Vaccine-Preventable Diseases

Hepatitis B

Hepatitis B virus is one of several viruses that cause hepatitis. Initial infection with the virus may be asymptomatic in up to 50% of cases. Acute illness, when it occurs, may last up to 3 months with an estimated case-fatality rate as high as 1%. An infected individual, with either symptomatic or asymptomatic acute infection, may become a chronic carrier. The risk of becoming a carrier varies inversely with the age at which infection occurs. It is highest in infants (90% to 95%) and relatively low in adults (6% to 10%). Infection with hepatitis B is usually associated with exposure to blood or infectious body fluids. Common means of transmission include heterosexual or homosexual contact, injection drug use, and perinatal transmission (mother to infant). The risk of transfusion-related hepatitis B is very low because of routine hepatitis B surface antigen (HBsAg) screening of donated blood and donor selection. Infections also occur rarely in settings of close personal contact via unrecognized contact with infective fluids. In a significant proportion of patients, no risk factor can be identified.

Data from the CIDPC National Notifiable Diseases Registry System (NNDRS) indicate that there has been little change in the reported incidence (an average of 2,868 cases or 10.3 per 100,000 population per year from 1990 to 1994) of hepatitis B in Canada over the last several years. However, there have been (and continues to be) substantial differences in types of hepatitis B infections reported from the provinces and territories to LCDC. For example, since 1990, Ontario excludes "carrier" cases and, for Quebec and British Columbia, "acute" and "indeterminate" cases are combined in the NNDRS. Further, national statistics for hepatitis B are driven by the large number of cases reported from British Columbia - 40% of all the cases in Canada from 1990 to 1994.

In the NNDRS, males have a consistently higher rate of reported hepatitis B than females (12.2 versus 8.8 per 100,000 population in 1994). The highest age-specific rates of reported hepatitis B are in those 20 to 39 years of age with low rates among those > 59 years of age, and very low rates among persons < 15 years of age.

In contradistinction to the NNDRS data, analysis of "acute cases" of hepatitis B from provinces and territories indicates that there has been a reduction in their rates in several jurisdictions (e.g. Alberta, Ontario) as well as in Canada as a whole in the last several years (close to 29% from 1992 to 1995 in Canada). A decrease in acute hepatitis B rates is consistent with that reported in the United States. The only reported outbreak of hepatitis B in Canada in 1995 to 1996 involved 75 cases in Ontario that were linked to the reuse of subdermal electrodes by a technician who carried hepatitis B e antigen.

Information about risk factors for acquiring hepatitis B is not routinely provided to the NNDRS. However, some provinces recently have reported risk-factor information for hepatitis B in provincial epidemiologic documents. For example, in Ontario, the following risk factors were found for "acute" cases in 1994 (a case could have more than one risk factor): injection drug use (13%), homosexual/bisexual male (6%), heterosexual with multiple partners (9%), sexual contact of a carrier (8%), household contact of a case (4%), other risk factors (23%), and no identifiable risk factor (38%).

1998 Update:  The 1998 crude incidence of 5.6/100,000 population for hepatitis B varied little from the 5.3/100,000 seen in 1997, but does continue to decline over time (Figure 1). The 1998 age-specific incidence remains highest among 25- to 29-year olds at 9.4/100,000 (207 cases) followed by  20- to 24-year olds at 8.3/100,000 (169 cases) and 30- to 39-year olds at 8.2/100,000 (430 cases). More cases continue to be diagnosed in males than females at a ratio of 5:2.

Figure 1) Crude incidence of hepatitis B reported in Canada, 1986 to 1998

Hepatitis B Vaccine

Two monovalent recombinant DNA hepatitis B vaccines are licensed in Canada: Recombivax HBT and Engerix-BT. Both vaccines contain purified HBsAg produced from a genetically engineered yeast strain. Recombivax HBT vaccine contains 10 µg/mL and Engerix BT vaccine 20 µg/mL of purified HBsAg. A preparation of Recombivax HBT containing 40 µg/mL is available for use in hemodialysis patients and others in whom hyporesponsiveness is likely. Trace amounts of yeast antigens are present in the vaccines, but no increase in yeast antibody titres has been observed following administration of either vaccine.

For hepatitis B vaccine, the required dose in micrograms should be established and that dose administered using any appropriate formulation (see the Table and the section Schedule and Dosage in the Guide).

