Canada Communicable Disease Report
Vol. 26 (ACS-4)
1 July 2000

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)* +

SUPPLEMENTARY STATEMENT ON HEPATITIS A VACCINE (ACS-4)

Adobe Downloadable Document (197 KB)

PREAMBLE

The 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). The manufacturer(s) has 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).

INTRODUCTION

This statement addresses several new developments pertinent to active immunization against hepatitis A virus (HAV). These developments are (1) the licensure of two new vaccine products against HAV, and (2) new data on the use of HAV vaccine for post-exposure prophylaxis.

This statement will supplement the information published in the 1998 Canadian Immunization Guide⁽¹⁾ which provides full details on recommended uses of HAV vaccine (Table 1). Also, please refer to the Canadian Immunization Guide for information on the recommended uses of all HAV vaccines, further information on the disease, and general information on vaccine administration. Combination vaccines against HAV and hepatitis B have been discussed in the Canada Communicable Disease Report^(2,3).

INACTIVATED HAV VACCINES NEWLY LICENSED IN CANADA

1. AVAXIM^TM, Aventis Pasteur Limited

Vaccine description AVAXIM^TM is a purified, formalin inactivated whole virus vaccine against HAV, obtained from the GBM strain cultured on MRC-5 human diploid cells. Each 0.5 mL dose contains 160  antigen units adsorbed to 0.6 mg of aluminum hydroxide. Other vaccine components are the following:

The vaccine is supplied in single dose pre-filled syringes.

Immunogenicity

After a single injection of AVAXIM^TM, 95.7% of immunocompetent adult recipients attained protective levels (titres > 20 mIU/L) after 14 days and 100% after 1 month⁽⁴⁾. Although simultaneous administration of immune globulin diminished the peak antibody response after the first dose, the percentage that attained protective antibody levels was still 100%⁽⁵⁾. Four weeks after a booster dose, highly protective antibody levels were demonstrated, even when immune globulin was given with the primary immunization. When administered concomitantly with typhoid fever vaccine (Vi) or a combination of Vi and yellow fever vaccines, there does not appear to be interference with the immunogenicity of any of the antigens given⁽⁶⁾. Duration of protection is thought to be at least 10 years after the booster dose is given.

Table 1 Recommended doses of currently licensed hepatitis A vaccine

Dosage and administration

This vaccine is licensed for use in persons >= 12 years of age.  A single 0.5 mL dose, followed by a booster dose 6 to 12 months later is expected to provide long-term protection.

The vaccine should be administered intramuscularly in the deltoid muscle.

Adverse reactions

No serious or long lasting adverse reactions have been observed. Side effects that have been documented include weakness (13.5%), pain at the injection site (11.7%), myalgia or arthralgia (10.3%), headache (9.7%), gastro-intestinal symptoms (6.1%) and fever (5.2%). Rarely, mild, transient elevations of serum transaminases have been reported. Reactions were reported less frequently after the booster dose than the primary dose.

Contraindications and precautions

Allergy to any component of the vaccine or a documented anaphylactic reaction to a previous dose are contraindications to immunization with AVAXIM^TM.

Persons who are immunocompromised may not achieve the expected immune response.

The effect of AVAXIM^TM on fetal development and on breast-feeding infants has not been assessed. Because hepatitis A vaccines are inactivated, any risk to fetus or infant is likely to be extremely low. When the risk of illness outweighs the risk of vaccine in pregnancy and in breast-feeding mothers, immunization against HAV is indicated.

2. EPAXAL BERNA^®, Swiss Serum and Vaccine Institute

Vaccine description

EPAXAL BERNA^® is a purified, formalin inactivated whole cell virus vaccine against HAV, obtained from the RG-SB strain cultivated on MRC-5 human diploid cells and adsorbed to immunopotentiating reconstituted influenza virosomes.

Each 0.5 mL dose contains at least 500 radioimmunoassay units of HAV antigen and the following other vaccine components:

This vaccine is the first against HAV that does not use aluminum hydroxide as an adjuvant.

