Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Hepatitis B Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage 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 B virus (HBV) is one of several viruses that cause hepatitis. HBV is a double-stranded DNA virus with three major antigens, known as hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). HBsAg can be detected in serum 30 to 60 days after exposure and persists until the infection resolves. Any person positive for HBsAg is considered infectious. In most cases, anti-HBs appears after HBsAg has disappeared and the infection has resolved. In severe acute HBV infections, anti-HBs may be present simultaneously with HBsAg. In a proportion that varies inversely with age, infection persists. Anti-HBs confers long-term immunity.

HBcAg never appears in serum. Anti-HBc develops in all HBV infections, is not protective and persists indefinitely as a serologic marker, both in chronic active infection and in resolved infection after clearance of HBsAg. Anti-HBc IgM is a marker of recent HBV infection. It appears during the first week of acute hepatitis illness and is usually present for 6-12 months. It can be used to diagnose recent acute hepatitis B. In 10%-15% of cases of chronic hepatitis B infection, IgM anti-HBc may also be detected, particularly when a replication HBV is present. HBeAg is associated with viral replication and high infectiousness. Anti-HBe usually indicates a reduction in replicating virus and lower infectiousness. Methods of quantification of HBV DNA in serum are available to assist in determining both infectiousness and prognosis.

Initial infection with HBV may be asymptomatic in up to 50% of adults and 90% of children. The incubation period is 45 to 160 days, with an average of 120 days. When symptoms occur, they include an insidious onset of anorexia, vague abdominal pain, nausea, vomiting and jaundice. Acute illness may last up to 3 months and has a case fatality rate of 1% to 2%, which increases with age. Fulminant hepatitis and death may also occur in pregnant women and in infants born to infected mothers.

An individual with either acute symptomatic or asymptomatic HBV infection may become a chronic carrier. A chronic carrier is an individual from whom serum samples taken 6 months apart are HBsAg positive or a single serum sample is HBsAg positive and anti-HBc IgM negative. The risk of becoming a chronic carrier varies inversely with the age at which infection occurs (infants: 90% to 95%; children < 5 years: 25% to 50%; adults: 3% to 10%). The risk of becoming a chronic carrier is also greater in immunocompromised patients. Chronic carriers often do not have overt disease but over time are at increased risk of developing hepatic cirrhosis and primary hepatocellular carcinoma. All carriers should be considered infectious.

Since the publication of the 2002 Canadian Immunization Guide the major change is the continuous decline in the incidence of hepatitis B with the increased use of the vaccine. New combination vaccines and new schedules have been approved. Research results have confirmed the safety of the vaccine.

Epidemiology

The epidemiology of the disease has been considerably modified by the introduction of the universal program of immunization and the increased use of vaccine in targeted groups. The incidence of hepatitis B has been decreasing in all age groups in recent years, coinciding with the increasing use of the vaccine (see Figure 5). HBV infection has virtually disappeared in the cohorts that have benefited from the universal immunization programs.

HBV is found mainly in the blood, vaginal secretions, semen and serous fluids of an infected person. It is present in the saliva at concentrations 1,000-10,000 times less than in blood. HBV is transmitted through percutaneous or mucosal contact with infectious biological fluids. It is transmitted from infected mothers to newborns and in settings of close personal contact through unrecognized contact with infectious bodily fluids. It is transmitted through sexual contact, both heterosexual and homosexual, and through contact with blood (needle stick, intravenous drug use with needle sharing). The risk of transfusion-related hepatitis B is extremely low because of routine HBsAg and anti-HBc screening of donated blood and exclusion of donors at risk of infection. The precise role of saliva in the transmission of HBV is not clearly known. Saliva is considered infectious in bite wounds with broken skin involving the percutaneous inoculation of saliva, or when it is visibly tainted with blood. In Canada, like elsewhere, almost one-third of infections have no identified risk factors, despite thorough enquiries.

The regions of the world with the highest prevalence of infection are South-East Asia and Africa, but the use of vaccine in some of these countries for the last 20 years has reduced drastically the incidence of hepatitis B. Although there are no national data on the prevalence of chronic HBV infection for the whole Canadian population, Canada is considered an area of low endemicity. It is estimated that < 5% of residents have markers of past infection, and < 1% are HBsAg carriers. This will vary in different subgroups of the population according to the presence of the factors listed earlier and the vaccine coverage achieved.

