Prevention of Hepatitis A Through Active or Passive Immunization

Prophylaxis Against Hepatitis A Virus Infection

Immune Globulin

IG is a sterile preparation of concentrated antibodies (immunoglobulins) made from pooled human plasma processed by cold ethanol fractionation ⁽⁶⁹⁾. In the United States, only plasma that has tested negative for a) hepatitis B surface antigen (HBsAg), b) antibody to human immunodeficiency virus (HIV), and c) antibody to hepatitis C virus (HCV) is used to manufacture IG. Cold ethanol fractionation can eliminate and inactivate HIV ⁽⁷⁰⁾. Furthermore, no transmission of hepatitis B virus, HIV, HCV, or other viruses has been reported from the intramuscular (IM) administration of IG ⁽⁷¹⁾. Anti-HAV titers differ between IG lots, and slightly lower titers have been observed in recent years, probably because of the decreasing prevalence of HAV infection among plasma donors ⁽⁷²⁾. However, no clinical or epidemiologic evidence of decreased protection has been observed.

IG provides protection against hepatitis A through passive transfer of antibody. The levels of anti-HAV achieved following IM administration of IG are below the level of detection of most commercially available diagnostic tests ⁽⁷³⁾. When administered for preexposure prophylaxis, a dose of 0.02 mL/kg IM confers protection for <3 months, and a dose of 0.06 mL/kg IM confers protection for £5 months (Table 3). When administered within 2 weeks following an exposure to HAV, IG is >85% effective in preventing hepatitis A ^(74-76). Efficacy is greatest when IG is administered early in the HAV incubation period; when administered later in the incubation period, IG often only attenuates the clinical expression of HAV infection ⁽⁷⁴⁾.

For administration of IG, an appropriate muscle mass (i.e., the deltoid or gluteal muscle) should be chosen into which a large volume of IG can be injected by using a needle length appropriate for the person's age and size ⁽⁷⁷⁾. If a gluteal muscle is used, the central region of the buttock should be avoided: only the upper outer quadrant should be used, and the needle should be directed anteriorly to minimize the possibility of injury to the sciatic nerve ⁽⁷⁷⁾.

Serious adverse events from IG are rare. Anaphylaxis has been reported after repeated administration to persons who have known IgA deficiency; thus, IG should not be administered to these persons ⁽⁷⁸⁾. Pregnancy or lactation is not a contraindication to IG administration.

IG does not interfere with the immune response to oral poliovirus vaccine or yellow fever vaccine, or, in general, to inactivated vaccines. However, IG can interfere with the response to live, attenuated vaccines (e.g., measles, mumps, rubella, and varicella) when vaccines are administered either individually or as combination vaccines. Administration of these vaccines should be delayed for at least 5 months after administration of IG for hepatitis A prophylaxis. IG should not be administered within 2 weeks after the administration of live, attenuated vaccines (or within 3 weeks after varicella vaccine) unless the benefits of IG administration exceed the benefits of vaccination ⁽⁷⁷⁾. If IG is administered within 2 weeks after administration of these vaccines (or within 3 weeks after administration of varicella vaccine), the person should be revaccinated, but not sooner than 5 months after the administration of IG ⁽⁷⁷⁾.

Hepatitis A Vaccine

Several inactivated and attenuated hepatitis A vaccines have been developed and evaluated in human clinical trials and in primate models of HAV infection ⁽⁷⁹⁾; however, only inactivated vaccines have been evaluated for efficacy in controlled clinical trials ^(3,4). The vaccines currently licensed in the United States are HAVRIX ® (manufactured by SmithKline Beecham Biologicals) and VAQTA ® (manufactured by Merck & Company, Inc). Both are inactivated vaccines.

Preparation

Inactivated hepatitis A vaccine is prepared by methods similar to those used for inactivated poliovirus vaccine ^(80,81). Cell-culture-adapted virus is propagated in human fibroblasts, purified from cell lysates by ultrafiltration and exclusion gel chromatography or other methods, formalin inactivated, adsorbed to an aluminum hydroxide adjuvant, and prepared with 2-phenoxyethanol (for HAVRIX ® ) as a preservative; VAQTA ® is formulated without a preservative. For HAVRIX ®, the antigen content of the final aqueous preparation is determined by reactivity in a quantitative immuno-assay for HAV antigen, and final vaccine potency (per dose) is expressed as enzyme-linked immunosorbent assay (ELISA) units (EL.U.). For VAQTA®, the antigen content is expressed as units (U) of hepatitis A antigen.