The vaccine is supplied in packages of one or 10 single-dose, pre-filled syringes.

Immunogenicity

After a single injection of EPAXAL BERNA^®, 88% of healthy seronegative adults seroconverted (titres > 20 mIU/L) after 14 days and 98% after 1 month^(7-11). Three to 12 months post-immunization, between 92% and 94% maintained protective antibody levels. One month after a booster dose, given approximately one year after primary immunization, 99.8% of vaccine recipients had high levels of protective antibody, with a 22-fold increase in geometric mean titre⁽⁶⁾.  Mathematical modelling by the manufacturer suggests that > 90% of vaccine recipients who receive primary  immunization and a booster at 1 year will retain protection for at least 10 years.

In children aged 12 months to 12 years, 96% seroconverted within 1 month after a single dose (Berna data on file: study reports KV 9108 [1995], KV 9111 [1996], KV 9205 [1996], KV 9301 [1998]).

Although final antibody titres are lower when immune globulin is administered concomitantly, the percentage of subjects who reach a protective level is not altered (Berna data on file: study reports KV 9108 [1995], KV 9111 [1996], KV 9205 [1996], KV 9301 [1998]). The vaccine immunogenicity was not significantly reduced when given with yellow fever vaccine, oral polio vaccine, oral typhoid vaccine, meningococcal A/C vaccine, combined diphtheria and tetanus vaccine, or anti-malarial drugs.

Dosage and administration

This vaccine is licensed for use in persons $1 year of age. A single 0.5 mL dose, followed 12 months later by a booster dose, is expected to confer immunity for at least 10 years.

The vaccine should be injected intramuscularly into the deltoid muscle.

Adverse reactions

No serious or persistent adverse reactions have been observed in clinical trials with this vaccine.  Side effects that have been documented include pain at the injection site (15.7%), headache (15.2%), malaise (8.6%), redness at the injection site (6.1%), induration at the injection site (6.1%), nausea (5.1%), anorexia (4.3%), swelling at the injection site (2.9%), fatigue (1.9%), and fever (1.7%). In children, all adverse reactions occurred less frequently except fever (4.6%). Reactions after the booster dose were comparable to those after primary immunization.

Contraindications and precautions

Allergy or known hypersensitivity to any component of the vaccine or an anaphylactic event after a previous dose are contraindications to immunization with EPAXAL BERNA^®.  

Persons who are immunocompromised may not achieve the expected immune response.

The comments on its use in pregnancy or in breast-feeding mothers as described for AVAXIM^TM apply to EPAXAL BERNA^® and all of the other vaccines containing HAV antigen.

INTERCHANGEABILITY OF VACCINES AGAINST HEPATITIS A

Data are not available that demonstrate conclusively that various HAV vaccines are fully interchangeable. Although there is no international standard for the measurement of HAV antigen in vaccine and each company has developed its own system of measuring antigen, effective boosting has been shown to occur nevertheless. Those vaccines shown to have boosting immunogenicity are EPAXAL BERNA^® (Berna data on file: study reports KV 9108 [1995], KV 9111 [1996], KV 9205 [1996], KV 9301 [1998]), AVAXIM^TM(12), and VAQTA^®(13), which  have all been shown to boost antibodies induced by HAVRIX^TM.

Because each of the HAV vaccines in Canada has similar HAV antigen and because each vaccine alone has been shown to induce high levels of protective antibody, it is likely that each vaccine will provide good boosting for the others. The unavailability of the identical product for boosting, therefore, should not be considered an impediment to administering a booster dose of HAV vaccine, nor is there a need to repeat the primary dose of vaccine in these circumstances. B

oth AVAXIM^TM and VAQTA^® may induce antibodies more rapidly, thereby providing protection a few days earlier than with the other HAV vaccines. This feature may be important when travellers are receiving their vaccine just prior to departure or when post-exposure prophylaxis cannot be done immediately after exposure.

