Hepatitis A vaccine: Canadian Immunization Guide
Key Information
What
- Hepatitis A (HA) infection usually causes clinical hepatitis in adults and older children; it often causes a febrile illness without jaundice or is asymptomatic in younger children.
- Pre-exposure HA immunization is at least 90% to 97% effective.
- Reactions to HA vaccine are generally mild and transient and include soreness and redness at the injection site.
Who
- Pre-exposure HA immunization is recommended for people at increased risk of infection or severe HA including:
	+ Travellers to HA-endemic countries
	+ Individuals with chronic liver disease
	+ Men who have sex with men (MSM)
	+ Injectable and non-injectable illicit drug users
	+ Individuals living in communities at risk of HA outbreaks or in which HA is endemic
	+ Household or close contacts of children adopted from HA-endemic countries
	+ Military personnel and humanitarian relief workers
	+ People receiving repeated replacement of plasma-derived clotting factors
	+ Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus
	+ Zoo-keepers, veterinarians and researchers who handle non-human primates
- Post-exposure prophylaxis should be offered to susceptible:
	+ household and close contacts of people infected with HA
	+ contacts in group child care centres and kindergartens
	+ co-workers and clients of infected food handlers
How
- Primary immunization is achieved with 1 dose of monovalent HA vaccine with a booster dose given 6 to 36 months later, depending on the product.
- With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to  in Part 4 for additional information about HAHB vaccine.
- HA vaccines may be administered concomitantly with other vaccines.
Why
- HA occurs worldwide and is one of the most common vaccine-preventable diseases in travellers.
- Recovery from HA infection may take months; about 25% of adult cases require hospitalization.
Epidemiology

# Disease description

## Infectious agent
Hepatitis A (HA) virus is single serotype, ribonucleic acid (RNA) virus of the *Picornaviridae- family.
For additional information about HA virus, refer to the .

## Reservoir
Humans, rarely chimpanzees and other non-human primates

## Transmission
HA is transmitted via the fecal-oral route, which can occur from direct person-to-person contact, from contamination of the environment or objects, or through contaminated food or water. Transmission through infected blood or blood products has also been reported. Symptoms appear after an incubation period of 15 to 50 days (average 28 days). Cases are typically infectious 2 weeks before the onset of symptoms and remain infectious until 1 week after the onset of jaundice. The virus may remain infectious in the environment for several weeks. Viral shedding can be greatly prolonged in immunocompromised individuals.

## Risk factors
Although many reported cases of HA have no identifiable risk factor, following individuals are considered to be at increased risk of HA infection:
- Travellers to HA-endemic countries. Studies estimate that 44% to 55% of reported HA cases in Canada are linked to travel. Low-budget travellers, volunteer humanitarian workers, and Canadian-born children of new Canadians returning to their country of origin to visit friends and relatives, may be at increased risk. The risk of HA for susceptible travellers to developing countries is estimated to range from 0.1/1,000 to 1/1,000 per month.
- Individuals living in communities at risk of HA outbreaks or in which HA is endemic.
- Household or close contacts of children adopted from HA-endemic countries.
- Men who have sex with men (MSM).
- Injectable and non-injectable illicit drug users.
- Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus.
- Military personnel and humanitarian relief workers who are likely to be posted to areas with high rates of HA.
- Zoo-keepers, veterinarians and researchers who handle non-human primates.
- People receiving repeated replacement of plasma-derived clotting factors.
Many reported cases of HA have no identifiable risk factors.
People at increased risk of severe illness or complications from HA infection include:
- Individuals with chronic liver disease
- Individuals over 60 years of age

## Spectrum of clinical illness
The severity of HA increases with age and can range from asymptomatic or a short lasting and mild illness to a severely disabling disease lasting several months. Children less than 6 years of age are commonly asymptomatic or present with mild disease without jaundice, and represent an important source of infection, particularly for household members and other close contacts. In older children and adults, HA is typically symptomatic with the majority of individuals developing anorexia, nausea, fatigue, fever and jaundice, usually lasting less than two months. Older persons, and individuals with chronic liver disease and immunocompromising conditions, have an increased risk of progressing to fulminant hepatic failure resulting in death.
Approximately 25% of adult cases are hospitalized. The overall case fatality rate is approximately 0.5%, but can reach 2.6% in adults over 60 years of age. Individuals with chronic liver disease and immunocompromising conditions have an increased risk of progressing to fulminant hepatic failure resulting in death. Chronic hepatitis and carrier states are not associated with HA; however, relapsing hepatitis lasting up to a year occurs in 15% of cases.

