatitis B vaccine, thimerosal, has been implicated in hypersensitivity reactions. Kirkland'6 reported no significant reactions in 9 of 462 vaccinees who had a history of hypersensitivity to thimerosal in contact-lens solutions. However, there have been case reports of confirmed hypersensitivity reactions to thimerosal after hepatitis B vaccination.'7",8 In addition, Cosnes,
-ct:. ;.vr j
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a 1)o r a t :. e
.:-ngerix.;s anc Heura'..-;. a !C : a c.
letlrIIYtI(
1024
:-
2-.i.
CAN MED ASSOC J 1992; 147 (7)
LE erOCTOBRE 1992
Flechet and Revuz'9 described two cases of persistent pruritic nodules at the vaccination site that represented delayed hypersensitivity reactions to aluminum salts in a plasma-derived vaccine (Hevac B). Allergy was confirmed by a series of patch tests; 100 control subjects had negative results. In a nonrandomized study involving 39 subjects a visible cutaneous macule larger than 1 cm2 was reported in all subjects within 24 hours after the second intradermal dose of Engerix-B.20 Subsequent doses resulted in larger macules and another macule at the previous injection site. Neurologic adverse reactions are not widely reported in the literature, and in none of the reported instances was a causal link to hepatitis B vaccination established. Shaw and associates2' conducted an extensive analysis of neurologic disorders after vaccination with Heptavax-B reported from 1982 to 1985 to the CDC. Only Guillain-Barre syndrome (GBS) was reported significantly more often than expected (p < 0.05). Conditions reported included convulsions, Bell's palsy, lumbar radiculopathy, brachial plexus neuropathy, optic neuritis and transverse myelitis. The analysis was limited by problems in estimating background rates of disease and validating some diagnoses. In the New Zealand program9 both GBS and nonfebrile convulsions occurred significantly more often than expected (p < 0.05). Other neurologic disorders reported after vaccination with plasma-derived vaccines include myasthenia gravis22 and inflammatory polyneuropathy.23 Data from the CDC surveillance system give no evidence of an association between yeast-derived vaccines and GBS;24 however, at least one case of this association has been documented.25 Other adverse events reported after vaccination with yeastderived vaccines include optic neuritis,25 demyelination of the central nervous system,26 vertigo with diplopia and evidence of demyelination,27 erythema multiforme with no history of this condition,28 cellulitis,'3 and headache and tightness of the chest for 24 to 72 hours.'3 The incidence of both local and general reactions reportedly decreases with successive vaccinations.4'2'3,2930 Bryan and collaborators3' reported an increasing incidence of local reactions with each dose. In a number of studies the overall and specific rates of reactions were found not to differ between the types of vaccine;7"'112 however, no statistical analyses were mentioned. This review of adverse events temporally related to hepatitis B vaccination has revealed a low incidence rate of severe reactions, no definite evidence of causation and no known reports of permanent disability or death. Although local and mild systemic events may be common they should not cause great OCTOBER 1, 1992
concern, because they are often temporary and resolve spontaneously. The occurrence of adverse events should be considered in context: approximately 3000 cases of hepatitis B are reported in Canada annually, and global estimates show that 6% to 10% of the adults and 50% to 90% of the infants become chronic carriers of the virus and are at high risk of cirrhosis and liver damage.32 Preventing illness and death through vaccination far outweighs the low risk of severe adverse reactions. LCDC will continue to monitor adverse events after hepatitis B vaccination and to publish regular reports on the topic. Any adverse events after receipt of vaccines should be reported to local health authorities. For more information on this reporting system contact the Childhood Immunization Division, Bureau of Communicable Disease Epidemiology, Laboratory Centre for Disease Control, Tunney's Pasture, Ottawa, ON KIA OL2; (613) 957-1340, fax (613) 998-6413. The help of all provincial and territorial epidemiologists and others who provided the data was greatly appreciated.
