Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Hepatitis A Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Outbreak control Schedule and dosage Route of administration

Booster doses and re-immunization Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Selected references

Hepatitis A virus (HAV) is an RNA virus of a single serotype. Infection usually causes clinical hepatitis in adults and school-aged children but is often asymptomatic in younger children. Jaundice develops in < 10% of children 6 years and under. Typical symptoms of illness include anorexia, nausea, fatigue, fever and jaundice. The severity of the illness increases with age. Recovery often takes 4 to 6 weeks but may take months. Recurrent hepatitis for up to a year occurs in about 15% of cases, but longer chronic infection is not known to occur. About 25% of reported adult cases require hospitalization. Fulminant disease with liver necrosis is rare but can be fatal. Individuals with pre-existing chronic liver disease are at increased risk of serious complications from HAV infection. The overall estimated case fatality rate associated with hepatitis A is 0.1% to 0.3%, but this rises to 1.8% in persons over the age of 50. It reaches 12.5% in patients over the age of 60 who are hospitalized because of the disease.

Since the publication of the 2002 Canadian Immunization Guide, new data have been obtained on the epidemiology of hepatitis A in Canada and on the immunization coverage of travellers to endemic countries.

Epidemiology

HAV is most frequently transmitted by the fecal-oral route, through direct contact with infected people or indirectly through ingestion of contaminated water or foods. On rare occasions, transmission has been reported after exposure to HAV-contaminated blood or blood products. It also occurs through sexual activities that include direct or indirect oro-anal contact but not through exposure to saliva, semen or urine. The virus may persist for days or weeks in the environment. Shedding of the virus in feces and thus maximum infectiousness occurs during the latter part of the incubation period with peak levels in the 2 weeks before clinical illness. Infectiousness diminishes rapidly thereafter and ends shortly after the onset of jaundice. Humans are the principal reservoir for HAV. Persistent infection does not occur. The incubation period ranges from 15 to 50 days with an average of 20 to 30 days. Lifelong immunity usually follows infection.

In Canada, between 1990 and 2004 the number of cases of HAV infection reported annually varied from 3,562 (1991) to 396 (2003), representing rates of 10.8 and 1.2 per 100,000 population respectively. During this period, there have been outbreaks involving men who have sex with men (MSM) in major Canadian cities. Since the introduction of the vaccine in 1996, no new major outbreak has occurred, and the incidence rate has slowly decreased. It is not known whether this is due to the impact of the targeted immunization programs. There is no information on the proportion of targeted groups being immunized, but it is likely low. The estimated coverage in MSM at the end of the massive immunization campaign during the Montreal outbreak was only 35%. Within Canada, there have been considerable geographic variations in the reported incidence, and this is observed even during periods of decline nationally. In the 5 year period of 1999 to 2004, no substantial sex difference in reported rates was observed. In 2004, the reported rate was 1.4 among females and 1.6 among males per 100,000 population. Age-specific incidence was highest among those 15-24 years old with a rate of 2.3 per 100,000 population, followed closely by those aged 5-14 (2.2 per 100,000 population).

Given asymptomatic infection, underdiagnosis and underreporting, the actual number of cases has been estimated to be 10 times higher than the number of notifications. A nationwide Canadian seroprevalence study has shown a seroprevalence of 2.0% in unvaccinated 8- to 13-year-olds. In this same study, HAV antibody prevalence was 1.1% in non-vaccinated, non-Aboriginal children born in Canada who did not travel to endemic countries. There are no other nationwide seroprevalence data. A systematic review of all seroprevalence studies conducted in Canada has been published recently and demonstrates an increase with age, which is probably due both to the cumulative incidence with increasing age and a cohort effect attributable to higher incidence rates in the past.

Risk factors for HAV infection in Canada include the following:

• Sexual behaviours involving anal contact, particularly between men (MSM). This resulted in the major outbreaks of the 90s.
• Travel to or residence in countries with endemic hepatitis A. In recent years 40% of all notified hepatitis A cases have been in travelers. Among those, 40% are taking low-risk trips (staying for short periods of time in luxury hotels where meals are provided). More than 5 million Canadians go to an HAV-endemic country in a year. Over 5 years, 30% of Canadians will travel to an endemic country, yet less than 15% of these travelers go to a travel clinic and receive hepatitis A vaccine.
• Immigrants or children of new Canadians who return to their country of origin to visit friends and relatives.
• Household contacts of an acute case.
• Residence in certain communities in rural or remote areas lacking adequate sanitation or a secure supply of potable water.
• Residence in certain institutions, such as correctional facilities and those for developmentally challenged individuals.
• Illicit drug use. In this group, transmission is seldom related to contaminated injection material. It is rather associated with a number of risk factors: low hygiene standards, contaminated drugs, and sharing of materials for oral or nasal use of drugs.