Preparations approved for use in Canada

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

• Engerix^®-B (hepatitis B vaccine, recombinant), GlaxoSmithKline Inc.
• Recombivax HB^® (hepatitis B vaccine, recombinant), Merck Frosst Canada Ltd.

Both vaccines contain purified HBsAg produced from a genetically engineered yeast strain. Recombivax HB^® vaccine contains 10 µg/mL and Engerix^®-B vaccine 20 µg/mL of purified HBsAg. A preparation of Recombivax HB^® 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.

The antigen is adsorbed onto aluminum hydroxide. In some preparations thimerosal is used as preservative. Thimerosal has been shown not to be associated with chronic neurological disease despite theoretical concerns raised a few years ago that resulted in the marketing of thimerosal-free HBV vaccines. It is to be emphasized strongly that post-exposure immunoprophylaxis for infants born to infected mothers must be undertaken without delay, regardless of the type of vaccine available, because of the high risk of long-term complications if infection occurs.

Hepatitis B vaccines are approved for use in Canada for pre-exposure and post-exposure prophylaxis.

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 blood-borne 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 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

Antigenic subtypes of HBV exist, but immunization provides immunity to all subtypes because of the presence of a common antigen. Seroconversion (anti-HBs ≥ 1 mIU/mL), seroprotection (anti-HBs ≥ 10 mIU/mL) and geometric mean titre (GMT) are used to assess the immune response. There is a general consensus that a titre of 10 mIU/mL of anti-HBs is an indication of protection. People who reach that titre after immunization are considered protected for life. The GMT reaches a peak 1 month after the last dose of the schedule, drops rapidly up to 6 months and decreases slowly thereafter. The anti-HBs will eventually disappear in most vaccinees, more quickly if the initial titre was low. Fortunately, many studies have demonstrated the persistence of an immune memory, despite the disappearance of anti-HBs. An anamnestic response can be detected 3-5 days after exposure to HBsAg.

The duration of the protection induced has not yet been fully determined since the vaccines began to be used 20 years ago. In endemic regions, the protection has been shown to persist for at least 15 years in most of the vaccinees. A large 15-year cohort study was started in Quebec in 1995 to assess the protection conferred by immunization in the schoolchildren universal programs. At the 5-year follow-up, the protection as measured by an anamnestic response to a booster dose had persisted in more than 99% of children who initially had anti-HBs titres ≥ 10 mIU/mL.

The major determinant of seroprotection rates achieved is the age at vaccination, but outcome also varies with the schedule used, the dosage and the underlying health status of the vaccinee. Children < 2 years of age have a 95% response rate with relatively low GMTs. The best response is observed in children between the ages of 5 and 15 years with 99% seroprotection rates and very high GMTs. On average, the response rate for older individuals is as follows:

• 20 to 29 years: 95%;
• 30 to 39 years: 90%;
• 40 to 49 years: 86%;
• 50 to 59 years: 71%;
• ≥ 60 years: 50% to 70%.

The immune mechanisms for suboptimal response to hepatitis B vaccine are only partially understood. 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%). Immunization of obese people, smokers and those with alcoholism may also produce lower antibody titres. Immunocompromised patients, such as those infected with HIV, will have a diminished response in proportion to the level of immune deficiency. Patients undergoing dialysis are particularly vulnerable because they do not respond well to the vaccine and do not develop an immune memory. For these reasons and because of their frequent contact with blood, they need a vaccine formulation with a much higher concentration of HBsAg and regular monitoring of their anti-HBs titre.

Recommended usage

Hepatitis B prevention should include programs for universal immunization of children, universal screening of all pregnant women for HBsAg, pre-exposure immunization of high-risk groups and post-exposure intervention for those exposed to HBV, particularly infants born to HBV-infected mothers.

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 HBV vaccine varies from jurisdiction to jurisdiction. The National Advisory Committee on Immunization (NACI) supports the use of available combination vaccines, including hepatitis B and other childhood vaccines, for the immunization of infants.

Pre-exposure prophylaxis

• Health care and emergency service workers and other occupational exposure:
  Immunization with hepatitis B vaccine is recommended for 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
  • Men having sexual contact with men
  • Those who have unprotected sex with new partners or have had more than one sexual partner in the previous 6 months, those with a history of sexually transmitted infections (STI), and persons attending an STI clinic or who otherwise engage in risky sexual practices
  • 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 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 or when visiting friends and relatives in their country of origin
  • Travelers to hepatitis B endemic areas
  • Children in child care settings in which there is an HBV-infected child
• Others for whom the vaccine is recommended:
  • People who have chronic liver disease or are taking hepatotoxic drugs, including persons infected with hepatitis C, who may not be at an increased risk of infection but may be at risk of more severe acute hepatitis B infection, should infection occur;
  • People with other conditions for which hepatotoxic medications are likely to be prescribed in the future;
  • People who have undergone hematopoietic stem cell transplantation (please refer to the Immunization of Immunocompromised Persons chapter for more information).