Vaccine Storage and Shipment

Hepatitis A vaccine should be stored and shipped at temperatures ranging from 35.6 F (2 C) to 46.4 F (8 C) and should not be frozen. However, the reactogenicity and immunogenicity of HAVRIX ® and VAQTA ® after storage at 98.6 F (37 C) for 1 week do not differ from those of vaccines stored at the recommended temperature ^{(82; Merck & Company, Inc., unpublished data)}.

Route of Administration, Vaccination Schedule, and Dosage

The vaccine should be administered intramuscularly into the deltoid muscle. A needle length appropriate for the vaccinee's age and size should be used ⁽⁷⁷⁾.

HAVRIX ® is currently licensed in three formulations, and the formulation and number of doses differ according to the vaccinee's age: for persons 2-18 years of age, 360 EL.U. per dose in a three-dose schedule and 720 EL.U. per dose in a two-dose schedule; for persons >18 years of age, 1,440 EL.U. per dose in a two-dose schedule (Table 4). VAQTA® is licensed in two formulations, and the formulation and number of doses differ according to the person's age: for persons 2-17 years of age, 25 U in a two-dose schedule; for persons >17 years of age, 50 U per dose in a two-dose schedule (Table 5).

Vaccine Performance

Detection of anti-HAV after vaccination. Concentrations of antibody achieved after passive transfer by IG or active induction by vaccination are 10-100-fold lower than those produced after natural infection and are often below the detection level of standard, commercially available assays ⁽⁷³⁾. To measure lower levels of antibody, more sensitive immunoassays have been developed that correlate more closely with neutralizing antibody assays ⁽⁷³⁾. The anti-HAV immunoassays commercially available in the United States can be modified to detect lower concentrations of antibody; however, the modified assays have not been reviewed by the U.S. Food and Drug Administration and are not approved for any clinical indication. Anti-HAV concentrations are measured in comparison with a World Health Organization reference immunoglobulin reagent and are expressed as milli-International Units per milliliter (mIU/mL). The lower limits of detection are approximately 100 mIU/mL by unmodified, commercially available assays and 10-12 mIU/mL by modified assays. Thus, a positive anti-HAV result by a standard assay indicates protection. However, after vaccination, persons who are anti-HAV negative by standard assays might still have protective levels of antibody.

The absolute lower limit of antibody required to prevent HAV infection has not been defined. In vitro studies using cell-culture-derived virus indicate that low levels of antibody (e.g., <20 mIU/mL) can be neutralizing ⁽⁸³⁾. Clinical studies have yielded few data from which a minimum protective antibody level can be derived because vaccine-induced levels of antibody have been high and few infections have been detected among vaccinated persons.

Experimental studies in chimpanzees indicate that low levels of passively transferred antibody (<10 mIU/mL) obtained from immunized persons do not protect against infection but do prevent clinical hepatitis and virus shedding ⁽⁸⁴⁾. To define a protective antibody response, most clinical studies conducted with HAVRIX® have been based on levels >20 mIU/mL as measured with a modified enzyme immunoassay, and studies conducted with VAQTA ® have been based on levels >10 mIU/mL as measured with a modified radioimmunoassay ^(85,86).

Immunogenicity in adults. HAVRIX ® is highly immunogenic in persons >18 years of age if two doses of 1,440 EL.U. are administered on a 0- and 6-to-12-month schedule ⁽⁸⁶⁾. Anti-HAV levels >20 mIU/mL developed in 88% (range: 80%-98%) of adults 15 days after the first dose and in 99%-100% of adults at 1 month. Among a sample of vaccinees, 54%-62% of persons were positive for neutralizing antibody 14 days after the first dose, and 94%-100% of persons were positive at 1 month (86 ; SmithKline Beecham Biologicals, unpublished data). After the second dose, all persons had protective levels of antibody (<20 mIU/mL) with a high geometric mean titer (GMT) (Table 6), and all were positive for neutralizing antibody (SmithKline Beecham Biologicals, unpublished data).

VAQTA® provides similar immunogenicity when administered to adults >18 years of age (Table 7). Among vaccinated persons who received 50 U at 0 and 6 months, 95% had protective anti-HAV levels at 1 month, and 100% had protective levels at 7 months. The GMT, measured by using a modified hepatitis A antibody (HAVAB) assay, was 37 mIU/mL at 1 month and 5,059 mIU/mL at 7 months ⁽⁸⁷⁾.

