Hepatitis A vaccine is approved for people 12 months of age and older and is given in a 2-dose schedule at least 6 months apart (AAP, 2003). Currently licensed vaccines (Havrix and Vaqta) are given intra-muscularly.

A combination hepatitis A/hepatitis B vaccine (Twinrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) is approved for people 18 years of age and older and is given in a 3-dose schedule (0, 1, and 6 months) or an accelerated 4-dose schedule (0, 7, and 21 to 30 days, and a 4th dose at 1 year). The first 3 doses of the 4-dose schedule are intended to provide protection equivalent to the first 2 doses of the original schedule. The new schedule is useful if travel or potential exposure is expected before the 2nd dose (at 1 month) on the original schedule.

The annual recommended childhood and adolescent immunization schedule for approved by the American Academy of Pediatrics (AAP), the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), and the American Academy of Family Physicians (Fiore et al, 2006) recommends universal administration to all children at 1 year (12 to 23 months) of age. Furthermore, the 2 doses in the series should be separated by at least 6 months. Children who are not vaccinated by age 2 years can be vaccinated at subsequent visits to their pediatricians.

Either vaccine can be used for either dose, but use of the same vaccine for both doses is preferable. The recommended dose interval is 6 to 18 months for Vaqta and 6 to 12 months for Havrix.

Havrix, Twinrix, and Vaqta are formulated without a preservative. These vaccines are administed intramuscularly.

Vaqta is licensed in two formulations. Persons aged 12 months through 18 years should receive 25 units of HAV antigen per dose in a 2-dose schedule; persons aged ≥19 years should receive 50 units per dose in a 2-dose schedule.

Havrix also is licensed in two formulations. Persons aged 12 months through 18 years should receive 720 ELISA units per dose in a 2-dose schedule; persons aged ≥19 years should receive 1,440 ELISA units per dose in a 2-dose schedule.

Twinrix is licensed for use in adults aged ≥18 years. Twinrix contains 720 ELISA units of HAV antigen (half of the Havrix adult dose) and 20 μg of recombinant HBV surface antigen protein (the same as the Engerix-B adult dose). Primary vaccination with Twinrix consists of 3 doses, administered on a 0-, 1-, and 6-month schedule, the same schedule as is commonly used for single-antigen HepB vaccine. After 3 doses of Twinrix, antibody responses to both HAV antigen and HBV surface antigens are equivalent to responses seen after the single-antigen vaccines are administered separately on standard schedules; additional information is available in the Twinrix package insert. Twinrix may be administered before travel or any other potential exposure on an accelerated schedule of 3 doses at 0, 7, and 21–30 days, followed by a booster dose at 12 months that provides long-term protection.

The AAP recommends that regions with immunization programs for 2- to 18-year old children should continue them and expand them to include 12- to 23-month olds. In areas without existing hepatitis A immunization programs, catch-up immunization of unvaccinated 2- to 18-year old children should be considered. In addition, previously unvaccinated children who will be living in, or traveling to, areas with intermediate or high hepatitis A endemicity should be immunized before departure.

The AAP recommends vaccinating children with immunocompromising conditions, as the vaccines do not contain living organisms. Hypersensitivity to vaccine components such as aluminum hydroxide and phenoxyethanol are contraindications to use of hepatitis A vaccines. Hepatitis A vaccine may be co-administered with other vaccines in the childhood immunization series.

The ACIP of the CDC recommends post-exposure prophylaxis with hepatitis A vaccine for healthy individuals between the ages of 1 and 40 years (CDC, 2007). Persons who have recently been exposed to hepatitis A virus and who have not been vaccinated previously should be administered a single dose of single-antigen hepatitis A vaccine or immune globulin (0.02 ml/kg) as soon as possible, within 2 weeks after exposure. All others should receive immune globulin, if possible.

The guidelines vary by age and health status (CDC, 2007). For healthy persons aged 12 months to 40 years, single-antigen hepatitis A vaccine at the age-appropriate dose is preferred to immune globulin because of vaccine’s advantages, including long-term protection and ease of administration, as well as the equivalent efficacy of vaccine to immune globulin. For persons aged more than 40 years, immune globulin is preferred because of the absence of information regarding vaccine performance in this age group and because of the more severe manifestations of hepatitis A in older adults. Vaccine can be used if immune globulin can not be obtained. The magnitude of the risk of hepatitis A virus transmission from the exposure should be considered in decisions to use vaccine or immune globulin in this age group. For children aged less than 12 months, immunocompromised persons, persons with chronic liver disease, and persons who are allergic to the vaccine or a vaccine component, immune globulin should be used.