More than 25% of cases have no identifiable risk factor. Food handlers are not at higher risk of hepatitis A because of their occupation. However, food handlers may belong to a demographic group with a higher incidence of hepatitis A and thus cause major outbreaks. They may also trigger very extensive public health interventions that become necessary when a food handler is found to be contagious, even if the number of secondary cases is ultimately small.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

• Avaxim^® (hepatitis A vaccine inactivated), Sanofi Pasteur Ltd.
• Avaxim^® Pediatric, Sanofi Pasteur Ltd.
• Havrix^® (hepatitis A vaccine, inactivated), GlaxoSmithKline Inc.
• Vaqta^® (hepatitis A vaccine, inactivated), Merck Frosst Canada Ltd.

There is some evidence that these vaccines may be used interchangeably, despite different schedules and systems of measuring antigen content.

In these vaccines, various strains of cell-culture-adapted virus are propagated in human fibroblasts, purified from cell lysates, inactivated with formalin and adsorbed to an aluminum hydroxide adjuvant.

Immune globulin (Ig) may be used for short-term protection against HAV in infants and in people who are immunocompromised (who may not respond fully to HAV vaccine), and in people for whom HAV vaccine is contraindicated. Please refer to the Passive Immunizing Agents chapter for more information.

Formulations combining antigens against both HAV and HBV are also marketed in Canada. Please refer to the Hepatitis Vaccines Combined chapter for more information.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

All the HAV vaccines have shown high levels of immunogenicity and at least 85% to 90% efficacy in preventing clinical illness. Epidemiologic studies of hepatitis A outbreaks have shown repeatedly that the use of vaccine in the susceptible population interrupts the outbreak, suggesting that receipt of vaccine before exposure is almost invariably protective. This conclusion is also supported by an Italian study, in which the use of vaccine in household contacts, after exposure, prevented secondary cases. Protection appears to occur rapidly within 2 weeks after immunization. Given the long incubation period of hepatitis A (2 to 7 weeks), vaccine given a few days after exposure can still elicit an adequate immune response to protect the vaccinee. In serologic studies of all HAV vaccines, 95% to 100% of individuals consistently developed protective levels of serum antibody against HAV 4 weeks after a single dose of any inactivated hepatitis A vaccine.

In the countries where universal immunization is in place, a decrease in incidence far in excess of the vaccine coverage has been demonstrated. This is indicative of herd immunity.

Recommended usage

Pre-exposure prophylaxis

Hepatitis A vaccine is recommended for pre-exposure prophylaxis of individuals at increased risk of infection or increased risk of severe hepatitis A:

• Travelers to countries where hepatitis A is endemic
• Residents of communities that have high endemic rates of HAV or are at risk of HAV outbreaks
• Members of the Canadian armed forces, emergency relief workers and others likely to be posted abroad at short notice to areas with high rates of HAV infection
• People with life-style risks for infection, including people engaging in illicit drug use and MSM
• People who have chronic liver disease or who are receiving hepatotoxic medications, including persons infected with hepatitis C who may not be at increased risk of infection but are at increased risk of fulminant hepatitis A, should infection occur
• People with other conditions for which hepatotoxic medications are likely to be prescribed in the future
• People with hemophilia A or B receiving plasma-derived replacement clotting factors; the solvent-detergent method used to prepare all the present plasma-derived factor VIII and some factor IX concentrates does not reliably inactivate HAV, since the virus does not have an envelope
• Zoo-keepers, veterinarians and researchers who handle non-human primates
• Workers involved in research on HAV or production of hepatitis A vaccine who may be exposed to HAV

The National Advisory Committee on Immunization (NACI) also encourages all those who wish to decrease their risk of acquiring HAV to be vaccinated

Post-exposure prophylaxis

HAV vaccine has been shown in one randomized study to be as effective as immune globulin (Ig) for the prevention of HAV. Although more studies of its use in post-exposure prophylaxis are needed to document its effect fully, HAV vaccine used in the first week after exposure appears to be highly effective as a post-exposure measure to prevent infection in identified contacts. It is recommended for this use in preference to Ig. Therefore, one dose of HAV vaccine should be given to contacts of HAV within 1 week of exposure. It should also be considered if > 1 week has elapsed since exposure, as there are no data on the outer limit of efficacy.