USE OF HAV VACCINES FOR OUTBREAK CONTROL AND POST-EXPOSURE PROPHYLAXIS

There have been several outbreaks in which HAV vaccine has been used  to arrest the transmission of HAV in communities^(14-18), which support its use in outbreak control. The outbreaks in which the vaccine was used successfully for this purpose include at least two Canadian outbreaks, in Kitchener-Waterloo in 1997⁽¹⁸⁾, in Montreal in 1997-1998⁽¹⁴⁾. Based on the data and experience documented in these studies, a single dose of HAV vaccine administered to each member of the affected community should be considered as an important control measure in a coordinated public-health response to hepatitis A community outbreaks. HAV vaccine should also be considered for routine use to prevent outbreaks among susceptible persons in communities with a high endemicity of HAV. A follow-up booster given at the appropriate time (Table 1) will ensure long-term protection against HAV for each individual.

A recent study on the use of HAV vaccine to prevent secondary HAV infection supports the use of this vaccine for post-exposure prophylaxis⁽¹⁹⁾. In this controlled trial, there were 12 secondary cases among 207 (5.8%) unvaccinated contacts but only two infections (1.0%) among the 197 who received post-exposure vaccine; both of these infections were asymptomatic. The protective efficacy of the vaccine was 79% (95% CI = 7 to 95). Although more studies of its use in post-exposure prophylaxis are needed to document its effect fully, HAV vaccine, used in the first week post exposure, appears to be highly effective as a post-exposure measure to prevent HAV infection in identified contacts and is recommended for this use.

The study does not address the time since exposure, after which HAV vaccine is no longer effective in preventing HAV infection, although it is known from experience with immune globulin that post-exposure prophylaxis should be undertaken as soon as possible⁽¹⁾. Nevertheless, the use of HAV vaccine > 1 week after exposure may be of benefit, and its use in these circumstances with documentation of results will provide the benefit of contributing to the knowledge of its period of post-exposure efficacy.

Because immune globulin (IG) is unlikely to be more effective than HAV vaccine, and is sometimes difficult to obtain, HAV vaccine without immune globulin is the preferred method of post-exposure immunoprophylaxis against this disease. In addition, the use of HAV vaccine alone will place less demand on potentially scarce IG, needed for other medical uses. IG is still the recommended  immunoprophylaxis for infants and those immunocompromised persons who may not respond fully to the vaccine.

CONSOLIDATION OF RECOMMENDATIONS

This supplementary statement expands the National Advisory Committee on Immunization's recommendations on the use of HAV vaccine. These recommendations are summarized in Table 2 below.

Table 2 Evidence-based recommendations

This statement, the Canadian Immunization Guide, "Statement on Combination Vaccines Against Hepatitis A and Hepatitis B"⁽²⁾  and "Supplementary Statement on Hepatitis Prevention - Hepatitis A and Hepatitis B Combination Vaccine for Children"⁽³⁾, both published in Canada Communicable Disease Report, Volume 25(ACS-3, 4), constitute the full, current recommendations of NACI on these vaccines. In summary, all vaccines against HAV licensed in Canada have been shown to provide high levels of protective antibody, particularly when a booster dose is used, and are presumed to provide excellent long term protection against this disease.

References

1. National Advisory Committee on Immunization. Canadian immunization guide. 5th ed. Ottawa, Ont.: Health Canada, 1998. (Minister of Public Works and Government Services Canada, Cat. No. H49-8/1998E.)

2. National Advisory Committee on Immunization. Statement on combination vaccines against hepatitis A and hepatitis B. CCDR 1999;25(ACS-3):17-8.

3. National Advisory Committee on Immunization.  Supplementary statement on hepatitis prevention - hepatitis A and hepatitis B combination vaccine for children. CCDR 1999;25(ACS-4):18-20.

4. Zuckerman J, Peyron F, Wallon M et al. Comparison of the safety and immunogenicity of two inactivated hepatitis A vaccines. Adv Ther 1997;14:116-24.

