ATC Class:J07BC02

VA Class:IM100

AHFS Class:

• Vaccines 80:12

Generic Name(s):

• Hepatitis A Virus Vaccine Inactivated

• Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine

Hepatitis A virus vaccine is an inactivated vaccine that contains cell culture-adapted, attenuated hepatitis A virus (HAV) and is used to stimulate active immunity to HAV infection.1,39,47,55,115,171,192 Hepatitis A virus vaccine is commercially available in the US as monovalent vaccines (Havrix^®, Vaqta^®)1,171 and in a fixed-combination vaccine with hepatitis B vaccine (HepA-HepB; Twinrix^®).186

Hepatitis A virus vaccine inactivated (hepatitis A vaccine) is used to stimulate active immunity to hepatitis A virus (HAV) infection in individuals 12 months of age and older.1,3,22,110,132,171,192,195,196

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) recommend routine vaccination with hepatitis A vaccine for all children at 1 year of age (i.e., at 12 through 23 months of age), unless the vaccine is contraindicated.3,132,192 In addition, the ACIP, AAP, and AAFP recommend preexposure vaccination for previously unvaccinated children, adolescents, or adults who are at high risk of exposure to HAV and for any other unvaccinated individual desiring protection from HAV infection.3,132,192,195,196 Hepatitis A vaccine also is used alone or in conjunction with passive immunization with immune globulin IM (IGIM) for postexposure prophylaxis† in susceptible individuals with recent (within 2 weeks) exposure to HAV.48,84,132,192,196 (See Uses: Postexposure Prophylaxis.)

Hepatitis A vaccine will not prevent hepatitis caused by other infectious agents (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], hepatitis E virus [HEV]). 1,171

When vaccination against both HAV and HBV is indicated in adults 18 years of age or older, the commercially available fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) can be used.186,192 The ACIP, AAP, and AAFP state that use of a combination vaccine generally is preferred over separate injections of the equivalent component vaccines;3,208 considerations should include provider assessment (e.g., number of injections, vaccine availability, likelihood of improved coverage, likelihood of patient return, storage and cost considerations), patient preference, and potential for adverse effects.3,208 However, the HepA-HepB (Twinrix^®) fixed-combination vaccine should not be used for HAV postexposure prophylaxis.196 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Past and Current Considerations Regarding Hepatitis A Vaccine Recommendations

Prior to the availability of hepatitis A vaccine, the principal means of preventing HAV infection involved hygienic and sanitary measures and prophylaxis with IGIM.26,32,37,40,41,42,49,54,63,74,75,107,120,128,132 From 1995-2005 after the vaccine became available, the strategy for HAV prevention and reduction in the overall incidence of the disease in the US consisted of selective vaccination of individuals in high-risk groups and in children residing in areas with consistently elevated rates of HAV infection.192 This limited strategy of selective vaccination in areas with consistently elevated rates of HAV infection reduced the overall incidence of the disease in the US to the lowest level ever recorded.192 The largest decreases occurred in areas where children received routine vaccination against HAV.192 Infection rates became more equally distributed in the US, with the highest rates reported in children who lived in areas of the country where selective vaccination had not been implemented.192

Therefore, in late 2005, the ACIP expanded their recommendations regarding vaccination against HAV to include universal vaccination of all children in the US at 1 year of age.192 Since the continued implementation of the previous selective immunization strategy was unlikely to further reduce the overall incidence of HAV infection in the US, the new recommendations were developed by the ACIP to achieve more widespread routine vaccination of children to prevent infection in this age group and eventually among older individuals and thereby achieve a sustained reduction in HAV infection rates with the goal of total elimination of HAV transmission in the US.192 It is expected that universal childhood immunization against HAV will substantially lower disease incidence and potentially may eliminate indigenous transmission of HAV infection in the US.192

