Hepatitis B vaccines are safe and effective methods of inducing protective immunity against this viral infection.  The initial plasma-derived vaccine was introduced in 1982 and, shortly thereafter, became a key element in a CDC sponsored program to reduce the incidence of Hepatitis B.  The key feature of this program was a plan to immunize individuals at high risk for infections. In 1987, the recombinant preparation was introduced , it proved to be equally efficacious.  The antigenic components of both the plasma derived and the recombinant forms are the hepatitis B surface antigen (HBsAg); immunization leads to the formation of protective HBsAg antibodies.

Hepatitis B is a major health problem.  Over the past decade, the incidence of reported infections has risen an alarming 37%.  Annually, more than 300,000 individuals are infected and there are 5,000 deaths directly attributable to this virus or its complications.  Unfortunately, the initial strategy of vaccinating individuals at high risk had a minimal public health impact.  Fewer than 10% of the estimated 22 million "high risk" individuals have been vaccinated.  Even among a supposedly knowledgeable group, health care workers, a population at risk for occupational exposures, only 25% have been immunized.

Because of this minimal impact, a revised and more comprehensive plan was recently recommended.  This emphasizes hepatitis B vaccination for individuals before they engage in behaviors or occupations that place them at risk of infection. Included in this strategy was the concept of universal vaccination of infants and adolescents.  Another component of this plan was the institution of OSHA regulations requiring that health care workers with any potential of exposure to blood or body fluids must be instructed as to the risks of hepatitis B and offered, at the employer's expense, the vaccine series.

At the present time, two types of hepatitis B vaccines, the plasma derived and the recombinant product are licensed in the United States.  Both produce comparable immune responses.  The plasma derived vaccine consists of a suspension of inactivated alum-adsorbed 22 nm HBsAg particles that have been purified from human plasma.   In the preparation of this vaccine, it is subjected to multiple steps, each of which inactivates representatives of all classes of viruses including HIV.  However, because of unfounded safety concerns, these vaccines had limited acceptance and are no longer produced.  Existing supplies are very limited.

The recombinant vaccine is produced in genetically engineered yeast cells in which the gene for HBsAg has been inserted.  Purified antigen is obtained by lysing the yeast cells and separating the HBsAg from yeast components by biochemical and biphysical techniques.  The final product contains more than 95% HBsAg protein; yeast derived proteins constitute no more than 5% of the final product.

The recommended schedule for the vaccine series in adults consists of three intramuscular 1.0 ml doses given at 0, 1 and 6 months.  Children less than 11 require 0.5 ml per injection.  The vaccine is to be administered in the deltoid muscle; immunization into the buttocks results in clearly lower antibody responses.   For hemodialysis and other immunocompromised patients, larger vaccine doses (two-four times normal adult dose) or an increased number of doses may be required to produce protective immunity.  The intradermal route is not recommended as it produces lower antibody responses.

The most common side effect from IM immunization is soreness at the site of injection.  Patients with allergies to yeast products rarely develop reactions.  The CDC indicates that pregnancy or lactation should not be considered a contraindication to the use of this vaccine.  The vaccine contains only non-infectious HBsAg particles; therefore its use in pregnant women should not result in any risk to the fetus.  In contrast, hepatitis B infection of a pregnant woman may result in severe disease for the mother and chronic infection of the newborn.

Using the recommended three dose schedule, 80-90% will develop protective immune responses.  This is defined as an anti-HBsAg concentration of >10 mlU/ml. Individuals who show antibody levels between 2-10 mlU/ml are considered hyporesponders and those with concentrations <2 mlU/ml are classified as nonresponders.   Only 2.5 - 5% of the population are nonresponders.

It is estimated that a significant fraction of individuals who do not develop adequate responses after the primary series will respond to revaccination.   The CDC reports that 15-25% respond after one additional dose and 30 - 50% after three doses.  There appears to be a difference between nonresponders and hyporesponders.  Among the nonresponders, a second course may induce detectable antibodies in up to 40%; however, the immune response tends to be feeble and limited in duration.  By contrast, in hyporesponders, revaccination is successful in almost all cases and the immune responses are sustained.

Chronic immunosuppression negatively affects the ability to respond.   For example, 40% of hemodialysis patients do not develop adequate antibody levels after the usual vaccine series. 70 - 80% of organ transplant recipients receiving immunosuppressive therapy, do not mount adequate antibody responses.  AIDS patients also tend to respond poorly to immunization.

A recent study showed that, in normal individuals, the ability to mount an antibody response to hepatitis B vaccine is linked to major histocompatibility complex.   A study of nonresponders showed that there was an increase incidence of individuals homozygous for the extended haplotype HLA-B8, Sc01, DR3.  These individuals appear to lack an immune response gene for HBsAg. This failure to mount antibody responses did not extend to other antigens such as tetanus toxoid.  Another extended haplotype associated with nonresponsiveness is B44, DR7, and FC31.

Factors related to the magnitude of the response include age, obesity, and smoking.  In a study of Connecticut public safety personnel, only 2.8% of those younger than 30 failed to produce adequate antibody responses.  By contrast, 42.1% of those over 60 did not show antibody concentrations >10 mlU/ml.  Virtually all infants who received the first vaccine dose at three months develop good immunity (97% had antibody titers >100 mlU/ml).

There is a time dependent loss of antibody titers.  The rate of anti-HBsAb declines at a similar rate among all vaccine recipients and is independent of the initial antibody response.  Up to 50% of adults who responded to the initial vaccine will have low or undetectable antibody levels within seven years after vaccination.

The significance of the loss of detectable antibody is unknown.   Specifically, are these individuals susceptible to infection?  The answer is not completely known.  However, it appears that after a single booster, previous responders show an anamnestic type immunity with the prompt appearance of high levels of antibodies.  Clinically, only a small number of previous responders will develop evidence of hepatitis B infections and in most, the only abnormalities is the appearance of additional antibodies.  Hepatitis B viremia or clinical disease is extremely rare.   Because of this uncertainty, the CDC has not made any recommendations for booster doses of Hepatitis B vaccine except for its use in dialysis patients.

Another unresolved question is whether individuals who have been vaccinated should have post-vaccination antibody titers measured and, if they do, at what time interval.  The CDC does not recommend routine post-vaccine testing for antibody titers but suggests testing for persons whose subsequent management depends upon knowing their immune status and in those in whom suboptimal responses may be contemplated.   They also suggest that health care workers at risk of needle stick or other exposure to blood borne pathogens consider post-vaccination testing.

At Central Blood Bank, we consider the risk of hepatitis B infection to be a serious problem and have taken a very conservative approach to protecting health care workers.  Not only are all employees offered the vaccine, but post-vaccine titers are routinely obtained post-immunization in order to detect poor responders.  These employees are offered additional boosters. We recommend routine antibody testing for initial responders and provide booster vaccine injections for those whose titer is <10 mlU/ml.