The ACIP recommendation is based upon evidence that hepatitis A vaccine is as effective as immune globulin in preventing transmission. Researchers randomized 1,090 susceptible household or day-care contacts of patients in Kazakhstan to prophylaxis with either hepatitis A vaccine or immune globulin within 2 weeks of exposure (Victor et al, 2007). The investigators found that the effect of the vaccine would be similar to immune globulin. Between 2 and 8 weeks after exposure, vaccine recipients showed a 1.35 relative risk (95 % confidence interval: 0.70 to 2.67) for developing symptomatic infection as compared with those receiving immune globulin.

The ACIP annually reviews the recommended adult immunization schedule to ensure that the schedule reflects current recommendations for the licensed vaccines.

Rowe et al (2012) stated that hepatitis A virus (HAV) super-infection in persons with hepatitis C virus (HCV) infection has been associated with a high mortality rate, and vaccination is recommended. The incidence of HAV is low, and the aim of this study was to determine the mortality risk of HAV super-infection and the consequences of routine vaccination in persons with HCV infection. To determine the mortality risk of HAV super-infection, a meta-analysis including studies reporting mortality in HCV-infected persons was performed. Data were extracted independently by 2 investigators and recorded on a standardized spread-sheet. The pooled mortality estimate was used to determine the number needed to vaccinate (NNV) to prevent mortality from HAV super-infection. The total vaccine cost was also calculated. A total of 239 studies were identified using a defined search strategy. Of these, 11 appeared to be relevant, and of these, 10 were suitable for inclusion in the meta-analysis. The pooled odds ratio (OR) for mortality risk in HAV super-infection of HCV-infected persons was 7.23 (95 % confidence interval: 1.24 to 42.12) with significant heterogeneity (I(2) = 56 %; p = 0.03) between studies. Using the pooled OR for mortality, this translates to 1.4 deaths per 1,000,000 susceptible persons with HCV per year. The NNV to prevent 1 death per year is therefore 814,849, assuming 90 % vaccine uptake and 94.3 % vaccine efficiency. The vaccine cost for this totals $162 million, or $80.1 million per death prevented per year. The authors concluded that these data challenge the use of routine HAV vaccination in HCV-infected persons and its incorporation into clinical practice guidelines. HAV vaccination of all HCV-infected persons is costly and likely to expose many individuals to an intervention that is of no direct benefit.

Gutierrez Domingo et al (2012) noted that in the absence of immunity, vaccination against HAV and hepatitis B virus (HBV) is recommended for patients with chronic liver disease and those evaluated for liver transplantation (OLT). HAV and HBV infections after OLT, which are frequent in this setting, are associated with a worse prognosis. These researchers estimated the need for vaccination against HBV and HAV among cirrhotic patients who were candidates for OLT and associations with gender, age, and etiologic factors. HBV and HAV serological markers HBsAg, anti-HBc, antiHBs, immunoglobulin G (IgG)-anti-HAV were investigated among 568 patients, including 75 % men. The overall mean age was 53.6 ± 8.9 years (range of 17 to 69) and 20 % were diabetic. The etiologies were alcohol (68 %), hepatitis C virus (35 %) or other causes (10.4 %). Child-Pugh classes were: A (26 %), B (44 %), and C (30 %). In contrast with 359 patients (63.2 %) who had negative HBV markers, 209 (36.8 %) were positive: HBsAg (+), 43 (7.6 %), isolated anti-HBc (+), 57 (10 %), isolated anti-HBs (+), 19 (3.3 %), anti-HBc (+)/anti-HBs (+), 90 (15.8 %). HBV vaccine indication was performed in 416 patients (73.2 %) who either had negative HBV markers or isolated anti-HBc (+). It was more frequently performed in women (82.3 % versus 70.3 %, p = 0.005), albeit with no differences according to age or etiology. There were only 8.2 % (44/538) IgG-anti-HAV-negative, an indication for vaccination against HAV, which was more frequent affecting patients who were younger [less than or equal to 45 years (27.6 %), 46 to 55 (7.2 %), greater than 55 (2.6 %); p < 0.0001)]; non-diabetic (9.5 % versus 2.8 %, p = 0.023); non-alcoholic (11.4 % versus 6.6 %, p = 0.056); and displayed negative HBV markers (10.2 % versus 4.6 %, p = 0.023). Only t3 patients with IgG-anti- HAV (-) were over 60 years. The authors concluded that there is a frequent indication for HBV vaccination among cirrhotic and especially HAV vaccine for under 45-year old patients undergoing evaluation for OLT.