# Disease distribution

## Incidence and prevalence

### Global
HA occurs worldwide. The World Health Organization (WHO) estimates an annual total of 1.5 million case of hepatitis A worldwide, but seroprevalence data suggest that tens of millions of infections occur each year. Regions with higher levels of HA endemicity and risk of transmission include: South Asia, Sub-Saharan Africa, Central Asia, Latin America, North Africa, Middle East, and Oceania. A  is available from the WHO.

### National
Since the introduction of HA vaccine in Canada in 1996, the incidence of HA has declined. The number of cases of HA reported annually has varied from 2,978 (1991) to 246 (2012). From 2006 to 2012, age specific-incidence was highest among children 5 to 9 years old with a rate of 2.24 per 100,000, followed by children aged 1 to 4 years of age. Given the under-diagnosis and under-reporting of HA and the occurrence of subclinical infections, the actual number of HA cases is estimated to be 7 times higher than reported. From 2006 to 2010, the annual hospitalization rate for individuals over 40 years of age was 30%.
Preparations Authorized for Use in Canada

# Hepatitis A-containing vaccines
- AVAXIM (adult formulation) and AVAXIM- Pediatric (paediatric formulation) (inactivated hepatitis A vaccine), Sanofi Pasteur Limited. (HA)
- HAVRIX 1440 (adult formulation) and HAVRIX 720 Junior (paediatric formulation) (inactivated hepatitis A vaccine), GlaxoSmithKline Inc. (HA)
- TWINRIX (adult formulation) and TWINRIX Junior (paediatric formulation) (combined hepatitis A and hepatitis B  in Part 4 for additional information about HAHB vaccine.
- VAQTA (adult presentation) and VAQTA (pediatric/adolescent presentation) (inactivated hepatitis A vaccine), Merck Canada Inc. (HA)

# Human immunoglobulin
- GamaSTAN (immunoglobulin ), Grifols Therapeutics LLC. (Ig)
Standard human immunoglobulin (GamaSTAN) is a sterile, concentrated solution for intramuscular (IM) injection containing 15% to 18% immunoglobulin. It is obtained from pooled human plasma from screened donors and contains mainly IgG with small amounts of IgA and IgM.
Preparations authorized for use in Canada may not be currently available for sale. Refer to Health Canada's  (DPD) for its drug status. Definitions of drug status can be found under .
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's .
Immunogenicity, Efficacy and Effectiveness

# Immunogenicity
Protective concentrations of antibody against HA develop in 95% to 100% of vaccine recipients after 1 dose of HA vaccine, and nearly 100% seroconvert after receiving 2 doses of vaccine.

## Pre-exposure
HA vaccine is recommended for pre-exposure immunization of persons 6 months of age and older at increased risk of infection or severe HA (refer to ). People who wish to decrease their risk of acquiring HA should also be encouraged to be vaccinated. With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to  in Part 4 for information about HAHB vaccine.

## Post-exposure
The use of HA vaccine in susceptible populations interrupts HA outbreaks. The protective efficacy of HA vaccine when used within 1 week of exposure is approximately 80%.
Recommendations For Use

# Pre-exposure immunization

## HA-containing vaccine
HA vaccine is recommended for pre-exposure immunization of persons 6 months of age and older at increased risk of infection or severe HA (refer to ). People who wish to decrease their risk of acquiring HA should also be encouraged to be vaccinated. With few exceptions, people with indications for both HA and hepatitis B (HB) vaccine should be immunized with combined HAHB vaccine. Refer to  in Part 4 for information about HAHB vaccine.