References 1. Adverse events temporally associated with immunizing agents -1987 report. Can Dis Wkly Rep 1989; 15: 151-157 2. Statement on universal immunization against hepatitis B. Can Dis Wkly Rep 1991; 17: 165 3. Alleged link between hepatitis B vaccine and chronic fatigue
syndrome. Ibid: 215-216 4. Andre FE: Overview of a 5-year clinical experience with a yeast-derived hepatitis B vaccine. Vaccine 1990; 8: 574-578 5. The safety of hepatitis B virus vaccine. MMWR 1983; 32: 134-136 6. Update on hepatitis B prevention. MMWR 1987; 36: 353360 7. Dahl-Hansen E, Siebke JC, Froland SS et al: Immunogenicity of yeast-derived hepatitis B vaccine from two different producers. Epidemiol Infect 1990; 104: 143-149 8. Delage G, Remy-Prince S, Ducic S et al: Combined passiveactive immunization against the hepatitis B virus of 132 newborns of chronic carrier mothers: long-term results. Pe-
diatr Infect Dis J 1988; 7: 769-776
9. Hepatitis-B vaccine: adverse effects (New Zealand). Pharm Newsl 1990; 9: 9 10. Polakoff S, Vandervelde EM: Immunisation of neonates at high risk of hepatitis B in England and Wales: national
surveillance. BMJ 1988; 297: 249-253
11. Phanuphak P, Phanpanich T, Wongurai S et al: Comparative immunogenicity study of four plasma-derived hepatitis B
vaccines in Thai young adults. Vaccine 1989; 7: 253-256
12. Yeoh EK, Lai CL, Lo HY: Comparison of the immunogenicity, efficacy and safety of 10 jig and 20 ,ug of a hepatitis B vaccine: a prospective randomized trial. J Hyg (Lond) 1986;
96: 491-499
13. Morris CA, Oliver PR, Reynolds F et al: Intradermal hepatitis B immunisation with yeast-derived vaccine: serological
response by sex and age. Epidemiol Infect 1989; 103: 387-394
14. Cottone J: Recent developments in hepatitis: new virus, vaccine and dosage recommendations. JAMA 1990; 120: 501-
508
15. Hammond GW, Parker J, Mimms L et al: Comparison of CAN MED ASSOC J 1992; 147 (7)
1025
16. 17.
18.
19. 20.
21.
22.
23. 24.
immunogenicity of two yeast-derived recombinant hepatitis B vaccines. Vaccine 1991; 9: 97-100 Kirkland L: Ocular sensitivity to thimerosal: A problem with hepatitis B vaccine? South MedJ 1990; 83: 497-499 Noel I, Galloway A, Ive FA: Hypersensitivity to thiomersal in hepatitis B vaccine [C]. Lancet 1991; 338: 705 Rietschel RL, Adams RM: Reactions to thimerosal in hepatitis B vaccines. Dermatol Clin 1990; 8: 161-164 Cosnes A, Flechet ML, Revuz J: Inflammatory nodular reactions after hepatitis B vaccination due to aluminium sensitization. Contact Dermatitis 1990; 23: 65-67 Leonardi S, Leggio T, Barone P et al: Immune response of subjects at high risk of hepatitis B to a new genetically engineered hepatitis B vaccine administered in low doses by the intradermal route. Acta Paediatr Jpn 1990; 32: 361-364 Shaw FE, Graham DJ, Guess HA et al: Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Am J Epidemiol 1988; 127: 337-352 Biron P, Montpetit P, Infante-Rivard C et al: Myasthenia gravis after general anesthesia and hepatitis B vaccine. Arch Intern Med 1988; 148: 2685 Ribera EF, Dutka AJ: Polyneuropathy associated with administration of hepatitis B vaccine [C]. N Engl J Med 1983; 309: 614-6 15 Recommendations of the Immunization Practices Advisory
Conferences
25. 26. 27. 28. 29.
30.
31. 32.