Immunogenicity in children and adolescents. Of persons 1-17 years of age who were administered three doses of 360 EL.U. of HAVRIX® on a 0-, 1-, and 6-month schedule, 95% developed protective levels of anti-HAV 1 month after the first dose ^(86,88-90). One month after the second dose, all persons had protective levels of antibody that persisted until administration of the third dose at 6 months. One month following the third dose, the GMT increased approximately tenfold and persisted at high levels 6 months later (Table 6).

Among children and adolescents 2-18 years of age who were administered two doses of HAVRIX® (720 EL.U. per dose at 0- and 6-month intervals), 99% had protective levels of antibody 1 month after receiving the first dose (Table 6). Similar 1-month results were obtained for adolescents who had been administered two doses of HAVRIX ® (1,440 EL.U. per dose).

When administered to persons 2-17 years of age in a variety of two-dose schedules (25 U per dose), VAQTA® was highly immunogenic. From 97% to 100% of children had protective levels 1 month after the first dose, and 100% had protective levels 1 month after administration of a second dose at 6, 12, or 18 months, with substantial increases in GMT after administration of the second dose (Table 7) ⁽⁸⁷⁾.

Immunogenicity in infants. Few data are available regarding the use of hepatitis A vaccine in children <2 years of age. Results from one study indicated that among infants without passively acquired maternal anti-HAV who had been administered hepatitis A vaccine (360 EL.U. per dose) at 2, 4, and 6 months of age, 100% of the infants had protective antibody levels with a GMT of 794 mIU/mL 1 month following the third dose ⁽⁹¹⁾ (Table 6). Infants with passively transferred maternal anti-HAV had a reduced anti-HAV GMT after vaccination (see Factors Associated with Reduced Immunogenicity).

IgM anti-HAV after vaccination. Hepatitis A vaccination rarely induces IgM anti-HAV that is detectable by standard assays. In one study, three of approximately 311 adult vaccine recipients transiently developed IgM anti-HAV 1 month after completing vaccination with 720 EL.U. of HAVRIX® on a 0-, 1-, and 6-month schedule ⁽⁹²⁾. In another study, none of 158 children studied had detectable IgM anti-HAV 1 month after receiving two doses of HAVRIX® (360 EL.U. per dose) (SmithKline Beecham Biologicals, unpublished data). IgM anti-HAV was detected in three of 15 persons at 2-3 weeks after having been administered VAQTA® ⁽⁹³⁾.

Efficacy. The efficacy of HAVRIX® was evaluated in a double-blind, placebo-controlled, randomized clinical trial conducted in Thailand among approximately 40,000 children 1-16 years of age living in villages that had high rates of hepatitis A ⁽⁴⁾. After two doses of vaccine (360 EL.U. per dose) administered 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval=79%-99%). A double-blind, placebo-controlled, randomized clinical trial using VAQTA ® was conducted among approximately 1,000 children 2-16 years of age living in a New York community that had a high rate of hepatitis A. The protective efficacy against clinical hepatitis A was 100% after administration of one dose (25 U) of vaccine ⁽³⁾.

Studies of chimpanzees indicate that hepatitis A vaccine can prevent HAV infection if administered shortly after exposure ⁽⁹⁴⁾. Because the incubation period of hepatitis A can be £50 days, the fact that no cases of hepatitis A occurred in vaccine recipients beginning 19 days after vaccination indicates a possible postexposure effect ⁽³⁾. A study comparing the postexposure efficacy of hepatitis A vaccine versus IG has not been done.

Effectiveness in outbreak settings. Several studies have examined the effectiveness of hepatitis A vaccine in controlling outbreaks in communities that have high rates of hepatitis A. Specifically, vaccination using VAQTA® of children 2-16 years of age during the clinical trial evaluating vaccine efficacy resulted in a substantial decrease in community hepatitis A rates ⁽³⁾. In addition, in several Alaskan villages in which hepatitis A outbreaks were occurring, vaccination of susceptible persons <30 years of age with one dose of HAVRIX® (720 EL.U.) resulted in a rapid decrease in the number of cases ⁽⁹⁵⁾. Both studies were carried out in small, well-defined communities in which an estimated 70% or more of the susceptible persons were vaccinated. Cost analyses have indicated that vaccination in communities that have high rates of hepatitis A can be cost-saving ⁽⁹⁶⁾. Hepatitis A vaccine has been used in several communities that had intermediate rates of hepatitis A and were experiencing outbreaks. In Butte County, California, hepatitis A cases decreased concurrently with the implementation of a program in which approximately 37% of children 2-12 years of age were administered one dose of VAQTA® ⁽⁹⁷⁾. In Memphis, Tennessee, following a targeted vaccination program in which one dose of HAVRIX® (360 EL.U.) was administered to 52% of eligible children 2-9 years of age, hepatitis A rates decreased in this target population ⁽⁹⁸⁾. In two villages in Slovakia, a communitywide outbreak ended 2 months after approximately two thirds of school-age children were vaccinated with two doses of HAVRIX® ⁽⁹⁹⁾. Further study is needed to determine the effectiveness of this strategy, the feasibility of implementation, and level of vaccination coverage required to interrupt disease transmission.

