Vaccine-Preventable Diseases

Hepatitis A

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. 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 mortality rate associated with hepatitis A is 0.1% to 0.3%, but this rises to 1.8% over the age of 50.

Epidemiology

HAV is transmitted by the fecal-oral route, through direct contact with infected people or indirectly through ingestion of contaminated water or foods, especially uncooked shellfish. 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. Although 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 1999, the annual number of cases of HAV infection reported to the National Notifiable Disease Registry varied from 890 to 3,020, with corresponding rates from 3.0 to 10.8 per 100,000 population. Given under- reporting and asymptomatic infection, however, the actual number of cases is considerably higher. In 1999, the reported rate was 1.6 times higher among males than females. Age-specific incidence rates were highest among those 25 to 59 years of age and lowest among those < 5 years or > 59 years; 18% of all cases were < 15 years old, an age group in which the disease is often asymptomatic. Although representative data are not available for the general Canadian population, a study in a cohort of women of child-bearing age by the British Columbia Centre for Disease Control shows that age-specific prevalence rates of anti-HAV, indicating past infection, increased consistently from age 15 and 16 (13.5%) to age 40 to 44 (40.6%).

Immunity to HAV infection increases with age. About 3% of children < 13 years old are immune to HAV, as compared with more than 60% of adults > 60. The difference in levels of immunity reflects progressive accumulation of immunity over time and the greater likelihood of exposure in the past, when the infection was more common.

Risk factors for HAV infection in Canada include the following:

• 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;
• oral or intravenous illicit drug use;
• sexual behaviours involving anal contact, particularly between men;
• travel to or residence in countries with inadequate sanitation.

Overall, the most commonly identified risk factor for HAV infection is household or sexual exposure to a recent case. Twenty-five percent of cases have no identifiable risk factor. In Canada, unlike in the U.S., outbreaks of HAV have not occurred in children or staff of child day care facilities in the absence of community outbreaks.

Cases in returned travellers and contacts of travellers, including children, account for a large proportion of reported cases; some cases have occurred in people who spent < 2 weeks in an endemic area. The risk for susceptible travellers to developing countries has been estimated at 3 to 5 cases per 1,000 travellers per month, increasing in people who eat or drink under poor hygienic conditions. Risk also increases in proportion to the relative incidence of HAV in different countries, related possibly to the likelihood of consuming food prepared by an infectious person.

Preparations Licensed for Immunization

Four inactivated monovalent hepatitis A vaccines are licensed in Canada. There is some evidence that these four vaccines may be used interchangeably, despite different schedules and systems of measuring antigen content. Two combined hepatitis A and hepatitis B vaccines, one for adults and one for children, are also licensed in Canada (see the Table and the chapter Hepatitis Vaccines Combined).

In three of the HAV vaccines (Havrix™, Vaqta^® and Avaxim^®) 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. In the fourth (Epaxal Berna^®), immunopotentiating reconstituted influenza virosomes are used as an adjuvant. Complete and detailed descriptions of these vaccines have been published previously in the Canada Communicable Disease Report.

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 (see Passive Immunizing Agents).

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 prevented secondary cases effectively. Protection appears to occur rapidly within 3 weeks after immunization.

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.

Recommended Usage

Pre-exposure prophylaxis

Hepatitis A vaccine is recommended for pre-exposure prophylaxis of individuals at increased risk of infection. Candidates for the vaccine are

• travellers to countries where hepatitis A is endemic, especially when there is travel to rural locations or places with inadequate sanitary facilities; the risk of acquiring HAV increases with the duration and frequency of travel, but most travel-related cases have occurred in people who spent ≤ 2 weeks in an endemic area;

• residents of communities that have high endemic rates of HAV or are at risk of HAV outbreaks;

• members of the armed forces, emergency relief workers and others likely to be posted abroad at short notice to areas with high rates of HAV infection;

• residents and staff of institutions for the developmentally challenged in which there is evidence of sustained HAV transmission;

• inmates of correctional facilities in which there is evidence of sustained HAV transmission;

• people with life-style risks of infection, including people engaging in oral or intravenous illicit drug use in unsanitary conditions, and males having sexual contact with other males, particularly when there is a likelihood of oral-anal contact;

• people with chronic liver disease who may not be at increased risk of infection but are at increased risk of fulminant hepatitis A, should infection occur;

• 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 hepatitis A virus or production of hepatitis A vaccine who may be exposed to HAV;

• any person who wishes to decrease his or her risk of acquiring HAV.

Outside the aforementioned risk groups, the probability of becoming infected in Canada is low.

Post-exposure prophylaxis

HAV vaccine has been shown in one study to be at least as effective as 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, since there are no data on the outer limit of efficacy.

Post-exposure immunoprophylaxis should be undertaken for household and other intimate contacts of proved or suspected cases of HAV. It should be considered when hepatitis A occurs in day care centres, and especially in those that have diapered children. 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 (see Outbreak Control, next section).

If HAV vaccine is unavailable or unaffordable 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 (see Passive Immunizing Agents for dosages).

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 for this purpose include three Canadian outbreaks - in Kitchener-Waterloo in 1997, in Montreal in 1997-98 and on Vancouver Island in 1995-96 - and a U.S. outbreak in Alaska. 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 in institutions.