In most preparations, the antigen is adsorbed onto aluminum hydroxide with thimerosal as preservative. A preparation of Recombivax HBT is available without thimerosal and contains 5 µg of HBsAg in 0.5 mL. It is recommended for the immunization of infants. If thimerosal-free vaccine is not available, post-exposure immunoprophylaxis for infants born to infected mothers should still be undertaken without delay, because of the high risk of long-term complications if infection occurs. With regard to other indications for immunization in infants, immunization should be deferred until 2 months of age unless a thimerosal-free vaccine is used. As this vaccine becomes more available and sufficient supplies for neonates are assured, it should become the vaccine preparation of choice against hepatitis B.

Hepatitis B vaccines induce anti-HBs production, which confers immunity to hepatitis B. A protective level of anti-HBs is 10 international units per litre. Antigenic subtypes of HBV exist, but immunization confers immunity to all subtypes because of the presence of a common antigen. Hepatitis B vaccines are licensed in Canada for pre-exposure and post-exposure prophylaxis.

Plasma-derived hepatitis B vaccine has not been available in Canada since the early 1990s.

Hepatitis B immune globulin (HBIG) is prepared from pooled human plasma from selected donors who have a high level of anti-HBs and are seronegative for bloodborne infections. It provides immediate short-term passive immunity. HBIG administered concurrently with vaccine, but at a different site, does not interfere with the antibody response of the vaccine.

Formulations combining antigen against both HAV and HBV are also licensed in Canada for adults and children (see Hepatitis Vaccines Combined in the Guide.

Efficacy and Immunogenicity

Use of the recommended schedule and routes of immunization results in seroconversion rates of 90% to 99% in immunocompetent individuals, depending on age. The antibody response is lower in patients with diabetes mellitus (70% to 80%), renal failure (60% to 70%) and chronic liver disease (60% to 70%) as well as in immunocompromised patients, such as those infected with HIV (50% to 70%). Immunization of obese people, smokers and those with alcoholism also produces lower antibody titres.

Antibody response in general decreases with age. Children between age 2 and 19 years have the highest response rate (99%), and children < 2 have a 95% response rate. The response rate for older individuals is as follows: 20 to 29: 95%; 30 to 39: 90%; 40 to 49: 86%; 50 to 59: 71%; and > 60: 50% to 70%. The immune mechanisms for suboptimal response to hepatitis B vaccine are not well understood.

Studies in areas of the world where HBV is endemic have consistently shown decreases in HBV incidence when hepatitis B vaccine is used in infant immunization programs. These studies also show persistence of protection until at least age 5, the highest risk period of transmission from infected mother to child. As well, hepatitis B vaccine reduces the incidence of hepatocellular carcinoma and liver cirrhosis by preventing chronic HBV carriage.

Recommended Usage

Universal immunization

Universal immunization against HBV is now part of the publicly funded vaccine programs offered in all provinces and territories. The age at which children and adolescents are offered hepatitis B vaccine varies from jurisdiction to jurisdiction. Should effective combination vaccines, including hepatitis B and other childhood vaccines, become available in Canada for infants, NACI would support their use. If childhood immunization against HBV is given in infancy, the level and duration of protection may be better if the last dose is given after the first birthday. Because of the possibility of persistence of maternal antibody, an unimmunized child who is positive for either anti-HBs or anti-HBc should still receive hepatitis B vaccine.

Pre-exposure prophylaxis

 Health care and emergency service workers and other occupational exposure

Immunization with hepatitis B vaccine is recommended for those people who are at increased risk of occupational infection, namely, those exposed frequently to blood, blood products and bodily fluids that may contain the virus. This group includes all health care workers and others who will be or may be exposed to blood or are at risk of injury by instruments contaminated by blood. For these workers, a series of hepatitis B immunizations should be initiated at the first opportunity. Students in these occupations should complete their vaccine series before possible occupational exposure to blood or sharps injuries. Emergency service workers, such as police and firefighters, may also be at higher risk of exposure, although there are currently no data to quantify their risk. Workers who have no contact with blood or blood products are at no greater risk than the general population.

Others at increased risk

• residents and staff of institutions for the developmentally challenged;
• males having sexual contact with other males;
• others with multiple sexual partners or with a recent history of a sexually transmitted disease;
• injection drug users;
• hemophiliacs and others receiving repeated infusions of blood or blood products;
• hemodialysis patients (40 µg of vaccine antigen per dose should be used);
• staff and inmates of long-term correctional facilities;
• household and sexual contacts of acute HBV cases and HBV carriers;
• populations or communities in which HBV is highly endemic;
• children < 7 years of age whose families have immigrated to Canada from areas where there is a high prevalence of hepatitis B and who may be exposed to HBV carriers through their extended families;
• travellers to hepatitis B endemic areas;
• children in child care settings in which there is an HBV infected child;
• any person who wishes to decrease his or her risk of acquiring HBV.

