The efficacy of HAVRIX® * was evaluated in a double-blind, controlled, randomized clinical trial in Thailand among 38,157 children 1-16 years of age living in an area with high endemic rates of hepatitis A. Following two doses of vaccine (360 EL.U. per dose) given 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval [CI], 79%-99%). A double-blind, placebo-controlled, randomized clinical trial using VAQTA® * was conducted among 1,037 children 2-16 years of age living in a single U.S. community with a high rate of hepatitis A. Within 18 days following one dose (25 U) of vaccine, the efficacy in protecting against clinical disease was 100% (95% CI, 85%-100%).

Both HAVRIX® and VAQTA® should be administered intramuscularly into the deltoid. A needle length appropriate for the vaccinee’s age and size should be used. HAVRIX® is available in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 720 EL.U. per dose in a two-dose schedule; and for persons greater than 18 years of age, 1,440 EL.U. per dose in a two-dose schedule. VAQTA® is also licensed in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 25 U in a two-dose schedule; and for persons greater than 18 years of age, 50 U per dose in a two-dose schedule.

Soreness at the site of injection is the most commonly reported side effect of hepatitis A vaccination (50%). Headache and malaise were reported by 15% and 7% of vaccinees, respectively.

Reviews of data from multiple sources for more than 5 years did not identify any serious adverse events among children or adults that could be definitively attributed to hepatitis A vaccine. The safety of the vaccine will continue to be assessed through ongoing monitoring of data from the Vaccine Adverse Events Reporting System (VAERS) and other surveillance systems.

The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk of hepatitis A in women who might be at high risk for exposure to HAV.

Hepatitis A vaccine should not be administered to persons with a history of a severe reaction to a dose of hepatitis A vaccine or allergy to a vaccine component. Because hepatitis A vaccine is inactivated, no special precautions are needed when vaccinating immunocompromised persons.
 

Among adults and children, studies have demonstrated that detectable antibody persists for at least 5-8 years after completing the vaccination series. Although data regarding long-term efficacy are limited, no cases among vaccinated children were observed in one community at 5-6 years of follow-up. Estimates of antibody persistence derived from mathematical models of antibody decline indicate that protective levels of anti-HAV persist for at least 20 years. Whether other mechanisms such as cellular memory also contribute to long-term protection is unknown.
 

The presence of anti-HAV at the time of vaccination appears to blunt the immune response. Administration of immune globulin (IG) concurrently with the first dose of hepatitis A vaccine did not decrease the proportion of adults who developed protective levels of antibody compared with adults who had been administered hepatitis A vaccine alone, but the geometric mean antibody concentrations (GMCs) among adults who received IG were lower 1 month after completion of the vaccination series than the GMCs of any adults who had been administered hepatitis A vaccine alone. The reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG does not appear to be clinically significant. IG and hepatitis A vaccine can be given concurrently if indicated.

Reduced vaccine immunogenicity also has been observed in infants who had passively-transferred antibody because of prior maternal HAV infection and were administered hepatitis A vaccine according to a number of different schedules. In most studies, all infants developed protective levels of antibody, but the final GMCs were approximately 1/3 to 1/10 those of infants born to anti-HAV-negative mothers.

Based on limited data, final antibody concentrations might be lower among older vaccinated persons.

Vaccination of adults with chronic liver disease of viral or nonviral etiology produced seroprotection rates similar to those observed in healthy adults. Final antibody concentrations, however, were substantially lower for each group of patients with chronic liver disease than for healthy adults.

In some studies, administration of hepatitis A vaccine to persons with HIV infection resulted in lower seroprotection rates and antibody concentrations. Among HIV-infected men, those who responded to hepatitis A vaccination had significantly more CD4+ T lymphocytes at baseline compared with those who did not respond. Being HIV positive, however, is not a contraindication for administering hepatitis A vaccine if the person is in a risk group for whom hepatitis A vaccine is recommended.

In one small study, none of the 8 patients who had received a liver transplant responded to hepatitis A vaccination; however, liver transplantation is not a contraindication for administering hepatitis A vaccine.