## Schedule

### Monovalent HA vaccine
One dose of monovalent HA vaccine should be given for primary immunization with a booster dose given at least 6 to 36 months later, depending on the product. .
There is no international standard for HA antigen measurement. Each manufacturer uses different units of measurement.
Ages for which the vaccine is recommended for use
ELISA: enzyme-linked immunosorbent assay

### HAHB vaccine
Once an HAHB vaccine series is started, it is preferable to complete the series with an HAHB vaccine. Monovalent HA vaccine may be used to complete a HA series started with HAHB vaccine. Refer to  for options for completing a HA vaccine series. Refer to  in Part 4 for additional information about HAHB vaccine.
Once an HAHB vaccine series is started, it is preferable to complete the series with an HAHB vaccine. HA vaccine may be given if HAHB vaccine is not available and only HA protection is needed.
In children, 8 to 10 years of age, a 2 dose schedule with paediatric HAHB vaccine given at months 0 and 6 has been tested with good results.
In children, 12 months to less than 16 years of age, 2 doses of adult HAHB vaccine is a recommended schedule. In children, 16 to less than 19 years of age, vaccine provider discretion is advised as there is no evidence or authorized schedule for this situation; an adult schedule of 3 doses should be considered.
Abbreviations:
 HA: hepatitis A
 HAHB: hepatitis A, hepatitis B

### Human immunoglobulin (pre-exposure prophylaxis)
HA vaccine is the preferred agent for pre-exposure prophylaxis. Human immunoglobulin (Ig) will provide protection against HA when administered intramuscularly before exposure and may be indicated for pre-exposure prophylaxis in the following groups:
- Infants less than 6 months of age
- Immunocompromised persons because their immune response to HA vaccine may be suboptimal. Ig should be considered in this group in addition to HA vaccine
- People for whom HA vaccine is contraindicated, i.e. individuals with a history of anaphylaxis after previous administration of the HA vaccine and those with proven immediate or anaphylactic hypersensitivity to any component of HA vaccine or its container
The effectiveness of Ig depends upon the timing of administration and the dose given. Administering Ig immediately before travel will ensure that protective concentrations of antibody are adequate for travel. The recommended dose of Ig varies according to the duration of required protection. The following doses of GamaSTAN are recommended for persons who plan to travel in areas where hepatitis A is common:
- Up to 1 month: 0.1 mL/kg of body weight
- Up to 2 months: 0.2 mL/kg
- 2 months and longer: repeat dose of 0.2 mL/kg every 2 months

# Booster doses and re-immunization
Protective concentrations of HA antibody will likely persist for at least 20 years, possibly for life, following immunization with 2 doses of HA-containing vaccine. Immune memory has been demonstrated, indicating that protection may persist even when antibodies are no longer measurable.

# Post-exposure immunization
Post-exposure prophylaxis should be offered to household and close contacts of proven or suspected cases of HA. It should be given to contacts when HA occurs in group child care centres and kindergartens, and should be offered to co-workers and clients of infected food handlers. Post-exposure prophylaxis is not necessary for other contacts, such as school, workplace or health care workers caring for HA cases, unless an outbreak is suspected.

## HA vaccine
HA vaccine is effective as post-exposure prophylaxis to prevent infection in household and close contacts and is recommended in preference to Ig for healthy people 6 months of age and older, unless contraindicated or unavailable. One dose of HA vaccine should be given to susceptible contacts as soon as possible and preferably within 14 days of last exposure. However, HA vaccine should still be considered if more than 14 days have elapsed since last exposure, as there are no data on the outer limit of efficacy.
Immunocompromised people and people with chronic liver disease should receive Ig in addition to HA vaccine. Susceptible adults, 60 years of age and older, may be given Ig in addition to HA vaccine.

## Human immunoglobulin (post-exposure prophylaxis)
Hepatitis A (HA) vaccine is the preferred agent for post-exposure prophylaxis. Ig is the recommended post-exposure immunoprophylactic agent in the following situations:
- for infants less than 6 months of age
- for persons with a history of anaphylaxis after previous administration of the HA vaccine and those with proven immediate or anaphylactic hypersensitivity to any component of the HA vaccine or its container
- for immunocompromised persons and people with chronic liver disease:
	+ these individuals should receive Ig in addition to HA vaccine because of increased risk of severe disease and a suboptimal immune response to HA vaccine
- susceptible adults, 60 years of age and older who are household or close contacts of a case of HA, may be given Ig in addition to HA vaccine because of the reduced response to HA vaccine and increased risk of severe disease with increasing age
- if HA vaccine is unavailable
For post-exposure prophylaxis, the recommended dose of GamaSTAN is 0.1 mL/kg of body weight. Ig should be given as soon as possible after an exposure. Efficacy of Ig is unknown if more than 14 days have elapsed since the last exposure, there is no recommendation for its use after this time period. Individuals receiving replacement intravenous Ig (IVIg, 400 mg/kg of body weight or higher) are considered protected and do not require Ig if the last dose of IVIg was received within the 3 weeks prior to HA exposure.
Vaccination of Specific Populations

# Persons with inadequate immunization records
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. HA vaccine may be given, if indicated, regardless of possible previous receipt of the vaccine or pre-existing immunity, because adverse events associated with repeated immunization have not been demonstrated.