Despite the relatively mild nature of HAV infection in most patients, the infection results in substantial morbidity and associated health-care and work-loss costs.38,59,63,75,192 Surveillance data indicate that 11-22% of individuals with clinical HAV infection will require hospitalization;192,203 the estimated duration of work loss is 33.2 days for adults with clinical illness requiring hospitalization and 15.5 days for those whose illness does not require hospitalization.192 The overall case fatality rate for HAV in the US is 0.3-0.6%, but increases to about 2% in patients older than 40 years of age.192,203 Epidemiologic changes in HAV during the past several decades are resulting in an increasingly larger proportion of older Americans who are susceptible to the disease (i.e., at an age when the risk of fulminant hepatitis is increased).9,31,38,57,75,92

Available data regarding use of hepatitis A vaccine indicate that the observed reductions in HAV infection rates among children appear to have been achieved with modest levels of vaccine coverage, which suggests a strong herd immunity effect associated with use of the vaccine.192 Observed reductions in HAV infection rates among adults also suggest that use of hepatitis A vaccine among children may reduce HAV transmission among other age groups through herd immunity.192 Similar observations supporting the effect of herd immunity associated with routine hepatitis A vaccination of infants or children have been reported from other countries (e.g., Israel, Spain).192 Models evaluating the association between HAV infection rates and HAV vaccine coverage also indicate a strong herd immunity effect which may be responsible for preventing 33% of the estimated number of HAV cases prevented by vaccination in the US.192

Types of Exposure

HAV infection is highly contagious with the principal mode of transmission being enteric (i.e., through fecal contamination and oral ingestion), most commonly from person to person, particularly from children to adults.4,16,21,30,32,37,42,50,57,58,76,85,91,92,94,97,110,120,132,167,192,203 HAV is shed in feces and is highly resistant to degradation by environmental conditions, which is a major factor in maintenance and common-source spread of HAV within populations.4,16,37,42,57,58,90,92,120,132,167,192 Depending on conditions, the virus may be environmentally stable for months; heating foods and beverages to temperatures exceeding 85°C for 1 minute or disinfecting surfaces with a 1:100 dilution of household bleach (sodium hypochlorite) is required for inactivation.37,42,120,203 Because HAV is so environmentally stable, transmission can occur by ingestion of contaminated water or food.6,16,28,59,75,85,91,92,94,120,132,133,134,135,136,137,167,192 While there is evidence from studies in nonhuman primates that the virus can be isolated from saliva during the incubation period, epidemiologic studies have not revealed evidence of transmission of HAV via saliva in humans.16,37,42,92,98,192,203

Prior to the availability of hepatitis A vaccine, most HAV infections within the US resulted from person-to-person transmission of HAV during communitywide outbreaks and the most common reported sources of infection were contact (household or sexual) with an HAV-infected individual (12-26% of cases),192,203 contact with children attending or employees of child-care centers (particularly those with inadequately toilet-trained children) or with a child-care-related case (14-16% of cases),24,83,92 international travel (4-6% of cases),203 or being part of a recognized common-source (food or waterborne) outbreak (2-3% of cases).6,16,21,22,24,26,27,28,29,31,37,40,43,51,57,58,74,76,80,84,85,91,92,93,95,97,110,120,126,133,134,135,136,137,139,147,149,203 Among international travelers who developed HAV during this period, about 36% of cases were reported in children and 84% of cases involved travel to Mexico.172 Although the number of international travel-related cases of HAV has remained relatively constant following the availability of hepatitis A vaccine, recently the overall incidence of such HAV cases has declined.192 During 2006, international travel was the identified risk factor for 15% of HAV infections.167 Illicit drug use remains another common source of HAV infection.16,125,126,132,147,192,203