Long-term protection. Data concerning the long-term persistence of antibody and of immune memory are limited because the currently available vaccines have been under evaluation for only 4-5 years. Among adults who received three doses of HAVRIX® (720 EL.U. per dose at 0-, 1-, and 6-month intervals), 100% of those persons had anti-HAV levels >20 mIU/mL 48 months after the initial dose, although antibody concentrations had decreased by approximately 50% (P. Van Damme, University of Antwerp [Belgium], unpublished data). Data regarding persons who were administered VAQTA® and who were monitored for 36 months also demonstrated a decrease in titer; however, protective levels of anti-HAV were still observed in 100% of these persons ⁽¹⁰⁰⁾. Estimates of antibody persistence derived from kinetic models of antibody decline indicate that protective levels of anti-HAV could be present for ^<20 years ^(100,101). Whether other mechanisms (e.g., cellular memory) also contribute to long-term protection is unknown. The long-term protective efficacy of hepatitis A vaccine needs to be determined in ongoing studies to detect clinical illness among vaccinees and in future postmarketing surveillance studies before recommendations can be made concerning the possible need for booster doses.

Factors associated with reduced immunogenicity. In one study, the percentage of adults who were administered IG concurrently with the first dose of hepatitis A vaccine and who had protective levels of antibody was similar to the percentage of adults who had protective levels and who had been administered hepatitis A vaccine alone; however, their GMTs were substantially lower 1 month after being administered three doses of HAVRIX® (720 EL.U. per dose) than GMTs of adults who had been administered hepatitis A vaccine alone (GMT 2,488 MIU/mL versus 3,614 mIU/mL, respectively) ⁽¹⁰²⁾. In both groups, the antibody levels were at least 100-fold higher than levels considered to be protective. A similar effect occurred with concurrent administration of IG and VAQTA® (Merck & Company, Inc., unpublished data). Therefore, the reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG is not expected to be clinically significant.

Reduced immunogenicity also was observed in infants who had passively acquired antibody because of prior maternal HAV infection ⁽⁹¹⁾. Infants who were administered HAVRIX ® (360 EL.U. per dose) at 2, 4, and 6 months of age and whose mothers were anti-HAV positive had antibody levels at 15 months of age that were one third the levels in infants who had been administered HAVRIX ® on the same schedule but whose mothers were anti-HAV negative (GMT 84 mIU/mL versus 231 mIU/mL, respectively). However, 93% and 100% of infants in each group, respectively, had anti-HAV levels >20 mIU/mL.

In one study, the proportion of persons >40 years of age who had protective antibody levels after three doses of HAVRIX ® (720 EL.U. per dose) was similar to that of persons £40 years of age, although the final GMTs were approximately 50% lower (SmithKline Beecham Biologicals, unpublished data). Data from one study of HIV-infected persons vaccinated with three doses of 720 EL.U. of HAVRIX ® indicate that both the proportion of those who developed protective antibody levels and their GMTs were lower than those in anti-HIV negative persons (77% versus 100%; 636 mIU/mL versus 1,687 mIU/mL, respectively) ⁽¹⁰³⁾.

Other factors associated with decreased immunogenicity to other vaccines (e.g., smoking) have not been evaluated for hepatitis A vaccine. No data are available pertaining to response rates to revaccination among persons who do not respond to the primary vaccination series.

Simultaneous administration with other vaccines. Limited data from studies conducted among adults indicate that simultaneous administration of hepatitis A vaccine with diphtheria, poliovirus (oral and inactivated), tetanus, oral typhoid, cholera, Japanese encephalitis, rabies, or yellow fever vaccine does not decrease the immune response to either vaccine or increase the frequency of reported adverse events ^{(104; SmithKline Beecham Biologicals, unpublished data)}. Studies indicate that hepatitis B vaccine can be administered simultaneously with either HAVRIX ® or VAQTA ® without either affecting immunogenicity or increasing the frequency of adverse events ⁽¹⁰⁵⁾.