Committee (ACIP): Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood immunization. MMWR 1991; 40: 1-19 Hepatitis B vaccines: reported reactions. WHO Drug Inf 1990; 4: 129 Herroelen L, de Keyser J, Ebinger G: Central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine. Lancet 1991; 338: 1174-1175 Australian Adverse Drug Reactions Advisory Committee: Reactions to hepatitis B vaccines. Austr Adverse Drug React Bull 1990; Aug Feldshon SD, Sampliner RE: Reaction to hepatitis B virus vaccine [C]. Ann Intern Med 1984; 100: 156-157 Heyward WL, Bender TR, McMahon BJ et al: The control of hepatitis B virus infection in Yupik Eskimos: demonstration of safety, immunogenicity, and efficacy under field conditions. Am JEpidemiol 1985; 121: 914-923 Szmuness W, Stevens CE, Harley EJ et al: Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980; 303: 833-841 Bryan JP, Sjogren M, Iqbal M et al: Comparative trial of low-dose, intradermal, recombinant- and plasma-derived hepatitis B vaccine. J Immunol 1990; 145: 2281-2285 The ABCs of viral hepatitis. Health News 1991; 9 (I): 3-6
Dec. 4-6, 1992: BCAS-WSSA Joint Annual Meeting (sponsored by the British Columbia Anaesthetists' Society and the Washington State Society of Anesthetists) Four Seasons Hotel, Vancouver Ms. Diane Wong, coordinator, BC Anaesthetists' Society, 114-1665 W Broadway, Vancouver, BC V6J 5A4; (604) 736-5551, ext. 243, fax (604) 736-2630
Jan. 10-15, 1993: World Congress on Tourist Medicine and Health (organized by the National University of Singapore, the Ministry of the Environment, Singapore, the Singapore Convention Bureau and the World Health Organization Collaborating Centre for Tourist Health and Tourist Medicine) Mandarin Hotel, Singapore Secretariat, World Congress on Tourist Medicine and Health, 336 Smith St., No. 06-302, New Bridge Centre, Singapore 0105, Republic of Singapore; telephone 011 65-227-9811, fax 011-65-227-0257
Dec. 5-11, 1992: International Conference on Nutrition (organized by the Food and Agriculture Organization [FAO] of the United Nations and the World Health Organization [WHO]) Rome FAO/WHO Joint Secretariat for the Conference, Viale delle Terme di Caracalla, 00100 Rome, Italy; telephone
Jan. 18-23, 1993: Free Radicals in Biology and Medicine (organized by the Free Radical Club CERLIB) Les Deux Alpes, France Mrs. Arlette Alcaraz, Laboratoire Biochimie C (Pr Favier), CHRUG 38700, La Tronche, France; telephone 01133-767-65754, fax 011-33-764-26664
continued from page 1020
011-39-6-5797-3097, fax 011-39-6-5797-6661 Dec. 9-13, 1992: American Back Society 10th Anniversary Meeting - The Industrial Back (in association with the Saint Francis Spine Center) Hyatt Regency Embarcadero Hotel, San Francisco Dr. Aubrey A. Swartz, executive director, American Back Society, 401-2647 E 14th St., Oakland, CA 94601; (510) 536-9929, fax (510) 536-1812 Dec. 17, 1992: Beyond Survival - Caring for Ourselves (part 9 of 9 in the Women Healing from Childhood Trauma Workshop Series) Feminist Therapies Services, 344 Dupont St., Toronto Registration coordinator, Community Resources and Initiatives, 106-344 Dupont St., Toronto, ON MSR 1V9; (416) 924-8998, fax (416) 924-8352 1026
CAN MED ASSOC J 1992; 147 (7)
Jan. 26-30, 1993: Human Rights, Mental Health and Therapy in a Radically Changing World (sponsored by the Calgary General Hospital and the World Health Organization, in collaboration with the World Psychiatric Association, the International Academy of Law and Mental Health, the International Council of Prison Medical Services, the Canadian Psychiatric Association and the University of Calgary) Banff, Alta. Dr. J. Arboleda-Florez, chair, Organizing Committee, or Heather Holley, chair, Local Arrangements, Calgary General Hospital, 841 Centre Ave. NE, Calgary, AB T2E OA1; (403) 268-9203, fax (403) 268-9201
continued on page 1030 LE 1 er OCTOBRE 1992
Adverse
events after hepatitis B vaccination
P ostmarketing surveillance of adverse events after any vaccination is important to estimate the rate of occurrence of such events and to identify previously undescribed events. This permits policymakers and health care providers to improve existing vaccination recommendations and to take appropriate measures, when necessary, to reduce the incidence of adverse events. Moreover, this information may assist potential vaccine recipients to make informed decisions about vaccination. In Canada postmarketing surveillance of adverse events temporally associated with the administration of vaccines is the responsibility of the federal government's Bureau of Communicable Disease Epidemiology (BCDE), Laboratory Centre for Disease Control (LCDC), Ottawa. The main source of information on such events is voluntary reporting by health care providers to provincial or territorial authorities. (Ontario is the only province in which reporting is mandatory.) These data, in addition to information from manufacturers and other agencies, are forwarded to the BCDE. Usually there is no definite evidence to support a causal link between the administration of a vaccine and an adverse event. Consequently the reporting system is guided by criteria' based primarily on temporal associations between the specific vaccine and the adverse event and on the exclusion of other identifiable causes or antecedent factors. The inclusion criteria for the LCDC surveillance system have been well defined.' Two hepatitis B vaccines, Recombivax HB and Engerix-B, are currently licensed for use in Canada; both are yeast-derived recombinant DNA vaccines. The manufacture and distribution of Heptavax-B, a plasma-derived vaccine originally licensed for use in