In approximately 45-50% of reported cases of HAV prior to widespread HAV vaccination, no specific risk factor was identified,21,31,57,92,203 but children played a major role in HAV transmission, and approximately 52% of households of such reported HAV cases contained a child younger than 6 years of age.80,92,110,120,147,152,192 About 33% of reported cases of HAV infection in the US occurred in children younger than 15 years of age, and many more pediatric cases presumably went unrecognized because of the increased likelihood of asymptomatic HAV infection in this age group.6,10,16,24,31,32,54,57,58,92,192 In addition, studies of household contacts of adults with HAV and in whom no source of infection is known indicate that 25-40% of contacts younger than 6 years of age had serologic evidence of acute HAV infection (i.e., immunoglobulin M [IgM] anti-HAV).192 Therefore, children serve as a major source of infection for members of the household.6,10,16,24,30,31,50,54,110,132,147,192 However, in recent years only about 9% of individuals with HAV infection report exposure to child-care centers.192

Person-to-person contact via the fecal-oral route is thought to be the principal source of HAV outbreaks among parenteral and nonparenteral illicit drug users and among homosexual and bisexual men.16,21,31,73,81,126,192 In addition, HAV transmission among parenteral drug users occurs by the percutaneous route through shared needles and other drug paraphernalia.192 Cyclic outbreaks continue to be reported among parenteral and nonparenteral illicit drug users and among men who have sex with men; before HAV vaccine was available, up to 15% of cases reported in the US involved individuals who reported one or more of these behaviors.192 Over the last couple of decades, the frequency of HAV outbreaks has been increasing among illicit drug users in the US; up to 48% of reported cases during such outbreaks involved illicit use of methamphetamine (injected or noninjected).192 HAV outbreaks continue to be reported among homosexual and bisexual men in the US.192,203

While HAV principally is spread enterically between close contacts,6,31,192 the virus also can be spread by infected food handlers,6,16,29,192,203 by a breakdown in usual sanitary conditions (e.g., sewage-contaminated drinking water),137 by raw or undercooked shellfish (e.g., clams, mussels, oysters) from contaminated waters,16,28,91,136,167 by contaminated foods (e.g. fruits, vegetables) that are eaten uncooked,167,192 by poor hygienic conditions during travel to certain areas of the world,16,22,26,27,90,167,192 by closed living conditions (e.g., among institutionalized children and adults),25 in health-care settings,192 and by parenteral transmission (e.g., transfusions of blood or plasma-derived preparations, sharing needles with infected individuals).2,16,21,27,32,42,58,63,74,76,84,92,94,97,138,139,165,166,192

A chronic carrier state has not been identified in individuals with HAV infection; however, relapse of clinical infection occurs in up to 15% of patients, and fecal viral shedding can recur at this time.6,16,17,30,32,37,42,74,86,92,164,192 During the convalescent phase of the disease, immunoglobulin G (IgG) anti-HAV can be detected in the patient's serum and generally remains present for the life of the patient, conferring lifelong immunity to HAV and presumably protection from reinfection.4,6,16,19,21,32,74,132,153,192

Risks of Exposure and Infection

Hepatitis A Epidemiology Prior to Availability of Hepatitis A Vaccine

The epidemiology of HAV infection in the US was fundamentally changed by the availability of hepatitis A vaccine and subsequent implementation of ACIP recommendations for use of the vaccine.192 The incidence of HAV infection in the US had been cyclic, with nationwide epidemics occurring every 10-15 years;31,63,114,192 the last reported nationwide increase in HAV morbidity was in 1995.63,80,97,161

The incidence of HAV infection was highest among children 5-14 years of age and approximately 33% of reported cases involved children younger than 15 years of age.192 Incidence models indicate that during 1980-1999, most HAV infections occurred among children younger than 10 years of age and the highest incidence was among those younger than 4 years of age.192 Before hepatitis A vaccine was available, the rate of HAV infection among Native Americans and Alaskans was 5 times the rate reported in other racial/ethnic populations, and the rate among Hispanics was approximately 3 times higher than rates among non-Hispanics.192