# Pregnancy and breastfeeding
The efficacy and safety of HA vaccines given during pregnancy has not been studied, but there is no theoretical reason to suspect an increased risk of adverse events to the mother or the infant. HA vaccine should be considered for pregnant women in high risk situations when benefits outweigh risks, such as for post-exposure prophylaxis or travel to HA-endemic areas. HA vaccine may be administered, if indicated, to women who are breastfeeding.

# Persons with chronic diseases

## Chronic renal disease and patients on dialysis
HA vaccine is recommended for people with chronic renal disease or undergoing dialysis if they are at increased risk of HA infection or severe HA (refer to ). A study assessing the immune response of hemodialysis patients to standard doses of HA vaccine demonstrated a good HA antibody response and no serious adverse effects.

## Chronic liver disease
HA immunization is recommended for susceptible persons with chronic liver disease, including those infected with hepatitis C and chronic HB carriers, because they are at risk of more severe disease if infection occurs. Vaccination should be completed early in the course of the disease, as the immune response to vaccine is suboptimal in advanced liver disease.

## Non-malignant hematologic disorders
HA immunization is recommended for people receiving repeated replacement of plasma-derived clotting factors. The solvent-detergent method used to prepare plasma-derived clotting factor concentrates from pooled plasma may not reliably inactivate HA virus. However, historically, there has been no evidence of HA transmission from clotting factors in Canada and the risk of transfusion-related HA is extremely low because all pooled plasma is tested for HA. Due to a theoretical possibility of infection, HA immunization of individuals receiving large quantities of plasma-derived products used in the treatment of conditions requiring clotting factor substitution may be considered.

# Immunocompromised persons
HA vaccine may be administered to immunocompromised persons. Vaccine efficacy may be reduced in immunocompromised people; however, HA vaccine will provide some protection and should be considered for pre-exposure and post-exposure use when indicated. In addition to HA vaccine, Ig should be considered for pre-exposure and post-exposure management of immunocompromised persons unless receiving routine Ig replacement therapy. Serologic testing to determine immune status may be considered in immunocompromised people when considering the use of Ig prior to potential exposure (for example, travel to HA-endemic areas).
When considering immunization of an immunocompromised person, consultation with the individual's attending physician may be of assistance. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.

# Travellers
Hepatitis A is one of the most common vaccine-preventable diseases in travellers. Protection against HA is recommended for all travellers to HA-endemic countries, especially to rural areas or places with inadequate sanitary facilities. A  is available from the WHO.
Given the long incubation period for HA and the demonstrated efficacy of post-exposure use of HA vaccine, HA vaccine may be administered up to the day of departure. Ig may be used for prophylaxis in people for whom HA vaccine is contraindicated or in people for whom HA vaccine may have reduced effectiveness, such as those who are immunocompromised. Refer to .
For travellers who are susceptible to both HA and HB virus, HAHB vaccine can be used, if appropriate. For travellers presenting less than 21 days before departure, monovalent HA and HB vaccines should be administered separately, with the completion of both vaccine series required after travel. Refer to .
Serologic testing may be considered in travellers likely to be already immune. Refer to . Refer to  in Part 3 for additional information.

# Persons new to Canada
Health care providers who see persons newly arrived in Canada should review the immunization status and update immunization for these individuals, as necessary. In many countries outside of Canada, HA vaccine is in limited use.
HA vaccination should be considered for all persons from HA-endemic countries. Individuals born in HA-endemic countries are more likely to be immune to HA; therefore, serologic testing for immunity before HA immunization should be considered. If persons from HA-endemic countries are not immune, they should be offered HA immunization because they are at increased risk for HA exposure through visits to their country of origin, or when receiving friends and family from their country of origin.
In addition, persons new to Canada should be tested for hepatitis C antibody and susceptible persons chronically infected with hepatitis C should be vaccinated against HA and HB. Persons new to Canada should also be tested for HB and vaccinated against HA if found to be a HB carrier. Household or close contacts of children adopted from HA-endemic countries should be immunized with HA-containing vaccine. Adults travelling to pick up adopted children from HA-endemic countries should be vaccinated before departure.