NACI also recommends that any person who wishes to decrease his or her risk of acquiring HBV be immunized.

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.

  The response to hepatitis B vaccine may be diminished in infants with birth weights below 2000 g. Routine immunization of infants of mothers known to be negative for HBsAg should be delayed until the infant reaches 2000 g or 1 month of age. Premature infants born to women who are HBsAg positive should receive HBIg and the appropriate dose of vaccine within 12 hours of birth. These latter infants require a fourth dose of hepatitis B vaccine and assessment of anti-HBs response after the series has been completed.

  If maternal testing has not been conducted during pregnancy, it should be done 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, vaccination should be completed, as described earlier. Should the mother's infection be recognized during the infant's first year of life, 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, bite) or mucosal exposure:
  Figure 6 and Figure 7 outline the management of vaccinated or unvaccinated individuals after potential exposure to hepatitis B, including injury by needles found on the street or deep bites associated with bleeding. 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. For those who were immunized in the school-based program, their antibody status should be assessed when they begin training in a health care profession. Those found to be negative should receive one dose of the vaccine and be tested 1 month later to document anamnestic response. If found negative again, they should complete the vaccination schedule.
  
  Testing of the source should be conducted according to the Health Canada/Public Health Agency of Canada guidelines An integrated protocol to manage health care workers exposed to bloodborne pathogens available at: http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/97vol23/23s2/index. html, 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 non-immune and non-infected sexual and household contacts of acute cases and chronic carriers should be immunized with hepatitis B vaccine. HBIg is not indicated for household contacts of an acute HBV case. An exception is made for infants < 12 months of age when the mother is acutely or chronically infected. For sexual contacts, a single dose of HBIg (0.06 mL/kg) should also be given within 14 days of the last sexual contact with the HBV-infected person. Unimmunized sexual assault victims should be managed in the same manner, i.e., with both vaccine and HBIg, 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 provided. People with identifiable exposure to the infected person's blood (sharing toothbrushes or razors) should be managed as described in the preceding section on mucosal exposure.

Schedule and dosage

Hepatitis B vaccines have a large number of different schedules and dosages, some of which have been officially approved, others have not. These schedules have been developed for a number of reasons: to accommodate immunization program constraints, to diminish either vaccine or administration costs, to provide protection to individuals with special needs in terms of accessibility of vaccine services, to accommodate the difference in immune response in specific groups, etc. It should be emphasized that the key element to evaluate a given schedule is the seroprotection rate achieved. High titres of anti-HBs bring longer persistence of antibodies. High titres of anti-HBs are also thought to be predictive of a longer duration of protection, although this has not been completely demonstrated yet (see section on Efficacy and Immunogenicity). A longer interval between doses will usually not change the seroprotection rates achieved but will increase the titres.

NACI's preferred schedule is 0, 1 and 6 months, with at least 1 month between the first and second dose, 2 months between the second and third dose and 4 months between the first and the third dose, particularly for children under 12 months of age. A schedule of 0 and 6 months with the pediatric dosage of Recombivax HB^® has been tested with good results (94.5% seroprotection rate) in Canadian schoolchildren. Vaccines produced by different manufacturers can be used interchangeably even though their antigen content is not the same, provided that the dosage used is the one recommended by the manufacturer for the appropriate age group and schedule.

Table 4. Doses and Schedules for Monovalent Hepatitis B Vaccines

Route of administration

All hepatitis B vaccines should be injected into the deltoid muscle of children and adults, and into the anterolateral thigh muscle of infants. Gluteal administration should not be used because of poor immune response, possibly the result of inadvertent deposition into fatty tissue. Immune responses following intradermal injection have been variable, and this route of vaccine administration should not be used.

Booster doses and re-immunization

Routine boosters in immunocompetent persons are not needed. Persons who have had a previously demonstrated protective antibody level will not contract the disease when exposed to HBV, whether or not the antibody has waned. 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. 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 adults who fail to respond after the first series of vaccines. For most school-age children in this same situation, one additional dose will produce a protective titre. 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 respond. Should protection be achieved and then wane, however, subsequent HBV exposure in these individuals can result in acute disease or carrier state. Therefore, in this population boosters may be necessary for those who have responded initially. The optimal timing of booster doses for immunocompromised individuals (dialysis patients in particular) who are at continued risk of HBV exposure and have responded initially 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 of HBV is still present. Should antibody testing show subsequent suboptimal protection, a booster dose and re-testing should be undertaken as necessary.

