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Canada Communicable Disease Report
An Advisory Committee Statement (ACS) SUPPLEMENTARY STATEMENT ON HEPATITIS PREVENTIONThe National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. Persons administering or using the vaccine(s) should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monograph(s). This statement was completed by NACI on the 18 March, 1997. INTRODUCTION This statement addresses three recent developments pertinent to active immunization against hepatitis A virus (HAV) infections: 1) licensure of a second, inactivated HAV vaccine (VAQTA®, Merck Frosst Canada Inc.) for use in children and adults, 2) approval for use in children of an inactivated HAV vaccine (HAVRIXTM, SmithKline Beecham Pharma Inc.) licensed in 1994, and 3) licensure of a combined hepatitis A and hepatitis B vaccine (TWINRIXTM, SmithKline Beecham Pharma Inc.). Additional information about hepatitis A vaccines can be found in two previous statements from the National Advisory Committee on Immunization (NACI)(1,2) and in a recent review article(3). INACTIVATED HEPATITIS A VACCINE 1. VAQTA®, Merck Frosst Canada Inc. This inactivated whole virus vaccine(4) is prepared using an attenuated seed strain of hepatitis A virus grown in human fibroblast (MRC-5) cell cultures and inactivated with formalin. Purified virus protein is adsorbed onto aluminum hydroxide and packaged without preservatives. Each 1.0 mL dose contains 50 units of virus protein, roughly equal to 50 nanograms of protein, along with traces of bovine albumen, residual formaldehyde, and residual neomycin. Dosage and Administration The adult formulation (1.0 mL dose) contains 50 units of HAV antigen, 0.45 mg of aluminum and 70µ sodium borate buffer in 0.9% saline. It is recommended for persons >= 18 years of age, given as a single primary dose with a booster dose 6 months later. The pediatric/adolescent formulation (0.5 mL dose) contains 25 units of HAV antigen, 0.225 mg of aluminum and 35µ sodium borate in 0.9% saline. It is recommended for persons 2 to 17 years old, given as a single primary dose with a booster dose 6 to 18 months later. Vaccine is given intramuscularly, preferably in the deltoid. Vaccine should be stored at 2º C to 8º C avoiding freezing. Vaccine is available as single-use vials or pre-filled individual syringes with color-coded labels distinguishing the adult (orange) and pediatric (purple) formulations. Vaccine Characteristics The vaccine is highly immunogenic in children and adults. Within 4 weeks following an initial dose of 25 units of vaccine, 97% of children and adolescents (aged 2 to 17 years) tested developed levels of anti-HAV in serum considered to be protective (>= 10 mIU/mL). Similarly among adults given 50 units of vaccine, 95% developed protective levels of antibody within 4 weeks after initial immunization. Two weeks following vaccination 69% of adults tested had >= 10 mIU/mL of antibody. Concurrent administration of vaccine and immune serum globulin at separate injection sites reduces the seroconversion rate and antibody levels in serum. The protective efficacy of this vaccine was demonstrated in a double-blinded, randomized, placebo-controlled trial involving 1,037 susceptible children aged 2 to 16 years living in a community with a high rate of HAV infection(5). Observed efficacy was 100% (95% confidence interval [CI] = 87.3 to 100) measured from 50 days post-immunization. No cases were observed in vaccinees 19 days or more after immunization. Booster doses were given after 6, 12, or 18 months. No cases occurred in vaccinees during the subsequent 4 years of follow-up despite the occurrence of outbreaks in nearby communities. The duration of protection is unknown. In most children, antibodies persist for 18 months following initial immunization; in adults, documented persistence after the initial dose is limited to 6 months. Booster immunization elicits high levels of antibodies. Based on the observed rate of decline, antibodies are projected to remain above protective levels for 21 years (95% CI = 14 to 27). Recommended Usage The vaccine is approved for pre-exposure prophylaxis of children and adults who are at risk of contracting or spreading infection, or those who are at risk of life-threatening disease if infected. NACI has previously identified individuals for whom vaccination is recommended(2) and for whom the need for vaccinations in uncertain. There continues to be little evidence of risk in Canada for HAV infection in children or staff associated with child day-care facilities in the absence of community outbreaks. It has not been determined if vaccination of food handlers would be effective in reducing foodborne outbreaks. Consumption of raw shellfish harvested commercially in Canada has not posed significant risk to date. Health-care workers are not considered to be at increased risk where standard infection control techniques can be exercised. A recent report from Quebec indicated that sewerage workers may be at increased risk during community outbreaks(6) but data are insufficient to recommend routine vaccination of such workers. Among those "at risk of life-threatening disease if infected" are persons with chronic, non-biliary liver disease, including cirrhosis and chronic hepatitis from viral infection or other causes(3,7). In the general population, fulminant hepatitis A is rare in people < 30 years of age but increases in frequency with advancing age, reaching peak rates in those > 50 years of age. While persons of any age with chronic liver disease can be considered for HAV vaccination, the adequacy of their immune responses has not been substantiated. The need for further booster doses is unknown. Adverse Reactions Injection site symptoms, generally mild and transient, are the most frequent complaints. No significant differences in local symptoms are evident between initial and booster doses. About 20% of children report local pain or tenderness, and about 8% have redness or swelling at the injection site. Among adults, local pain or tenderness is reported by about 50%; about 15% report redness, swelling