5. Zanetti A, Pregliasco F, Andreassi A et al. Does immunoglobulin interfere with the immunogenicity to Pasteur Mérieux inactivated hepatitis A vaccine?  J Hepatol 1997;26:25-30.

6. Dumas R, Forrat R, Lang J et al. Safety and immunogenicity of a new inactivated hepatitis A vaccine in concurrent administration with a typhoid fever or a typhoid fever and yellow fever vaccine. Adv Ther 1997;14:160-67.

7. Glück R, Mischler R, Brantschen S et al.  Immunopotentiating reconstituted influenza virus virosome vaccine delivery system for immunisation against hepatitis. Am J Clin Invest 1992;90:2491-95.

8. Loutan L, Bovier P, Althaus B et al. Inactivated virosome hepatitis A vaccine. Lancet 1994;343:322-24.

9. Poovorawan Y, Tieamboonlers A, Chumdermpadetsuk S et al. Safety, immunogenicity and kinetics of the immune response to a single dose of virosome-formulated hepatitis A vaccine in Thais. Vaccine 1995;13:891-93.

10. Holzer B, Hatz C, Schmidt-Sissolak D et al. Immunogenicity and adverse effects of inactivated virosome versus alum-adsorbed hepatitis A vaccine. Vaccine 1996;14:982-86.

11. Just M, Berger R, Drechsler H et al. A single vaccination with an inactivated hepatitis A liposome vaccine induces protective antibody after only two weeks. Vaccine 1992;10:737-39.

12. Zuckerman J, Kirkpatrick C, Huang M. Immunogenicity and reactogenicity of AVAXIM^TM as compared with HAVRIX^TM as a booster following primary immunization with HAVRIX^TM against hepatitis. Am J Trav Med 1998;5:18-22.

13. Connor B, Phair J, Sack D et al. Preliminary hepatitis A antibody responses in a cohort of healthy adults who received HAVRIX followed by VACTA or HAVRIX  6-12 months later. In: Program and Abstracts of the Second Asia Pacific Travel Health Congress, July 10-13, 1988, Taipei, Taiwan. Hong Kong: Asia Pacific Travel Health Association, 1998:23. Abstract.

14. Deshaies D, Dion R, Valiquette L. Immunization against hepatitis A during an outbreak in a Jewish orthodox community - Quebec, 1997-1998.  CCDR 1998;24:145-51.

15. McMahon BJ, Beller M, Williams J et al. A programme to control an outbreak of HAV in Alaska by using an inactivated hepatitis A vaccine. Arch Paediatr Adolesc Med 1996;150:733-39.

16. Prikazsky V, Olear V, Cernoch A et al. Interruption of an outbreak of hepatitis A in two villages by vaccination. J Med Virol 1994;44:457-59.

17. Poovorawan Y, Tieamboonlers A, Chumdermpadetsuk S et al. Control of a Hepatitis A outbreak by active immunisation of high-risk susceptibles. J Infect Dis 1994;169:228-29.

18. Hockin J, Isaacs S, Kittle D et al. Hepatitis A outbreak in a socially contained religious community in rural southern Ontario.  CCDR 1997;23:161-66.

19. Sagliocca L, Amoroso P, Stroffolini T et al. Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised trial. Lancet 1999;353:1136-39.

*  Members: Dr. V. Marchessault (Chairperson), Dr. J. Spika (Executive Secretary), N. Armstrong (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. P. DeWals, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, A. Zierler.

Liaison Representatives: Dr. J. Carsley (CPHA), Dr. G. Delage (CPS), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. J. Livengood (CDC), Dr. A.E. McCarthy (ND), Dr. J. Salzman (CATMAT), Dr. L. Samson (CIDS), Dr. J. Waters (CCMOH).

Ex-Officio Representatives: Dr. J. Calver (BBR), Dr. A. King (LCDC), Dr. P. Riben (MSB).

⁺ This statement was prepared by Dr. I. Gemmill and approved by NACI.

[Canada Communicable Disease Report]