Post-exposure prophylaxis

 Infants
Because of the importance of preventing hepatitis B infection in infants, all pregnant women should be routinely tested for HBsAg. All infants born to infected mothers should be given the initial dose of HBV vaccine within 12 hours of birth. The second and third dose of the vaccine series should be given 1 and 6 months after the first. An intramuscular dose of 0.5 mL HBIG should also be given immediately after birth, since its efficacy decreases sharply after 48 hours. Vaccine and HBIG may be given at the same time but at different sites. If exceptional circumstances prevent immediate administration of vaccine and HBIG, they should be given at the first possible opportunity. Their administration, however, should never be delayed unnecessarily.

Neonates weighing less than 2000 g born to infected mothers should have an individualized schedule that includes at least four doses of vaccine, HBIG and assessment of antibody response after the series has been completed.

If maternal testing has not been done during pregnancy, it should be done on an urgent basis at the time of delivery. If maternal HBV status is not available within 12 hours of delivery, serious consideration should be given to administering vaccine and HBIG while the results are pending, taking into account the mother's risk factors and erring on the side of providing vaccine and HBIG if there is any suspicion that the mother could be infected. If the mother is ultimately shown to have HBV infection, a series of vaccine should also be given to the infant, as described earlier.

Should the mother's infection be recognized during lactation, the infant's HBV status should be assessed urgently and the infant started immediately on full immunoprophylaxis, which should be completed if the infant is found not to be already infected or immune.

When a mother is infected with HBV, testing of the infant for HBsAg and anti-HBs is recommended 1 month after completion of the vaccine series to monitor the success of immunoprophylaxis. If HBsAg is found, the child is likely to become a chronic carrier. If the infant is negative for both HBsAg and anti-HBs (i.e., a non-responder), additional doses up to a second full course of vaccine should be given, with repeated serologic testing for antibody response.

Accountability mechanisms should be in place to ensure that every infant born to an infected mother receives a full course of vaccine and HBIG expeditiously as well as testing for serologic response to the vaccine (see Serologic Testing).

Percutaneous (needlestick) or mucosal exposure
Figures 1 and 2 on pages 108-110 of the Guide, outline the management of vaccinated or unvaccinated individuals after potential exposure to hepatitis B, including injury by needles found on the street. The management of potential percutaneous or mucosal exposure to HBV should be based on the immunization and antibody status of the injured person and the infectious status, if known, of the source. It is critically important to ascertain whether the exposed individual has received a full and properly administered course of hepatitis B vaccine and to assess the post-vaccination anti-HBs antibody level. Therefore, all health care workers and health care students should have their antibody status assessed and documented after immunization.  

Testing of the source should be conducted according to Health Canada guidelines (CCDR 1997;23S2) with informed consent and respect for confidentiality. If the assessment results of the injured person and the source are not available within 48 hours, management of the injured person should assume possible exposure.

Sexual and household contacts of hepatitis B
All sexual and household contacts of acute cases and chronic carriers should be immunized with hepatitis B vaccine. If prophylaxis can be started within 14 days of the last sexual contact with the HBV infected person, a single dose of HBIG (0.06 mL/kg) should also be given. Unimmunized sexual assault victims should be managed in the same manner if the assailant is infected with HBV or cannot be assessed. All sexual partners of people with HBV infection should be counselled that protection from infection cannot be ensured until the course of vaccine has been completed and protective levels of anti-HBS demonstrated. Counselling on the use of condoms and their ability to reduce but not eliminate the risk of transmission should be completed.

HBIG is not indicated for household contacts of an acute HBV case; exceptions are infants < 12 months of age when the mother or primary care giver is acutely or chronically infected, sexual contacts as described above, and people with identifiable exposure to the infected person's blood, as occasioned by shared toothbrushes or razors.

People who do not routinely require hepatitis B vaccine

• Social contacts of HBV cases and carriers who do not live in the same household and are not sexual contacts
• Workers whose jobs do not normally involve exposure to infectious blood, bodily fluids or items potentially contaminated with HBV

Schedule and Dosage

If the vaccine is given in a more condensed schedule, earlier protection will be provided. Engerix-BT may be used in a rapid schedule at 7, 14, 21 and 365 days.