Andersson et al (2013) stated that liver transplant recipients are at an increased risk for liver failure when infected with HAV and HBV. Therefore, it is important to vaccinate these individuals. These investigators evaluated how well liver transplanted patients in their unit were protected against HAV and HBV infection. Furthermore, they investigated the vaccination rate and the antibody response to vaccination in these liver transplanted patients. Patients liver transplanted from January 2007 until August 2010 with a post-transplant check-up during the period March to November 2010 were included (n = 51). Information considering diagnosis, date of transplantation, Child-Pugh score, and vaccination were collected from the patient records. Anti-HAV IgG and anti-HBs titers in serum samples were analyzed and protective levels were registered. Of the patients, 45% were protected against hepatitis A infection and 29 % against hepatitis B infection after transplantation. Only 26 % were vaccinated according to a complete vaccination schedule and these patients had a vaccine response for HAV and HBV of 50 % and 31 %, respectively. An additional 31 % received greater than or equal to 1 doses of vaccine, but not a complete vaccination and the vaccine response was much lower among these patients, stressing the importance of completing the vaccination schedule. The authors concluded that even when patients were fully vaccinated, they did not respond to the same degree as healthy individuals. They stated that patients seemed to be more likely to respond to a vaccination if they had a lower Child-Pugh score, suggesting that patients should be vaccinated as early as possible in the course of their liver disease.

Young (2018) noted that earlier in 2018, the CDC reported hepatitis A outbreaks among high-risk people, including the homeless, in California, Indiana, Kentucky, Michigan, Missouri, Utah, and West Virginia. Homeless people have 2 to 3 times the risk for hepatitis A infection and 2 to 4 times the risk for severe outcomes if infected, according to an unpublished study cited by CNN. On February 14, 2019, the CDC recommended hepatitis A vaccination for people aged 1 year and older who are homeless. Routine vaccination consists of a 2-dose schedule or a 3-dose schedule when combined hepatitis A and B vaccine is administered. The CDC stated that "Persons experiencing homelessness might have difficulty implementing recommended non-vaccine strategies to protect themselves from exposure (e.g., access to clean toilet facilities, regular hand-washing, and avoidance of crowded living conditions). For this reason, vaccination is the most reliable protection from HAV infection for persons experiencing homelessness. HepA vaccination of persons experiencing homelessness will provide individual protection and increase herd immunity over time, reducing the risk of large-scale, person-to-person outbreaks in this population. The recommendation facilitates routine HepA vaccination of persons experiencing homelessness through facilities that already provide health care services for the homeless population".

Nelson et al (2018) provided and update to the recommendations of the ACIP for use of Hep A vaccine for postexposure prophylaxis (PEP) and for preexposure prophylaxis for international travel. The authors stated that HepA vaccine is recommended for persons aged ≥ 12 months for PEP. Providers may also administer immune globulin (IG) to adults aged > 40 years, if indicated. In addition, simultaneous administration of MMR and HepA vaccines is recommended for infants aged 6–11 months traveling internationally. Persons who are immunocompromised or have chronic liver disease and who have been exposed to HAV within the past 14 days and have not previously completed the 2-dose HepA vaccination series should receive both IG (0.1 mL/kg) and HepA vaccine simultaneously in a different anatomic site (e.g., separate limbs) as soon as possible after exposure. For long-term immunity, the HepA vaccination series should be completed with a second dose at least 6 months after the first dose; however, the second dose is not necessary for PEP. A second dose should not be administered any sooner than 6 months after the first dose, regardless of HAV exposure risk.