Post-exposure immunoprophylaxis should be undertaken for household and other intimate contacts of proven or suspected cases of HAV. It should be given when hepatitis A occurs in day care centres and kindergartens. Post-exposure prophylaxis is not necessary for other contacts, such as school, workplace or health care workers caring for HAV cases unless an outbreak is suspected or likely (see Outbreak Control, below).

If HAV vaccine is unavailable for post-exposure prophylaxis, Ig may be used as a substitute. Ig is still the recommended immunoprophylactic agent for infants < 1 year of age, immunocompromised people, who may not respond fully to the vaccine, and those for whom vaccine is contraindicated. Please refer to the Passive Immunizing Agents chapter for information on dosage.

Outbreak control

There have been several outbreaks in which HAV vaccine has been used to arrest the transmission of the virus in communities. This observation supports its use in outbreak control. The outbreaks in which the vaccine has been used successfully include those in Toronto and Vancouver in 2002, in Kitchener-Waterloo in 1997, in Montreal in 1997-98 and on Vancouver Island in 1995-96. In accordance with the data and experience documented in these reports, HAV vaccine should be considered as an important control measure in a coordinated public health response to hepatitis A outbreaks in the community and also in institutions (correctional facilities, institutions for the developmentally challenged, etc). When a food handler is infected, co-workers and clients should receive post-exposure prophylaxis.

Universal immunization

Universal immunization programs against HAV are possible because of the availability of safe and effective vaccines. In the United States, universal immunization of 2-year-old children started in states in which the incidence of HAV exceeded the national average. Since these states now have incidence rates lower than the formerly low-incidence states, universal immunization has been extended to the whole country. Israel and provinces of Spain and Italy have also introduced universal programs.

Universal immunization programs against HAV should be considered in Canada, but the decision to implement such programs will depend on circumstances in each jurisdiction.

The establishment of a universal program would benefit people who may be at risk but who do not seek pre-exposure immunization. For example, more than 85% of travelers to endemic areas do not go to a travel clinic to obtain the vaccine. Because of their large numbers and high turnover, a universal program is also the only feasible way to achieve high immunization rates among food handlers.

In Canada, it is also possible to give the vaccine efficiently by using combined hepatitis A and B vaccines. Please refer to the Hepatitis Vaccines Combined chapter for more information.

Schedule and dosage

The dosage schedules of the three HAV vaccines for adults and children are listed in Table 3, along with antigen content and volumes of doses.

If the second dose in the hepatitis A vaccine series is missed, it can be given at a later time without repeating the first dose.

Because each of the HAV vaccines approved for use 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 any HAV vaccine will provide an effective second dose after a first dose of one of the others. Lack of availability of the identical product, therefore, should not be considered an impediment to administering the second dose of HAV vaccine, nor is there a need to repeat the first dose of vaccine in these circumstances. The timing of the second dose in this situation should be based on the vaccine used for the second dose.

Table 3. Doses and Schedules for Monovalent Hepatitis A Vaccines

Route of administration

Hepatitis A vaccines should be administered intramuscularly.

Booster doses and re-immunization

Although the duration of protection and thus the need for additional booster doses after two doses of HAV vaccine are unknown, kinetic models of antibody decline suggest that protective levels of antibody will likely persist for at least 20 years. Immune memory has been demonstrated in a number of studies, with the implication that protection may persist even when antibodies are no longer measurable, as is the case for hepatitis B vaccine. Should future study results indicate the need for booster doses, recommendations will be made at that time.

Serologic testing

Pre-immunization

Pre-immunization serologic testing is only cost-effective in populations that have a high level of immunity. Variations in the cost of testing and of vaccine will affect these analyses and the specific level of population immunity at which testing will become cost-effective. Nevertheless, pre-immunization testing for immunity against HAV should be considered in populations with the potential for higher levels of pre-existing immunity. Older Canadians and people from HAV-endemic areas of the world are examples of these populations. In addition, people with a history of hepatitis or jaundice that may have been caused by HAV should be considered for assessment of immunity before immunization is undertaken.

Post-immunization

The high response rate to immunization makes routine serologic testing unnecessary. Moreover, commercial assay kits are not universally reliable for detecting vaccine-induced antibody.