During the several decades prior to the availability of hepatitis A vaccine, the highest rates of HAV infection occurred in a limited number of states and counties in the US, especially in the western and southwestern US, including Arizona, Alaska, Oregon, New Mexico, Utah, Washington, Oklahoma, South Dakota, Idaho, Nevada, and California.192,203 Although annual infection rates in these states fluctuated, 50% (annual average) of reported cases during the period from 1987-1997 were from these states, where average disease rates exceed 20 cases per 100,000 during 1987-1997 (twice the national average rate); however, the combined population in these states is only about 22% of the US population.192 During this period, an additional 18% of cases were from states with average annual HAV infection rates that were higher than the national average but less than twice the national average (e.g., Missouri, Texas, Colorado, Arkansas, Montana, Wyoming).192

Seroepidemiologic studies indicated that the likelihood of prior HAV infection in the US was related to age, household size, and ethnic/socioeconomic status.6,16,21,31,76,80,84,88,92,94,120,132 During 1988-1994, the Third National Health and Nutrition Examination Survey (NHANES-III) indicated that approximately 31-33% of the US population had serologic evidence of previous HAV infection.192,203 Serologic evidence of exposure was present in 9% of Americans 6-11 years of age,203 in 19% of those 20-29 years of age, in 33% of those 40-49 years of age, and in 75% by age 70.6,16,21,31,192,203 Age-adjusted anti-HAV serologic prevalence was considerably higher among Mexican-American (70%) compared with black (39%) and white (23%) individuals, and among foreign-born (69%) compared with US-born (25%) individuals.192,203

Hepatitis A Epidemiology Following Availability of Hepatitis A Vaccine

Following US Food and Drug Administration (FDA) approval of hepatitis A vaccine in 1995, the rate of HAV infection declined sharply in the US, especially after ACIP recommendations in 1999 regarding routine vaccination of children living in areas with consistently elevated rates of HAV infection.192 In 2004, a total of 5683 cases of HAV infection (rate: 1.9 cases per 100,000 population) were reported; considering underreporting, the actual number of cases of acute HAV that year is estimated to be approximately 24,000.192 This is the lowest rate of HAV infection ever reported in the US and is 79% lower than the previously reported low rate in 1992.192

The recent decline in the rate of HAV infection is also reflected in other fundamental changes in the epidemiology of HAV infection.192 Since age-specific rates of HAV declined more rapidly among children than adults during the past decade, rates have become similar across all age groups.192,203 In addition, differences in HAV rates among racial/ethnic populations have also narrowed following the availability of hepatitis A vaccine.192 Recent HAV rates among Native Americans and Alaskans have decreased by 99% compared with rates before the vaccine was available; the rates in these populations are now approximately the same as or lower than those of other racial/ethnic populations.192 Although the rate of HAV infection remains higher among Hispanics than among non-Hispanics, the rates among Hispanics did decline 87% during this period, from 20.6 cases per 100,000 during 1990-1997 to 2.7 per 100,000 in 2004.192

Previous geographic differences in incidence rates have also been eliminated; since 2001, the incidence of HAV in states with vaccination programs is similar to that in the rest of the US.192 Recently, counties with higher rates have varied annually and have been distributed throughout the entire US.192 Following implementation of the 1999 ACIP recommendations for routine vaccination in children in areas with a high prevalence of HAV infection, the incidence of HAV decreased sharply in states with previously consistently elevated rates.192 As a result, the majority of HAV infections during recent years have been reported from states with previously low rates where routine use of hepatitis A vaccine of children has not been widely implemented.192 In addition, the decrease or elimination of differences in age, race/ethnicity, and state-specific rates in the US can be attributed largely to changes that occurred in the states with programs for routine vaccination of children.192 Approximately 66% of the 6000 cases of HAV reported in 2004 were from states where the ACIP did not recommend routine childhood vaccination.192 The rate of HAV among all Hispanics in these states in 2004 remained 4 times higher than among non-Hispanics and was 7 times higher among Hispanic children compared with non-Hispanic children.192 The highest rate of HAV infection reported in any demographic subgroup was among Hispanic children in states that did not have routine childhood HAV vaccination programs.192