Freedman and colleagues (2020) stated that "In June 2019, ACIP recommended all persons with HIV aged 1 year or older be routinely vaccinated with hepatitis A vaccine. The list of other populations at risk for hepatitis A infection or severe hepatitis A disease has not changed significantly and includes persons with chronic liver disease; travelers in countries with high or intermediate endemic hepatitis A; persons with close, personal contact with an international adoptee in the first 60 days after arrival from a country with high or intermediate endemic hepatitis A; men who have sex with men; persons who use injection or non-injection drugs; persons experiencing homelessness; and persons who work with hepatitis A virus in a laboratory or nonhuman primates infected with the virus. Clotting factor disorders has been removed from the list. The definition of chronic liver disease has been expanded and includes, but is not limited to, persons with hepatitis B, hepatitis C, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level greater than twice the upper limit of normal. A 2-dose series HepA (or 3-dose series HepA-HepB) is recommended for pregnant women if they are at risk for infection or severe outcome from infection during pregnancy. Lastly, hepatitis A vaccination is recommended for persons working in settings of exposure (e.g., those working in health care settings for injection or non-injection drug users or group homes and nonresidential day care facilities for developmentally disabled persons). In addition, any person who is not at risk for hepatitis A virus infection but wants protection against it may be vaccinated".

Per ACIP (Nelson et al, 2020), the following includes adults at risk for HAV infection or for severe disease from HAV:

Groups and settings with low risk for hepatitis A (Nelson et al, 2020):

ACIP overview of recommendations for the prevention of hepatitis A virus in the United States (Nelson et al, 2020) :

ACIP (2020) recommendations for hepatitis A vaccine:

ACIP best practice guidance states that HCT recipients who received vaccines before their HCT should be vaccinated or revaccinated routinely after HCT, regardless of the source of the transplanted stem cells; revaccination doses of HepA vaccine are recommended after HCT. The Infectious Disease Society of America has guidance for vaccination of the immunocompromised host. The guidance states that solid organ transplant candidates who are unvaccinated, undervaccinated, or seronegative for hepatitis A, particularly liver transplant candidates, aged 12–23 months (strong recommendation, moderate-quality evidence) and ≥2 years (strong recommendation, moderate-quality evidence) should receive a HepA vaccine series (Nelson et al, 2020).

One or Two Doses of Hepatitis A Vaccine

Andani et al (2022) stated that HAV is a global health concern as outbreaks continue to occur. Since 1999, several countries have introduced universal vaccination (UV) of children against HAV according to approved 2-dose schedules. Other countries have implemented 1-dose UV programs since 2005; the long-term impact of this schedule is unclear. In a systematic review, these investigators examined available evidence in 4 electronic databases for data published between January 2000 and July 2019 to evaluate scientific literature on 1-dose and 2-dose UV of children with non-live HAV vaccines and described their global impact on incidence, mortality, and severity of hepatitis A, vaccine effectiveness, vaccine effectiveness, and antibody persistence. A total of 3,739 records screened, 33 peer-reviewed articles and 1 conference abstract were included. Rapid declines in incidence of hepatitis A and related outcomes were observed in all age groups following introduction of UV programs, which persisted for at least 14 years for 2-dose and 6 years for 1-dose programs according to respective study durations. Vaccine effectiveness was 95 % or more over 3 to 5 years for 2-dose programs. Vaccine effectiveness was 98 % or more over 0.1 to 7.5 years for 1-dose vaccination. Antibody persistence in vaccinated individuals was documented for up to 15 years (90 % or more) and 10 years (74 % or more) for 2-dose and 1-dose schedules, respectively. The authors concluded that experience with 2-dose UV of children against HAV is extensive, demonstrating an impact on the incidence of hepatitis A and antibody persistence for at least 15 years in many countries globally. Because evidence is more limited for 1-dose UV, these investigators were unable to draw conclusions on immune response persistence beyond 10 years or the need for booster doses later in life. These researchers stated that ongoing epidemiological monitoring is essential in countries implementing 1-dose UV against HAV. Based on current evidence, 2 doses of non-live HAV vaccines are needed to ensure long-term protection.

Scope of Policy

This Clinical Policy Bulletin addresses Hepatitis A vaccine.

Medical Necessity

Policy Limitations and Exclusions

Disclosure of a risk factor for HAV infection or complication is not necessary for HepA vaccination. Because a person might not disclose a risk factor to the provider, ACIP recommends that any person who has not previously completed the HepA vaccine series may receive HepA vaccine (Nelson et al, 2020).