Universal immunization

Universal immunization programs against HAV are possible because of the availability of safe and effective vaccines. In the United States, programs exist in states in which the incidence of HAV exceeds the national average. The WHO, however, recommends targeted programs for countries with low endemicity, such as Canada. There are several pros and cons of universal hepatitis programs in Canada:

Pros

• the vaccine is highly effective;

• the illness may be moderately severe, and deaths occur; greater numbers of older adults are now susceptible because they are less likely than previous generations to have been exposed as children, and if they do become infected they are more likely than younger people to have severe disease;

• the illness has social and economic costs to those affected;

• more travellers would be immunized before travel to endemic areas, thereby preventing illness after their return and the potential for secondary cases in Canada;

• there would be fewer outbreaks and consequently lower costs for control and intervention;

• targeted programs have not been evaluated and may not be cost-effective, and some of those at risk may be missed in targeted programs.

Cons

• the vaccine is expensive, although competitive pricing may reduce costs;

• the illness has low prevalence in the general population;

• there are significant costs to deliver the vaccine to recipients;

• there are other vaccines competing for public funding;

• public acceptance of a vaccine program for an infection with low incidence may itself be low.

A universal immunization program against HAV should be considered in Canada, but the decision to implement such programs will depend on circumstances in each jurisdiction. Further discussion is needed nationally, possibly through a consensus conference, and cost-benefit analysis should be undertaken before implementation. The establishment of programs would benefit people who may be at risk but who do not seek pre-exposure immunization, such as unimmunized travellers to endemic areas and their close contacts. Although the lifetime risk of HAV changes with time and population cohort and is therefore difficult to quantify, over half of those now > 60 have had this disease. The current lifetime risk is likely to be lower, but may still be significant with increased travel.

People who do not need routine HAV immunization

• Children and staff of child-care facilities. Outbreaks in this type of setting have not been frequently reported in Canada. In addition, serologic testing has not indicated an increased risk of infection for workers or children.

• Health care workers are not considered to be at increased risk if standard infection control techniques can be exercised. Data from serosurveys of health care workers have not shown a greater prevalence of HAV infection in that segment of the population.

• Sewage workers may be at increased risk of infection during community outbreaks, but the data are insufficient to make a recommendation for routine immunization.

• Food handlers may be a source of food-borne outbreaks of hepatitis A but are not themselves at increased risk of infection occupationally. It has not been determined to what extent immunization of such workers would be practical or effective in reducing food-borne outbreaks.

Schedule and Dosage

The dosage schedules for adults and children of the four HAV vaccines are listed in the Table, 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 the need to repeat the first dose.

Because each of the HAV vaccines licensed 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 different HAV vaccine. 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 primary dose of vaccine in these circumstances. The timing of the dose in this situation should be based on the vaccine used for that dose.

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 is unknown, kinetic models of antibody decline suggest that protective levels of antibody will likely persist for at least 20 years. Should future study indicate the need for booster doses, recommendations will be made at that time.

Serologic Testing

Pre-immunization

Some studies have indicated that pre-immunization serologic testing is only cost-effective in populations that have a significant level of immunity. Variations in the cost of testing and 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 afterwards 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° C and 8° C and should not be frozen. Opened vials of Vaqta^® should be used promptly since they contain no preservative.

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.

Combined vaccines against hepatitis A and B are licensed in Canada for adults and children (see the Table). Clinical trials have not demonstrated any increase in side effects or clinically significant reduction in protection against either infection - rather, there is possibly increased efficacy - when the combined vaccine is used.

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

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 manufacturer's description of the vaccine.

Precautions

The safety of HAV vaccine given during pregnancy has not been studied in clinical trials. Since the vaccine is prepared from inactivated virus, however, the risk to the developing fetus is likely to be negligible. 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 HAV 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 the immunosuppressed 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 2001;19:743-50.

De Serres G, Laliberte D. Hepatitis A among workers from a waste water treatment plant during a small community outbreak. Occup Environ Med 1997;54:60-2.

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

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(4):160-67.

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.

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 Pediatr Adolesc Med 1996;150:733-39. National Advisory Committee on Immunization. Supplementary statement on hepatitis A vaccine. CCDR 2000;26(ACS-4, ACS-5):12-19.

National Advisory Committee on Immunization. Statement on combination vaccines against hepatitis A and hepatitis B. CCDR 1999;25(ACS-3):1-2.

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

National Advisory Committee on Immunization. Supplementary statement on hepatitis prevention. CCDR 1997;23 (ACS-4):1-3.

National Advisory Committee on Immunization. Supplementary statement on hepatitis A prevention. CCDR 1996;22:1-3.

National Advisory Committee on Immunization. Statement on the prevention of hepatitis A infections. CCDR 1994;20:133-36, 139-43.

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.

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.

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.

Vento S, Garofano T, Renzini C et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis. N Engl J Med 1998;388:286-90.

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

Wu J, Zou S, Giulivi A. Hepatitis A and its control. In: Bloodborne Pathogens Division, Health Canada. Viral hepatitis and emerging bloodborne pathogens in Canada. CCDR 2001;27S3:7-9.