Individuals Considered at Risk

Household and Sexual Contacts

Household and sexual contacts of individuals with confirmed HAV infection are at high risk of exposure to HAV.21,192,203 Approximately 13% of reported cases in the US during 2002-2004 were attributable to such contact.192 Cyclic outbreaks of HAV have been reported frequently in male homosexuals and bisexuals in urban areas of the US, Canada, Europe, and Australia, and the likelihood of prior HAV infection is related to the nature and duration of homosexual activity and number of sexual partners.192

Travelers

HAV infection remains one of the most commonly reported vaccine-preventable diseases in travelers.167,192 HAV infection is common (high or intermediate endemicity) in developing countries, and travelers to these countries are at risk and should be vaccinated against the disease.167,203 Travelers to countries with low HAV endemicity (e.g., Australia, Canada, western Europe, Japan, New Zealand) are at no greater risk for infection than individuals living or traveling in the US.196 The risk of acquiring HAV while traveling varies with living conditions, length of stay, and incidence of HAV infection in the area visited.167 Many cases of HAV occur in travelers to developing countries with standard tourist itineraries, accommodations, and food consumption behaviors.167 The Centers for Disease Control and Prevention (CDC) website ([Web]) should be consulted for information regarding which countries have high or intermediate levels of HAV endemicity.167

Occupational Risk

Individuals at high risk of occupational exposure to HAV in the US include those working with HAV-susceptible nonhuman primates and those working with the live virus in a research laboratory setting.2,76,99,161,192 Nonhuman primates (i.e., great apes, several species of old- and new-world monkeys) are susceptible to HAV infection, and outbreaks of HAV have occurred in workers handling such animals.63,85,99,108,120

The risk of occupational exposure to HAV has not been shown to be increased in other occupational groups in the US, including health-care workers, those working in a child-care setting, or food handlers.63,119,178,192 When proper infection control practices are followed, nosocomial HAV transmission is rare and occupational exposure generally does not increase the risk of infection for health-care personnel.132,178,192 Although some epidemiologic evidence from abroad suggests that workers with sewage exposure may be at high risk of HAV exposure, the quality of the evidence has been questioned (e.g., other risk factors such as socioeconomic status were not controlled for).192 In addition, data from 3 serologic surveys of US wastewater workers with appropriate control populations indicate that there is no substantial or consistent increase in the serologic prevalence of anti-HAV among wastewater workers and no work-related cases of HAV transmission or outbreaks among such workers have been reported to date in the US.74,76,89,192

Others Considered at Risk

Other individuals considered at high risk of exposure to HAV include individuals engaging in high-risk sexual activity (e.g., homosexually and bisexually active adolescent and adult males);2,21,73,81,120,126,192 users of illicit injectable or noninjectable drugs;2,45,58,192 and residents of a community that is experiencing an outbreak of HAV.2,76,85,192 Although not at increased risk of HAV infection, individuals with chronic liver disease, including those with alcoholic cirrhosis, chronic HBV or HCV infection, autoimmune hepatitis, or primary biliary cirrhosis and those awaiting or having received liver transplants are at increased risk of developing severe consequences of HAV infection, including fatal fulminant hepatitis and hepatic failure.16,74,103,110,192,203

Because blood products (e.g., whole blood, packed red blood cells, plasma) and plasma-derived preparations (e.g., albumin human, antihemophilic factor [human], anti-inhibitor coagulant complex, factor IX [human], factor IX complex) are potential vehicles for transmission of human viruses, including HAV, individuals who receive frequent and/or large-volume transfusions of blood products or plasma-derived preparations (e.g., individuals with hemophilia or thalassemia) may be at increased risk for HAV.66,67,68,70,100,101,138,139,165,168,169,192 (See Recipients of Blood Products and Plasma-derived Preparations, under Uses: Preexposure Vaccination in High-risk Groups.)