or bruising at the injection site. Systemic complaints are reported at similar rates after vaccine and placebo. Severe adverse events following immunization are rare. Contraindications and Precautions HAV vaccine should not be given to persons with hypersensitivity to any of its constituents, including neomycin. Safety and effectiveness in children < 2 years of age have not been established. Safety in pregnancy has not been established. Because the vaccine is prepared from inactivated HAV, risk to the developing fetus is expected to be low when vaccine is given to pregnant women. Immunization of a pregnant woman may be indicated when the risk of disease outweighs the risk of the vaccine for both the mother and the fetus. Compatibility of HAV vaccine with other vaccines given concurrently at separate injection sites has not been established. Comparison of Available Products Direct comparisons of the immunogenicity and reactogenicity of VAQTA® and HAVRIXTM are not yet available. Methods of describing the HAV protein content (unitage) differ between the two products. Comparing reports of the individual products, no striking differences in properties are evident(3). Interchangeability of the two products for booster doses has not been assessed. 2. HAVRIXTM 720 Junior, SmithKline Beecham Pharma Inc. A formulation of HAVRIXTM inactivated hepatitis A vaccine was recently approved for use in children and youths 1 to 18 years of age. Referred to as HAVRIXTM 720 Junior, this formulation contains 720 enzyme-linked immunosorbent assay (ELISA) units of viral antigen per 0.5 mL dose, i.e. one-half the content of the current adult formulation. A single dose is sufficient for primary immunization. In clinical trials involving subjects aged 1 to 18 years, antibodies directed against hepatitis A virus were detected in 93% of subjects by 15 days after primary immunization and in 99% by one month. A booster dose of vaccine should be given 6 to 12 months after the primary dose to ensure long-term protection. Booster doses of 360 ELISA units were previously shown to be sufficient for this age group(2) and can be considered if convenient. As with the adult formulation of HAVRIXTM, the junior formulation is adsorbed on aluminum hydroxide, preserved with 2-phenoxyethanol and may contain traces of neomycin sulfate. Vaccine should be administered intramuscularly. The deltoid is the preferred site except for children < 2 years of age in whom the anterolateral thigh is preferred. Minor adverse events reported after vaccination of children are similar to those in adults but are less frequent. Appropriate indications for vaccine use in children have previously been published by NACI(2). A high level of protective efficacy (94%, 95% CI = 79 to 99) has been demonstrated in children vaccinated with two primary doses each containing 360 ELISA units of viral antigen(8). The updated HAVRIXTM product monograph also lists subjects with chronic liver disease or who are at risk of developing chronic liver disease (e.g. chronic carriers of hepatitis B and hepatitis C) as candidates for vaccination. As mentioned with VAQTA® above, the adequacy of immune responses to HAVRIXTM among such individuals has not been determined. HEPATITIS A AND HEPATITIS B COMBINATION VACCINE 1. TWINRIXTM, SmithKline Beecham Pharma Inc. TWINRIXTM is a combined vaccine for adults formulated from the same bulk vaccines that are used to produce HAVRIXTM (inactivated hepatitis A vaccine) and Engerix-B® (hepatitis B surface antigen, recombinant). Each 1.0 mL dose contains 720 ELISA units of inactivated hepatitis A viral antigen and 20µ of hepatitis B purified surface antigen protein. The viral proteins are adsorbed on aluminum hydroxide and aluminum phosphate. The vaccine also contains 2-phenoxyethanol preservative and traces of formaldehyde and neomycin sulfate. The recommended adult dose is 1.0 mL, injected intra-muscularly, preferably in the deltoid region. Three primary doses are recommended, at intervals of 0, 1, and 6 months. The need for and timing of booster doses have not been established. In clinical studies involving over 800 healthy seronegative subjects, > 99% had serum antibodies to HAV and > 96% had antibodies to hepatitis B surface antigen 1 month after the second dose. The corresponding figures were 100% and 99%, with the latter values for anti-HBs exceeding 10 IU/L, 1 month after a third dose. The most frequent adverse effect is mild injection-site soreness, reported after about 40% of doses(9). Redness and/or swelling at the injection site are seen after about 5% of doses. Local changes occur at the same frequency after each dose in the series. Headache and fatigue are reported after 10% of doses(9). Infrequent adverse effects also include malaise, nausea, and vomiting. Side-effects of the combined vaccines do not differ in frequency or severity from the monovalent vaccines. The combined vaccine is recommended for pre-exposure prophylaxis of HAV and HBV infections in adults at risk, such as those residing in or travelling to areas where both infections are highly endemic. Other candidates are people frequently receiving blood products (e.g. hemophiliacs) or those whose personal lifestyle exposes them to both infections (e.g. users of street drugs, sex-trade workers, men who have sex with men). Details regarding vaccine use can be obtained from the product monograph. The product is supplied as monodose vials. Vaccine should be stored at 2º to 8º C, avoiding freezing. References
* Members: Dr. D. Scheifele (Chairman); Dr. J. Spika (Executive Secretary); N. Armstrong (Advisory Committee Secretariat Officer); Dr. P. DeWals; Dr. S. Halperin; Dr. B. Law; Dr. M. Naus; Dr. B. Ward;Dr. I. Gemmill; Dr. W. Schlech III; Dr. P. Orr; Dr. G. DeSerres. Liaison Members: Dr. D. Carpenter (ND); Dr. A. Carter (CMA); Dr. T. Freeman (CFPC); Dr. S. Hadler (CDC); Dr. V. Marchessault (CPS); Dr. Salzman (CATMAT); Dr. J. Waters (ACE). Ex-Officio Members: Dr. P. Duclos (LCDC); Dr. L. Palkonyay (DD).
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Last Updated: 2002-11-08 |  |
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