Hepatitis A vaccine is safe and immunogenic for infants who do not have antibody to HAV that was passively-transferred from a mother who had hepatitis A in the past. A number of studies of infants vaccinated according to different dosages and schedules have shown that the presence of passively-acquired maternal antibody blunts the immune response. In most studies, all infants developed protective levels of antibody, but the final GMCs were approximately 1/3 to 1/10 those of infants born to anti-HAV-negative mothers. Although the age at which this passively-transferred antibody disappears is unclear, it is probably no longer detectable in most infants by 15 months of age. Currently, hepatitis A vaccines are not licensed by the FDA for children under 2 years of age.
 

Twinrix® is a combined hepatitis A and hepatitis B vaccine approved in 2001 by the Food and Drug Administration (FDA) for persons 18 years of age or older. Twinrix® contains 720 EL.U. of hepatitis A antigen and 20 μg of hepatitis B surface antigen.

Primary immunization consists of three doses, given on a 0-, 1-, and 6-month schedule, the same schedule as that used for single-antigen hepatitis B vaccine. Immunogenicity of the combined vaccine appears to be similar to that of the single-antigen vaccines when given separately.

Twinrix® can be used for immunization of persons 18 years of age or older who have indications for vaccination against both hepatitis A and hepatitis B, such as users of illicit injectable drugs, men who have sex with men, and persons with clotting factor disorders who receive therapeutic blood products. Formulation for children is available in many other countries.

For international travel, hepatitis A vaccine is recommended for travelers to areas of high or intermediate hepatitis A endemicity (see slide 10). Hepatitis B vaccine is recommended for travelers to areas of high or intermediate hepatitis B endemicity who plan to live or work for at least 6 months in highly endemic countries.


Antibody production in response to HAV infection results in lifelong immunity to hepatitis A and, presumably, to HAV infection. Vaccination of a person who is immune because of prior infection does not increase the risk of adverse events. In populations that are expected to have high rates of prior HAV infection, prevaccination testing might be considered to reduce costs by avoiding vaccination of persons who have prior immunity. Testing of children is not indicated generally because of their expected low prevalence of infection. For adults, the decision to test should be based on the expected prevalence of immunity, the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit), and the likelihood that testing will not interfere with initiating vaccination. For example, if the cost of screening (including laboratory and office visits) is one third the cost of the vaccine series, then screening potential recipients in populations where the prevalence of infection is likely to be greater than 33% should be cost-effective.

Persons for whom prevaccination testing will likely be most cost-effective include adults who were born in or lived for extensive periods in geographic areas that have a high endemicity of HAV infection, older adolescents and young adults in certain population groups (i.e., Native Americans, Alaska Natives, and Hispanics), and adults in certain groups that have a high prevalence of infection (e.g., injecting drug users[IDU]). In addition, the prevalence might be high enough among all older U.S.-born adults to warrant prevaccination testing. Commercially available tests for total anti-HAV should be used for prevaccination testing.

Post-vaccination testing is not indicated because of the high rate of vaccine response among adults and children. In addition, testing methods that have the sensitivity to detect low, but protective, anti-HAV concentrations after vaccination are not approved for routine diagnostic use in the United States.

The recommendations for hepatitis A vaccination are based on several guiding principles. To reduce overall hepatitis A incidence, it was felt that a comprehensive strategy was needed and that routine vaccination of children should be the cornerstone of this strategy. Herd immunity could play an important role in extending the effects of hepatitis A vaccination of young children to older children and to adults.

Creative approaches, however, were needed because hepatitis A vaccine is not licensed for use in children under 2 years of age, which is the age group in which we generally administer routine vaccinations to children in the United States. Thus, the ACIP recommendations for routine vaccination of children built on the epidemiology in an incremental fashion, starting with areas in which the disease burden was greatest. In 1996, the ACIP recommended routine vaccination of children living in communities with historically the highest rates, such as Native American and Alaska Native communities.

In 1999, the ACIP took another incremental step, recommending routine vaccination of children living in areas with consistently elevated rates during a defined baseline period.

The third step will be to vaccinate all children nationwide.