The epidemiology of HAV infection does not permit identification of other specific populations at high risk of disease, but outbreaks of HAV infection or exposure to HAV have been described in a variety of populations in which hepatitis A vaccine may be useful, such as certain institutional workers (e.g., caretakers for the developmentally disabled), employees of child-care centers, and individuals exposed to HAV.16,83,84,192 Additional study is needed to define the benefit, if any, of hepatitis A vaccine if an outbreak occurs in such settings.107,120,192

Settings Associated with Risk of Transmission

In addition to populations considered at high risk for HAV infection, certain settings are associated with a high risk of outbreaks of the virus.192 Such settings include child-care centers,16,21 institutions for the developmentally disabled, health-care settings, correctional facilities, and areas of common-source outbreaks.29,58,74,84,85,132,192

Child-care Centers

HAV outbreaks in children attending child-care centers and in child-care employees have been reported since 1970; however, the frequency of such outbreaks has decreased with the recent decline in HAV prevalence in children.192 Lack of hygienic practices among diapered children in addition to changing and handling of diapers by staff contribute to the spread of HAV in child-care centers.21,51,83,92,96,97,132,192 Outbreaks rarely occur in centers that serve only nondiapered children.24,83,192 Because pediatric HAV infection usually is mild or asymptomatic, outbreaks in child-care centers often go unrecognized until an adult contact (usually a parent) becomes symptomatic.10,83,192 Although outbreaks among children and employees of child-care centers may be the source of larger outbreaks in certain communities, HAV infection in child-care centers more often is indicative of extended transmission from the community.10,16,24,83,84,132,192 Despite the occurrence of such outbreaks, child-care center staff and children and adolescents with a history of child-care center attendance do not exhibit an increased rate of HAV seropositivity.192

Institutions for the Developmentally Disabled

HAV historically was endemic in institutions for the developmentally disabled.45,51,58,74,92,192 While the incidence and prevalence of HAV infection in these institutions has declined secondary to declining censuses and improvements in living conditions, sporadic outbreaks continue to occur in this setting.192

Correctional Facilities

The AAP recommends that hepatitis A vaccine be given to incarcerated adolescents in correctional facilities located in states with existing programs for hepatitis A immunization of adolescents.132 Because of the likelihood that adolescents in the juvenile correctional system have indications for the vaccine, other correctional facilities also should consider routine hepatitis A immunization of all adolescents under their care.132 Incarcerated adolescents with signs or symptoms of hepatitis should be tested for acute HAV, HBV, and HCV infection.132 Those with HAV should be reported to the local health department and appropriate postexposure prophylaxis with hepatitis A vaccine should be given to susceptible exposed residents.132

Schools

Transmission of HAV between children within primary and secondary schools is uncommon in developed countries, but outbreaks can occur.32,114,132,161,192 In developing countries, transmission of HAV between children within primary schools is more common.7,151,161

Cases of HAV infection in primary or secondary schools in the US generally indicate community disease transmission.192 Child-to-child disease transmission in the school setting is uncommon;192 however, if multiple cases of HAV occur among children at a particular school, common-source infection should be excluded by epidemiologic investigation.192

Health-care Settings

Nosocomial transmission of HAV in health-care settings is rare.58,119,139,192 Occasional outbreaks have occurred in neonatal intensive-care settings secondary to transmission by staff exposed to a neonate who acquired the infection from transfused blood products.68,96,192 Outbreaks in health-care settings also can occur secondary to staff handling of infected adults who are fecally incontinent, although most hospitalized patients with HAV infection are admitted subsequent to jaundice onset, at which time peak infectivity has passed.58,92,192 Epidemiologic evidence from many types of US and European health-care workers has not revealed any evidence of an increased rate of HAV seropositivity compared with that in other workers.192