# Workers
Pre-exposure HA vaccination is recommended for:
- Military personnel and humanitarian relief workers likely to be posted abroad to areas with high rates of HA
- Zoo-keepers, veterinarians and researchers who handle non-human primates
- Workers involved in research on HA virus or production of HA vaccine who may be exposed to HA virus
Serologic Testing

# Pre-immunization
Pre-immunization serologic testing should be considered in populations with potentially higher levels of pre-existing immunity, such as Canadians born before 1945, people from HA-endemic areas, and people with a history of hepatitis or jaundice that may have been caused by HA.

# Post-immunization
Serologic testing is not recommended after receiving HA-containing vaccine. Post-HA vaccine serologic testing has poor sensitivity. If the serologic test result is positive after immunization, the person can be presumed to be immune; however, a negative test result does not mean that the person is susceptible.
Administration Practices

# Dose
For the dosage of human immunoglobulin for post-exposure prophylaxis, refer to .

# Route of administration
HA-containing vaccine should be administered intramuscularly.
Large volumes of immunoglobulin for IM injection (greater than 2 mL for children or greater than 3 to 5 mL for adults, depending on muscle mass) should be divided and injected at 2 or more sites.

# Interchangeability of vaccines
Monovalent HA vaccines may be used interchangeably. Any HA-containing vaccine indicated for the age of the vaccine recipient will provide an effective booster dose after a first dose of vaccine from a different manufacturer.

# Concurrent administration of vaccines
HA vaccine may be administered concomitantly with other vaccines or with Ig. Different injection sites and separate needles and syringes must be used for concurrent parenteral injections.
If concurrently providing HA-containing vaccine and Ig, separate anatomic injection sites (different limbs) should be used for each injection.
Passive immunization with human Ig preparations can interfere with the immune response to measles-mumps-rubella (MMR), measles-mumps-rubella-varicella (MMRV) and univalent varicella vaccines (Var). These vaccines should be given at least 14 days prior to administration of a human Ig preparation, or delayed until the antibodies in the Ig preparation have degraded. Refer to  in Part 1 for additional information.
Storage Requirements
Human Ig preparations should be stored at +2C to +8C. Do not freeze.
Safety and Adverse Events

# Common and local adverse events

## HA vaccine
HA vaccine is well tolerated. Reactions are generally mild and transient, and are usually limited to soreness and redness at the injection site. Other less frequent reactions include headache, irritability, malaise, fever, fatigue and gastrointestinal symptoms. Injection site reactions occur less frequently in children (21%) than in adults (56%) as do mild, systemic events (2% to 9% versus 16%). No significant difference in reactions is evident between initial and subsequent doses of vaccine or in the presence of pre-existing immunity.

## HAHB vaccine

## Ig
Injection site reactions following receipt of standard human Ig include tenderness, erythema and stiffness of local muscles, which may persist for several hours. Mild fever or malaise may occasionally occur.

# Less common and serious or severe adverse events
Less common side effects following receipt of standard human Ig include flushing, headache, chills and nausea. Urticaria, angioedema and anaphylactic reactions may occur rarely.

# Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.

# Contraindications and precautions
HA-containing vaccines and Ig are contraindicated in persons with a history of anaphylaxis after previous administration of the product and in persons with proven immediate or anaphylactic hypersensitivity to any component of the product. Human Ig preparations should not be given to people with known isolated IgA deficiency unless the benefit outweighs the risk, in which case the product should be given with caution and under close observation. Refer to  in Part 1 for lists of vaccines and passive immunizing agents authorized for use in Canada and their contents. Refer to  in Part 4 for information about HAHB vaccine.
The efficacy and safety of HA vaccine given during pregnancy has not been studied in clinical trials, but there is no theoretical reason to suspect an increased risk of adverse events to the mother or the infant.
Administration of HA-containing vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness, with or without fever, may be vaccinated.