Storage requirements

Hepatitis A vaccine should be stored at a temperature between +2^o C and +8^o C and should not be frozen.

Simultaneous administration with other vaccines

Concomitant administration of other vaccines at other injection sites is unlikely to interfere with the immune response to HAV vaccine. There have been studies on concomitant administration of some of the HAV vaccines with various other vaccines, such as yellow fever, typhoid and cholera, which demonstrated no immune interference; however, complete data on all HAV vaccines are not available.

Adverse reactions

Side effects reported in vaccine recipients are generally mild and transient, and limited to soreness and redness at the injection site. Other less frequent side effects include headache, malaise, fever, fatigue and gastrointestinal symptoms. Local side effects in children appear to be less frequent than in adults. No significant difference in reactions is evident between initial and subsequent doses or in the presence of pre-existing immunity. Rare cases of anaphylaxis have been reported.

Contraindications and precautions

HAV vaccine should not be given to any person who has had an anaphylactic reaction to any component of the vaccine preparation. Since each HAV vaccine has different components, it is important to ascertain the specific cause of previous anaphylaxis, if possible, and refer to the package insert.

The safety of HAV vaccine given during pregnancy has not been studied in clinical trials. Since the vaccine is prepared from inactivated virus, however, there is no apparent risk to the developing fetus. Therefore, HAV vaccine may be given to pregnant women when indicated. HAV vaccine can be used safely in breast-feeding women.

HAV vaccine can also be used safely in those with chronic illnesses or immunosuppression. Although the efficacy of the vaccine may be reduced in those who are immunosuppressed, the vaccine still provides some protection against HAV in these populations and should be considered for pre-exposure use when there is an indication for the vaccine. Ig is still recommended for immunosuppressed persons for post-exposure immunoprophylaxis.

Selected references

Bryan JP, Henry CH, Hoffman AG et al. Randomized, cross-over, controlled comparison of two inactivated hepatitis A vaccines. Vaccine 2000;19(7-8):743-50.

Dagan R, Leventhal A, Anis E et al. Incidence of hepatitis A in Israel following universal immunization of toddlers. Journal of the American Medical Association 2005;294(2):202-10.

De Serres G, Duval B, Shadmani R et al. Ineffectiveness of the current strategy to prevent hepatitis A in travelers. Journal of Travel Medicine 2002;9(1):10-6.

De Serres G, Laliberte D. Hepatitis A among workers from a waste water treatment plant during a small community outbreak. Occupational and Environmental Medicine 1997;54(1):60-2.

Deshaies D, Dion R, Valiquette L et al. Immunization against hepatitis A during an outbreak in a Jewish orthodox community Quebec 1997-1998. Canada Communicable Disease Report 1998;24(18):145-51.

Duval B, De Serres G, Ochnio J et al. Nationwide Canadian study of hepatitis A antibody prevalence among children eight to thirteen years old. Pediatric Infectious Disease Journal 2005;24(6):514-19.

Fiore AE. Hepatitis A transmitted by food. Clinical Infectious Diseases 2004;38(5):705-15.

Hockin J, Isaacs S, Kittle D et al. Hepatitis A outbreak in a socially contained religious community in rural southern Ontario. Canada Communicable Disease Report 1997;23(21):161-66.

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. Archives of Pediatrics and Adolescent Medicine 1996;150(7):733-39.

Pham B, Duval B, De Serres G et al. Seroprevalence of hepatitis A infection in a low endemicity country: a systematic review. BioMed Central Infectious Diseases 2005;5:56. URL: <http://www.biomedcentral.com/1471-2334/5/56>.

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(9159):1136-39.

Scheifele DW. Hepatitis A vaccines: the growing case for universal immunisation of children. Expert Opinion on Pharmacotherapy 2005;6(2):157-64.

Vento S, Garofano T, Renzini C et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. New England Journal of Medicine 1998;338(5):286-90.

Werzberger A, Kuter B, Shouval D et al. Anatomy of a trial: a historical view of the Monroe inactivated hepatitis A protective efficacy trial. Journal of Hepatology 1993;18(Suppl. 2): S46-S50.

Wu J, Zou S, Giulivi A. Hepatitis A and its control. In: Health Canada. Viral hepatitis and emerging bloodborne pathogens in Canada. Canada Communicable Disease Report 2001;27(S3):7-9.

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