The last dose should be given as closely as possible to 12 months after the first, since there is evidence that the antibody response will be greater and more durable. There is no benefit in giving the last dose later than 12 months after the first, with the possible exception of infants. If Engerix-BT is used at 0, 1 and 2 months, the manufacturer recommends a fourth dose at 12 months.

Recombivax HBT has been licensed for a two-dose schedule in 11 to 15 year olds, using the adult formulation of 10 µg at 0 and 4-6 months.

For infants born to HBsAg infected mothers, for those who may have a diminished response to the vaccine and for the two-dose adolescent schedule, the timing of doses should be carefully respected.

Vaccines produced by different manufacturers can be used interchangeably when three or more doses are given, despite different levels of antigen. The dosage used should be that recommended by the manufacturer. The exception to interchangeability is the two-dose adolescent schedule.

Interruption of the immunization schedule does not require that any dose be repeated if the minimum intervals between doses are respected. If any dose has not been given according to an approved schedule, it should be given at the first opportunity.

If years have elapsed between the first and second dose, it may be prudent to assess antibody response when the series is complete, especially if the patient is at significant risk of infection.

The dose of vaccine administered varies with age, the product used and with some medical conditions. In general, higher doses of antigen, more frequent doses and a greater number of total doses may assist in improving the antibody response in people likely to respond poorly. Doses of 40 µg are recommended for adult hemodialysis patients and others listed in Recommended Usage in whom response may be less than optimal.

A specific formulation for dialysis patients and others is available (Recombivax HBT), which contains 40 µg per mL, to be given at 0, 1 and 6 months. When the required dose is achieved using two adult vials of Engerix BT (20 µg per mL each), the manufacturer recommends a series of four immunizations at 0, 1, 2 and 6 months. If patients will be at continued risk of exposure to HBV, post-immunization testing should be carried out to assess antibody levels and additional doses of vaccine given to those not adequately protected.

For children undergoing hemodialysis, the common practice is to double the dose for the child's age and assess the antibody response when the series is complete.

Route of Vaccine Administration

Booster Doses and Re-immunization

Routine boosters in immunocompetent people are not needed since protection has been shown to last for at least 15 years. In addition, people who have had protective antibody level previously demonstrated will not develop markers of infection when exposed to HBV, whether or not antibody has waned. This observation is likely due to an anamnestic response to HBV challenge. Thus, absence of detectable anti-HBs in a person who has been previously demonstrated to have anti-HBs does not mean lack of protection, because immune memory persists. Booster doses in this situation are not indicated. Studies of long-term protective efficacy, however, will determine whether booster doses of vaccine are ever needed.

Additional doses of vaccine up to three doses will produce a protective antibody response in 50% to 70% of otherwise healthy people who fail to mount a response after the first series of vaccines. Administration of additional doses with testing for response after each dose should be undertaken when the response to vaccine needs to be ensured. Individuals who fail to respond to three additional doses of vaccine are unlikely to benefit from further immunization.

Immunocompromised people often respond suboptimally to the vaccine and may need additional antigen to mount a response. Should protection be achieved and then wane, however, subsequent HBV exposure in these individuals can result in acute disease or the carrier state. Therefore, in this population boosters may be necessary for those who have mounted an initial response. The optimal timing of booster doses for immunocompromised individuals who are at continued risk of HBV exposure and have mounted an initial response is not known. Periodic monitoring for the presence of anti-HBs should be considered, taking into account the severity of the compromised state and whether the risk for HBV is still present. Should antibody testing show subsequent suboptimal protection, a booster dose and re-testing should be undertaken as necessary.

Serologic Testing for Hepatitis B Antigen and Antibody Pre-immunization

 Pregnancy
All pregnant women should be routinely tested for HBsAg at the first prenatal visit. If testing has not been done during pregnancy, it should be done at the time of delivery.

A pregnant woman who has no markers of acute or chronic HBV infection but who is at high risk of acquiring HBV should be offered the vaccine at the first opportunity and tested for antibody response. Repeat testing before delivery may be considered in uninfected and unimmunized women with continuing high-risk behaviour. Infants born to HBsAg positive mothers should receive post-exposure prophylaxis.

Adopted children at high risk
Children adopted from countries, geographic regions or family situations in which there is a high prevalence of HBV infection should be screened for HBsAg, and if they are positive the household contacts should be immunized before adoption.