Serologic testing

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 during the pregnancy 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 immediately after delivery.
• 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 of the adopting family should be immunized before adoption if possible, or as soon as possible thereafter.
• Others at high risk of 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 infection. This testing will identify those already infected or immune, for whom vaccine will provide no benefit. Testing will also assist in the medical management and contact follow-up of those individuals found to be infected and will prevent the mistaken belief that they pose no risk to others.

Post-immunization

Post-immunization testing for universal programs is not necessary. It is recommended, however, if it is important to ensure that there is protection against a continual known or repeated potential exposure to hepatitis B. People included in these circumstances are infants born to infected mothers, sexual partners and household contacts of chronic carriers, and those who have been immunized because of occupational exposure. If anti-HBs is < 10 mIU/mL, re-immunization should be conducted as described earlier (see Boosters and Re-immunization).

In particular, post-immunization testing for anti-HBs should be conducted among 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 (see Figure 6). 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 testing is done beyond the recommended 6-month window, a negative test may indicate primary vaccine failure or waning antibody as indicated previously. Re-immunization should be conducted as described in the section above.

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 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 in the section on Boosters and Re-immunization.

Storage requirements

Hepatitis B 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

Hepatitis B vaccine may be administered simultaneously with other vaccines at different sites. A separate needle and syringe should be used for each vaccine.

Adverse reactions

Hepatitis B vaccines are well tolerated and safe to administer to adults and children. Reported side effects are usually mild, transient and generally limited to soreness at the injection site and temperature no greater than 37.7^o C. Pain occurs no more frequently than with placebo.

As with all vaccines, anaphylaxis is very rare but can occur. A number of studies have demonstrated no link between hepatitis B vaccine and chronic fatigue syndrome, multiple sclerosis, Guillain-Barré syndrome (GBS), rheumatoid arthritis or sudden infant death syndrome.

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 and precautions

Hepatitis B vaccine is contraindicated if the person is allergic to any component of the vaccine or has had a previous anaphylactic reaction.

Hepatitis B vaccine can be used safely in pregnancy and during breast-feeding and should be administered when indicated, since acute hepatitis B in a pregnant woman may result in severe disease for the mother and chronic infection of the infant.

Selected references

Ascherio A, Zhang SM, Hernan MA et al. Hepatitis B vaccination and the risk of multiple sclerosis. New England Journal of Medicine 2001;344(5):327-32.

Banatvala J, Van Damme P, Oehen S et al. Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory. Vaccine 2000;19(7-8):877-85.

Confavreaux C, Suissa S, Saddier P et al. Vaccinations and the risk of relapse of multiple sclerosis. New England Journal of Medicine 2001;344(5):319-26.

Duval B, Boulianne N, De Serres G et al. Should children with isolated anti-HBs or anti-HBc be immunized against hepatitis B virus? Journal of the American Medical Association 1997;287(13):1064.

Duval B, Gîlca V, Boulianne N et al. Comparative long-term immunogenicity of two recombinant hepatitis B vaccines and the effect of a booster dose given after 5 years in a low endemicity country. Pediatric Infectious Disease Journal 2005;24(3):213-18.

FitzSimons D, François G, Hall A et al. Long-term efficacy of hepatitis B vaccine, booster policy, and impact of hepatitis B virus mutant. Vaccine 2005;23(32):4158-66.

Health Canada. An integrated protocol to manage health care workers exposed to blood-borne pathogens. Canada Communicable Disease Report 1997;23S2. URL: <http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/97vol23/23s2/index.html>,

Jarrosson L, Kolopp-Sarda MN, Aguilar P et al. Most humoral non-responders to hepatitis B vaccines develop HBV-specific cellular immune responses. Vaccine 2004;22(27-28):3789-96.

McMahon BJ, Bruden DL, Petersen KM et al. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up. Annals of Internal Medicine 2005;142(5):333-41.

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(23-24):3164-68.

Zhang J, Zou S, Giulivi A. Hepatitis B in Canada. Canada Communicable Disease Report 2001;27(S3):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. Canadian Journal of Infectious Diseases 2001;12(6):357-63.

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