Canada, ceased in 1989; however, lots distributed in 1989 continued to be used in 1990. Public interest in the safety of hepatitis B vaccination was heightened recently by recommendations of the National Advisory Committee on Immunization for universal vaccination2 and by media reports of an alleged link between hepatitis B vaccine and chronic fatigue syndrome. The BCDE found no epidemiologic evidence of an association between the vaccine and this syndrome.3 This paper summarizes BCDE data on the incidence of adverse events after hepatitis B vaccination and reviews selected published reports on the safety of the vaccines. Like the BCDE investigation a review of the literature revealed no evidence of a link between the administration of hepatitis B vaccine and chronic fatigue syndrome. In 1989 the rate of adverse events after hepatitis B vaccination reported to the BCDE was 27.7 per 100 000 doses distributed. In 1990 the rate was 20.7, and the last available rate for 1991 was 13.5. (Data for 1991 may be incomplete because of a varying lag time between an adverse event and receipt of a report.) Table I shows the number of adverse events in Canada in 1989 and 1990. The review of the literature on the postmarketing surveillance of Engerix-B administration uncovered an overall rate of 1 adverse event per 15 500 doses distributed. However, local reactions were reported to be the only events unequivocally related to the vaccine (at a rate of 1 in 85 000 doses).4 The US Centers for Disease Control (CDC), Atlanta, received reports of "vaccine-associated" illness in 118 of more than 200 000 vaccinees during a 2-year postlicensure surveillance of reactions to Heptavax-B.s Of those 118 events 56 were considered
Based on material previously reported in Canada Communicable Disease Report (a publication of the Bureau of Communicable Disease Epidemiology, Laboratory Centre for Disease Control [LCDC], Department ofNational Health and Welfare, Ottawa, Ont.) (1992; 18: 49-53) by Adwoa Bentsi-Enchill, MB, ChB, University ofOttawa and the Childhood Immunization Division, Bureau of Communicable Disease Epidemiology, LCDC. Publication in CMAJ is with permission of the author and the bureau. Reprint requests to: Dr. Philippe Duclos,
Chief, Childhood Immunization Division, Bureau of Communicable Disease Epidemiology,
Laboratory Centre for Disease Control, Tunney's Pasture, Ottawa, ON KJA OL2 OCTOBER 1, 1992
CAN MED ASSOC J 1992; 147 (7)
1023
not likely to be attributable to the vaccine, and the other 62 were described as possibly background illnesses rather than adverse reactions. In several reports the adverse events were mild or moderate only.4'6-'0 The most consistently reported local reactions were pain, swelling or induration, and erythema. General reactions included fever, malaise, fatigue or lethargy, nausea and vomiting. Other mild events, reported less frequently, included irritability, diarrhea, rash, lymphadenopathy and joint pain.8,9 l -13 The actual reported incidence rates of adverse events varied considerably (e.g., from 0.08% to 23% for pain) and generally appeared to be associated with the number of vaccine doses received or the number of vaccinees, as well as the extent to which passive reports of adverse events were investigated. The high overall rate of adverse events in one prospective study (44.7% among people given Recombivax HB and 32.0% among those given Engerix-B) was attributed to a reporting bias (the vaccinees were all health care personnel) and the rigour of instructions for reporting.7 Andre4 found that when parents reported adverse events for their infants and children vaccinated with Engerix-B the rates were lower (6% and 13% respectively) than when adults reported events for themselves (50%) in the same series. Hypersensitivity to yeast has been cited as a contraindication to yeast-derived vaccines. '4However, in one report on Engerix-B "no proven yeast