Others at high risk for HBV infection
Routine pre-immunization serologic testing for hepatitis B, including HBsAg, anti-HBs or anti-HBc, is recommended for people at high risk of having been infected. This testing will identify those already infected or immune, for whom vaccine will confer no benefit. Testing will also assist in the medical management and contact follow-up of those individuals found to be already infected, and will prevent the mistaken belief that they pose no risk to others. The cost of such testing may or may not be less than the cost of immunization, depending on the HBV prevalence in the high-risk population. Routine pre-immunization serologic screening, however, is not practical for universal immunization programs.

Post-immunization

In particular, post-immunization testing for anti-HBs should be conducted on all health care workers and students in health care disciplines to establish antibody response and the need for re-immunization should the first course of vaccine fail to provide protection. Ideally, testing should be undertaken at least 1 month but no later than 6 months after the last dose of vaccine. If a health care worker has completed immunization against HBV more than 6 months previously, testing for anti-HBs should still be done as part of the routine occupational health assessment or when a potential exposure occurs. This type of routine assessment will be even more important as new professionals, immunized as adolescents, begin their training.

The results of post-immunization testing should be recorded in the individual's medical file and provided to the tested person. If protective antibody is documented, testing need not be repeated nor should further immunization be undertaken, even when a definite exposure occurs. If a health care worker never before tested is found not to have protective antibody, re-immunization with a second course of vaccine is indicated. If testing is done beyond the recommended 6-month window, a negative test may indicate primary vaccine failure or waning antibody but with an anamnestic response to challenge with virus or vaccine. In either case, re-immunization is indicated, as it is impossible to differentiate between these two possibilities.

Testing for protective levels of anti-HBs after each dose of a second series may eliminate the need for further doses, once a protective level has been achieved.

Determination of antibody response after re-immunization is complete will identify those who do not respond to two courses of vaccine and who will need passive immunization after potential exposure to hepatitis B.

In addition, those who are immunocompromised should also be tested after the vaccine course is complete. If protective antibody is not present, the vaccine course should be repeated, and if protective antibody is still not present, the individual should receive counselling on alternative risk reduction measures. If an antibody response ultimately occurs in an immunocompromised person, periodic reassessment of antibody and booster doses may be indicated, as noted above.

Storage Requirements

Simultaneous Administration with Other Vaccines

Adverse Reactions

As with all vaccines, anaphylaxis is very rare but can occur. Cases of rheumatoid arthritis and demyelinating diseases of the central nervous system have been reported rarely, but a causative link to hepatitis B vaccine has not been identified despite exhaustive and ongoing research. It is likely that any temporal association is coincidental.

Adverse reactions have not been observed when hepatitis B vaccines have been given to people who are immune to hepatitis B or who are hepatitis B carriers.

Contraindications

The only contraindication to hepatitis B vaccine is a previous anaphlyactic reaction to any component of the vaccine.

Precautions

Selected References

Ascherio A, Zhang SM, Hernan MA et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001;344:327-32.

Banatvala J, VanDamme P, Oehen S et al. Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory. Vaccine 2001;19:877-85.

Belloni C, Pistorio A, Tinelli C et al. Early immunisation with hepatitis B vaccine: a five-year study. Vaccine 2000;18:1307-11.

Confavreau C, Suissa S, Saddier P et al. Vaccinations and the risk of relapse of multiple sclerosis. N Engl J Med 2001;344:319-26.

 Duval B, Boulianne G, De Serres G. Should children with isolated anti-HBs or anti-HBc be immunized against hepatitis B virus? JAMA 1997;287:1064. 

Health Canada. An integrated protocol to manage health care workers exposed to bloodborne pathogens. CCDR 1997;23S2. 

Health Canada. Proceedings of the Consensus Conference on Infected Health Care Workers: Risk for Transmission of Bloodborne Pathogens . CCDR 1998;24S4. 

Monteyne P, Andre F. Is there a causal link between hepatitis B vaccine and multiple sclerosis? Vaccine 2000;18:1994-2001.

Salisbury D, Begg, N. Immunisation against infectious disease. HMSO 1996.

Watson B, West DJ, Chilkatowsky A et al. Persistence of immunologic memory for 13 years in recipients of a recombinant hepatitis B vaccine. Vaccine. 2001;19:3164-68.

Zhang J, Zou S, Giulivi A. Hepatitis B in Canada. CCDR 2001;27S3:10-12. 

Zou S, Zhang J, Tepper M et al. Enhanced surveillance of acute hepatitis B and acute hepatitis C in four health regions in Canada 1998-1999. Can J Infect Dis 2001;12(6):357-63.