Several studies are being conducted among infants to evaluate the effect of simultaneous administration of hepatitis A, diphtheria-tetanus-pertussis (DTP), and oral poliovirus vaccines on the immunogenicity and reactogenicity of these vaccines.

Side Effects and Adverse Events

Data concerning adverse events are derived from prelicensure clinical studies worldwide and from reports following vaccine licensure of HAVRIX ® in Europe and Asia. Approximately 50,000 persons have been administered HAVRIX ® in clinical studies. No serious adverse events have been attributed definitively to hepatitis A vaccine. Among adults, the most frequently reported side effects occurring within 3 days after the 1,440 EL.U. dose were soreness at the injection site (56%), headache (14%), and malaise (7%); the incidence of side effects generally has been similar to that of hepatitis B vaccine. In clinical studies among children, the most frequently reported side effects were soreness at the injection site (15%), feeding problems (8%), headache (4%), and injection-site induration (4%). No serious adverse events were reported for approximately 40,000 children who were administered the 360 EL.U. dose of hepatitis A vaccine in the protective efficacy study ⁽⁴⁾.

Approximately 9,200 persons have been administered VAQTA ® in clinical studies. No serious adverse events were reported among participants in the clinical studies. Among adults, the most frequent side effects that occurred within 5 days following vaccination include tenderness (53%), pain (51%), and warmth (17.3%) at the injection site (53%) and headache (16.1%). Among children, the most common side effects reported were pain (19%), tenderness (17%), and warmth (9%) at the injection site.

An estimated 1.3 million persons have been vaccinated with HAVRIX ® since it was licensed in Europe and Asia. Postlicensure reports of serious adverse events, without regard to causality, received by the vaccine manufacturer have included anaphylaxis, Guillain-Barré syndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis, encephalopathy, and erythema multiforme (SmithKline Beecham Biologicals, unpublished data). Most of these events have occurred among adults, and approximately one third have occurred among persons receiving other vaccines concurrently. For serious adverse events for which background incidence data are known (e.g., Guillain-Barré syndrome and brachial plexus neuropathy), the rates for vaccine recipients are not higher than would be expected for an unvaccinated population (CDC, unpublished data). In Europe, the ratio of reported adverse events to the number of doses distributed is similar for the manufacturer's hepatitis A and hepatitis B vaccines (SmithKline Beecham Biologicals, unpublished data).

Because VAQTA ® was recently licensed, postmarketing data are limited. An estimated 20,000 persons have been administered VAQTA ® since it was licensed in the United States and Germany, and no serious adverse events have been reported (Merck & Company, Inc., unpublished data).

Any adverse event suspected to be associated with hepatitis A vaccination should be reported to the Vaccine Adverse Events Reporting System (VAERS). VAERS forms can be obtained by calling 1-800-822-7967.

Contraindications and Precautions

Hepatitis A vaccine should not be administered to persons with a history of hypersensitivity reactions to alum or, in the case of HAVRIX ®, to the preservative 2-phenoxyethanol.

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 for hepatitis A in women who may be at high risk for exposure to HAV. Because hepatitis A vaccine is inactivated, no special precautions need to be taken when vaccinating immunocompromised persons.

Prevaccination Serologic Testing for Susceptibility

HAV infection produces 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 for adverse events. In populations that have expected high rates of prior HAV infection, prevaccination testing may be considered to reduce costs by not vaccinating persons who have prior immunity. Testing of children is not indicated because of their expected low prevalence of infection. For adults, the decision to test should be based on a) the expected prevalence of immunity; b) the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit); and c) 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 >33% should be cost effective ⁽¹⁰⁶⁾.

Persons for whom prevaccination testing will likely be most cost effective include adults who were either born in or lived for extensive periods in geographic areas that have a high endemicity of HAV infection (Figure 3); older adolescents and adults in certain population groups (i.e., American Indians, Alaskan Natives, and Hispanics); and adults in certain groups that have a high prevalence of infection (e.g., men who have sex with men). In addition, among older adults, the prevalence may be high enough to warrant prevaccination testing. For example, the anti-HAV prevalence among persons >40 years of age, determined by NHANES-III testing, is generally >33% (regardless of race/ethnicity or income level). Thus, if the cost of screening is one third the cost of the vaccination series, prevaccination testing of any person >40 years of age would likely be cost effective. Commercially available tests for total anti-HAV should be used for prevaccination testing.

Postvaccination Testing for Serologic Response

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