Food Service Establishments

Common-source foodborne HAV outbreaks, although relatively uncommon in the US, appear to be on the increase and require intensive public health intervention when they occur.63,91,97,133,134,135,136,192 Foodborne outbreaks in the US often result from contamination of food during preparation by an HAV-infected food handler,29,172 although contamination of uncooked produce or fruit (e.g., green onions, lettuce, raspberries, strawberries), shellfish, and sandwiches prior to arrival at the food service establishment has been reported with increasing frequency.16,21,28,37,45,54,74,75,85,91,120,133,134,135,136,175,192 In contrast to the relatively low risk in the US, contaminated food (e.g., fruit, shellfish, uncooked vegetables or other foods) is a common source of HAV transmission during international travel.32,59,63,75,90,120,167

Other Settings

Common-source waterborne outbreaks are infrequent in the US and other developed countries and usually are related to sewage contamination of drinking water or inadequately treated water.37,74,75,85,120,137,192,203 In contrast, water is a common source of HAV transmission during international travel.32,59,75,90,120,167

Communitywide Risk

Prior to the availability of hepatitis A vaccine, most HAV infections within the US resulted from person-to-person transmission of HAV in households and extended family settings during communitywide outbreaks.92,114,192 These outbreaks often spread throughout the community; a single risk factor or group generally was not identified.192 Such communitywide outbreaks often persisted for 1-2 years and were difficult to control.8,31,114,143,144,192,203 HAV infection in children often is asymptomatic or not recognized; therefore children played a key role in sustaining HAV transmission during these outbreaks.88,144,192 Since the implementation of selective childhood hepatitis A vaccination programs, large communitywide HAV outbreaks have decreased considerably.192 It is expected that universal childhood vaccination against HAV will substantially lower disease incidence and may potentially eliminate indigenous transmission of HAV infection in the US.192

Although there has been some interest in the use of hepatitis A vaccine to interrupt ongoing communitywide epidemics by vaccinating children in affected populations, such vaccine programs have been difficult to implement.192 First-dose vaccine coverage during such programs has generally been low (20-45%) and the benefit of HAV vaccination was limited to vaccinated age groups that were not representative of groups reporting high rates of HAV infection.192 Sustained efforts to implement routine childhood vaccination with hepatitis A vaccine to maintain high levels of immunity are expected to prevent future epidemics.192

Primary Immunization

Children 12 Months of Age and Older

The ACIP, AAP, and AAFP recommend that all children 1 year of age (i.e., 12 through 23 months) receive primary immunization against HAV infection using hepatitis A vaccine, unless the vaccine is contraindicated.3,132,192 Children who are not vaccinated by 2 years of age may be vaccinated at subsequent visits.3,132,192 The ACIP also recommends that states, counties, and communities with existing selective preexposure hepatitis A vaccination programs for children 2 through 18 years of age maintain these programs.192 (See Uses: Preexposure Vaccination in High-risk Groups.) In such areas, new efforts focused on routine vaccination of children at 1 year of age should enhance, not replace, ongoing programs directed at a broader population of children132,192 In areas without existing selective preexposure hepatitis A vaccination programs, catch-up vaccination of unvaccinated children 2 through 18 years of age may be considered.132,192 Catch-up vaccination programs may be warranted in the context of rising incidence or ongoing outbreaks of HAV among children or adolescents.132,192

Infants Younger than 12 Months of Age

Safety and efficacy of hepatitis A vaccine have not been established in children younger than 12 months of age.1,171 Data regarding the use of the vaccine in neonates and infants younger than 12 months of age are limited;1,171 the optimal dose and vaccination schedule in this age group as well as the effect of passively acquired maternal antibody on vaccine immunogenicity remain to be more fully elucidated.77,172 (See Cautions: Pediatric Precautions.)