hypersensitivity reactions . . . and no significant changes in specific anti-yeast antibodies were detected after vaccination."4 In a prospective study of this vaccine one recipient had severe acute urticaria followed by psoriasis 10 days after a second dose was given; however, a similar episode had occurred several years earlier, after the patient had measles."' In a comparative study of Recombivax HB and Engerix-B a patient with no history of allergies reportedly had an urticarial reaction to a first dose of Engerix-B.'5 As for plasma-derived vaccines, the CDC,6 during a 5-year postlicensure surveillance of adverse events after vaccination with Heptavax-B, noted no reports of allergic reactions or reactions that could be related to the titres of antibodies to yeast-derived antigens during clinical trials, although yeast-derived protein constitutes up to 4% of the protein in the vaccine. An incidence rate of 1 hypersensitivity reaction per 1000 children was reported during a mass vaccination program involving 166 757 children in New Zealand;9 the types of hepatitis B vaccine were not identified. Another component of hepatitis B vaccine, thimerosal, has been implicated in hypersensitivity reactions. Kirkland'6 reported no significant reactions in 9 of 462 vaccinees who had a history of hypersensitivity to thimerosal in contact-lens solutions. However, there have been case reports of confirmed hypersensitivity reactions to thimerosal after hepatitis B vaccination.'7",8 In addition, Cosnes,
-ct:. ;.vr j
*-~ v P , - t;
a 1)o r a t :. e
.:-ngerix.;s anc Heura'..-;. a !C : a c.
letlrIIYtI(
1024
:-
2-.i.
CAN MED ASSOC J 1992; 147 (7)
LE erOCTOBRE 1992
Flechet and Revuz'9 described two cases of persistent pruritic nodules at the vaccination site that represented delayed hypersensitivity reactions to aluminum salts in a plasma-derived vaccine (Hevac B). Allergy was confirmed by a series of patch tests; 100 control subjects had negative results. In a nonrandomized study involving 39 subjects a visible cutaneous macule larger than 1 cm2 was reported in all subjects within 24 hours after the second intradermal dose of Engerix-B.20 Subsequent doses resulted in larger macules and another macule at the previous injection site. Neurologic adverse reactions are not widely reported in the literature, and in none of the reported instances was a causal link to hepatitis B vaccination established. Shaw and associates2' conducted an extensive analysis of neurologic disorders after vaccination with Heptavax-B reported from 1982 to 1985 to the CDC. Only Guillain-Barre syndrome (GBS) was reported significantly more often than expected (p < 0.05). Conditions reported included convulsions, Bell's palsy, lumbar radiculopathy, brachial plexus neuropathy, optic neuritis and transverse myelitis. The analysis was limited by problems in estimating background rates of disease and validating some diagnoses. In the New Zealand program9 both GBS and nonfebrile convulsions occurred significantly more often than expected (p < 0.05). Other neurologic disorders reported after vaccination with plasma-derived vaccines include myasthenia gravis22 and inflammatory polyneuropathy.23 Data from the CDC surveillance system give no evidence of an association between yeast-derived vaccines and GBS;24 however, at least one case of this association has been documented.25 Other adverse events reported after vaccination with yeastderived vaccines include optic neuritis,25 demyelination of the central nervous system,26 vertigo with diplopia and evidence of demyelination,27 erythema multiforme with no history of this condition,28 cellulitis,'3 and headache and tightness of the chest for 24 to 72 hours.'3 The incidence of both local and general reactions reportedly decreases with successive vaccinations.4'2'3,2930 Bryan and collaborators3' reported an increasing incidence of local reactions with each dose. In a number of studies the overall and specific rates of reactions were found not to differ between the types of vaccine;7"'112 however, no statistical analyses were mentioned. This review of adverse events temporally related to hepatitis B vaccination has revealed a low incidence rate of severe reactions, no definite evidence of causation and no known reports of permanent disability or death. Although local and mild systemic events may be common they should not cause great OCTOBER 1, 1992
concern, because they are often temporary and resolve spontaneously. The occurrence of adverse events should be considered in context: approximately 3000 cases of hepatitis B are reported in Canada annually, and global estimates show that 6% to 10% of the adults and 50% to 90% of the infants become chronic carriers of the virus and are at high risk of cirrhosis and liver damage.32 Preventing illness and death through vaccination far outweighs the low risk of severe adverse reactions. LCDC will continue to monitor adverse events after hepatitis B vaccination and to publish regular reports on the topic. Any adverse events after receipt of vaccines should be reported to local health authorities. For more information on this reporting system contact the Childhood Immunization Division, Bureau of Communicable Disease Epidemiology, Laboratory Centre for Disease Control, Tunney's Pasture, Ottawa, ON KIA OL2; (613) 957-1340, fax (613) 998-6413. The help of all provincial and territorial epidemiologists and others who provided the data was greatly appreciated.
References 1. Adverse events temporally associated with immunizing agents -1987 report. Can Dis Wkly Rep 1989; 15: 151-157 2. Statement on universal immunization against hepatitis B. Can Dis Wkly Rep 1991; 17: 165 3. Alleged link between hepatitis B vaccine and chronic fatigue
syndrome. Ibid: 215-216 4. Andre FE: Overview of a 5-year clinical experience with a yeast-derived hepatitis B vaccine. Vaccine 1990; 8: 574-578 5. The safety of hepatitis B virus vaccine. MMWR 1983; 32: 134-136 6. Update on hepatitis B prevention. MMWR 1987; 36: 353360 7. Dahl-Hansen E, Siebke JC, Froland SS et al: Immunogenicity of yeast-derived hepatitis B vaccine from two different producers. Epidemiol Infect 1990; 104: 143-149 8. Delage G, Remy-Prince S, Ducic S et al: Combined passiveactive immunization against the hepatitis B virus of 132 newborns of chronic carrier mothers: long-term results. Pe-
diatr Infect Dis J 1988; 7: 769-776
9. Hepatitis-B vaccine: adverse effects (New Zealand). Pharm Newsl 1990; 9: 9 10. Polakoff S, Vandervelde EM: Immunisation of neonates at high risk of hepatitis B in England and Wales: national
surveillance. BMJ 1988; 297: 249-253
11. Phanuphak P, Phanpanich T, Wongurai S et al: Comparative immunogenicity study of four plasma-derived hepatitis B
vaccines in Thai young adults. Vaccine 1989; 7: 253-256
12. Yeoh EK, Lai CL, Lo HY: Comparison of the immunogenicity, efficacy and safety of 10 jig and 20 ,ug of a hepatitis B vaccine: a prospective randomized trial. J Hyg (Lond) 1986;
96: 491-499
13. Morris CA, Oliver PR, Reynolds F et al: Intradermal hepatitis B immunisation with yeast-derived vaccine: serological
response by sex and age. Epidemiol Infect 1989; 103: 387-394
14. Cottone J: Recent developments in hepatitis: new virus, vaccine and dosage recommendations. JAMA 1990; 120: 501-
508
15. Hammond GW, Parker J, Mimms L et al: Comparison of CAN MED ASSOC J 1992; 147 (7)
1025
16. 17.
18.
19. 20.
21.
22.
23. 24.
immunogenicity of two yeast-derived recombinant hepatitis B vaccines. Vaccine 1991; 9: 97-100 Kirkland L: Ocular sensitivity to thimerosal: A problem with hepatitis B vaccine? South MedJ 1990; 83: 497-499 Noel I, Galloway A, Ive FA: Hypersensitivity to thiomersal in hepatitis B vaccine [C]. Lancet 1991; 338: 705 Rietschel RL, Adams RM: Reactions to thimerosal in hepatitis B vaccines. Dermatol Clin 1990; 8: 161-164 Cosnes A, Flechet ML, Revuz J: Inflammatory nodular reactions after hepatitis B vaccination due to aluminium sensitization. Contact Dermatitis 1990; 23: 65-67 Leonardi S, Leggio T, Barone P et al: Immune response of subjects at high risk of hepatitis B to a new genetically engineered hepatitis B vaccine administered in low doses by the intradermal route. Acta Paediatr Jpn 1990; 32: 361-364 Shaw FE, Graham DJ, Guess HA et al: Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Am J Epidemiol 1988; 127: 337-352 Biron P, Montpetit P, Infante-Rivard C et al: Myasthenia gravis after general anesthesia and hepatitis B vaccine. Arch Intern Med 1988; 148: 2685 Ribera EF, Dutka AJ: Polyneuropathy associated with administration of hepatitis B vaccine [C]. N Engl J Med 1983; 309: 614-6 15 Recommendations of the Immunization Practices Advisory
Conferences
25. 26. 27. 28. 29.
30.
31. 32.
Committee (ACIP): Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood immunization. MMWR 1991; 40: 1-19 Hepatitis B vaccines: reported reactions. WHO Drug Inf 1990; 4: 129 Herroelen L, de Keyser J, Ebinger G: Central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine. Lancet 1991; 338: 1174-1175 Australian Adverse Drug Reactions Advisory Committee: Reactions to hepatitis B vaccines. Austr Adverse Drug React Bull 1990; Aug Feldshon SD, Sampliner RE: Reaction to hepatitis B virus vaccine [C]. Ann Intern Med 1984; 100: 156-157 Heyward WL, Bender TR, McMahon BJ et al: The control of hepatitis B virus infection in Yupik Eskimos: demonstration of safety, immunogenicity, and efficacy under field conditions. Am JEpidemiol 1985; 121: 914-923 Szmuness W, Stevens CE, Harley EJ et al: Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 1980; 303: 833-841 Bryan JP, Sjogren M, Iqbal M et al: Comparative trial of low-dose, intradermal, recombinant- and plasma-derived hepatitis B vaccine. J Immunol 1990; 145: 2281-2285 The ABCs of viral hepatitis. Health News 1991; 9 (I): 3-6
Dec. 4-6, 1992: BCAS-WSSA Joint Annual Meeting (sponsored by the British Columbia Anaesthetists' Society and the Washington State Society of Anesthetists) Four Seasons Hotel, Vancouver Ms. Diane Wong, coordinator, BC Anaesthetists' Society, 114-1665 W Broadway, Vancouver, BC V6J 5A4; (604) 736-5551, ext. 243, fax (604) 736-2630
Jan. 10-15, 1993: World Congress on Tourist Medicine and Health (organized by the National University of Singapore, the Ministry of the Environment, Singapore, the Singapore Convention Bureau and the World Health Organization Collaborating Centre for Tourist Health and Tourist Medicine) Mandarin Hotel, Singapore Secretariat, World Congress on Tourist Medicine and Health, 336 Smith St., No. 06-302, New Bridge Centre, Singapore 0105, Republic of Singapore; telephone 011 65-227-9811, fax 011-65-227-0257
Dec. 5-11, 1992: International Conference on Nutrition (organized by the Food and Agriculture Organization [FAO] of the United Nations and the World Health Organization [WHO]) Rome FAO/WHO Joint Secretariat for the Conference, Viale delle Terme di Caracalla, 00100 Rome, Italy; telephone
Jan. 18-23, 1993: Free Radicals in Biology and Medicine (organized by the Free Radical Club CERLIB) Les Deux Alpes, France Mrs. Arlette Alcaraz, Laboratoire Biochimie C (Pr Favier), CHRUG 38700, La Tronche, France; telephone 01133-767-65754, fax 011-33-764-26664
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011-39-6-5797-3097, fax 011-39-6-5797-6661 Dec. 9-13, 1992: American Back Society 10th Anniversary Meeting - The Industrial Back (in association with the Saint Francis Spine Center) Hyatt Regency Embarcadero Hotel, San Francisco Dr. Aubrey A. Swartz, executive director, American Back Society, 401-2647 E 14th St., Oakland, CA 94601; (510) 536-9929, fax (510) 536-1812 Dec. 17, 1992: Beyond Survival - Caring for Ourselves (part 9 of 9 in the Women Healing from Childhood Trauma Workshop Series) Feminist Therapies Services, 344 Dupont St., Toronto Registration coordinator, Community Resources and Initiatives, 106-344 Dupont St., Toronto, ON MSR 1V9; (416) 924-8998, fax (416) 924-8352 1026
CAN MED ASSOC J 1992; 147 (7)
Jan. 26-30, 1993: Human Rights, Mental Health and Therapy in a Radically Changing World (sponsored by the Calgary General Hospital and the World Health Organization, in collaboration with the World Psychiatric Association, the International Academy of Law and Mental Health, the International Council of Prison Medical Services, the Canadian Psychiatric Association and the University of Calgary) Banff, Alta. Dr. J. Arboleda-Florez, chair, Organizing Committee, or Heather Holley, chair, Local Arrangements, Calgary General Hospital, 841 Centre Ave. NE, Calgary, AB T2E OA1; (403) 268-9203, fax (403) 268-9201
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