Internationally Adopted Children and Other Immigrants

Individuals seeking an immigrant visa for permanent US residency must provide proof of age-appropriate vaccination according to the US Recommended Childhood and Adolescent Immunization Schedules or the US Recommended Adult Schedule .60 Although this vaccination requirement applies to all immigrant infants and children entering the US, internationally adopted children younger than 11 years of age are exempt from the overseas vaccination requirements; however, adoptive parents are required to sign a waiver indicating their intention to comply with the vaccination requirements within 30 days after the infant or child arrives in the US.60 The CDC states that more than 90% of newly arrived internationally adopted children need catch-up vaccinations to meet the US Recommended Immunization Schedules.167

The fact that immunization schedules of other countries may differ from US schedules (e.g., different recommended vaccines, recommended ages of administration, and/or number and timing of vaccine doses) should be considered.60 Vaccines administered outside the US can generally be accepted as valid if the administration schedule was similar to that recommended in the US childhood and adolescent immunization schedules.60 Only written vaccination records should be considered as evidence of previous vaccination since such records are more likely to accurately predict protection if the vaccines administered, intervals between doses, and child's age at the time of vaccination are similar to US recommendations; however, the extent to which an internationally adopted child's immunization record reflects their protection against disease is unclear and it is possible there may be transcription errors in such records (e.g., single-antigen vaccine may have been administered although a multiple-antigen vaccine was recorded).60 Although vaccines with inadequate potency have been produced in other countries, most vaccines used worldwide are immunogenic and produced with adequate quality control standards.60

For internationally adopted children whose immune status is uncertain, vaccinations can be repeated or serologic tests performed to confirm immunity.60 For hepatitis A vaccine, the ACIP states that the simplest approach is to revaccinate according to the US recommended immunization schedule in children 12 months of age or older.60 Alternatively, test for serologic evidence of susceptibility to HAV.60

When a child is being adopted from a country with high or intermediate HAV endemicity, the ACIP states that all previously unvaccinated individuals who anticipate close personal contact with the adoptee during the child's initial 60 days in the US (e.g., household members, regular babysitters) should receive routine vaccination with hepatitis A vaccine, with the first dose given as soon as adoption is planned (ideally at least 2 weeks before the child's arrival).209 The CDC website ([Web]) should be consulted for information regarding which countries have high or intermediate levels of HAV endemicity.167

Preexposure Vaccination in High-risk Groups

The ACIP, AAP, and AAFP recommend preexposure vaccination for previously unvaccinated children, adolescents, or adults who are at high risk of exposure to HAV and for any other unvaccinated individual desiring protection from HAV infection.3,132,192,195,196 Hepatitis A vaccine is used for selective immunization of previously unvaccinated children 12 months of age or older who reside in states, counties, or communities where the rate of HAV infection is high and for preexposure vaccination in unvaccinated individuals who are or will be at high risk of exposure to HAV, including travelers, populations with a high risk of infection, individuals at risk because of their sexual practices, individuals with potential occupational exposure, military personnel, and other individuals at risk of exposure.3,45,59,74,76,110,149,177,192,196 Preexposure vaccination also is recommended for unvaccinated individuals with chronic liver disease because of the potentially serious consequences of HAV infection if it were to occur.1,16,103,177,192,195

IGIM generally is used for preexposure passive immunoprophylaxis in situations when hepatitis A vaccine cannot be used for preexposure vaccination (e.g., when the vaccine is contraindicated, unavailable, or is cost prohibitive) and when short-term protection is required.26,32,37,40,42,59,74,107,128,132,161,196

Children Who Reside in High-risk Areas

The ACIP, AAP, and AAFP recommend routine vaccination of previously unvaccinated children who reside in states, counties, and communities where the rate of HAV infection is high.3,192 The strategy of routine primary immunization against HAV in all children at 1 year of age (i.e., 12 through 23 months of age) is expected to eventually eliminate transmission of HAV in the US.192 (See Children 12 Months of Age and Older under Uses: Primary Immunization.) The ACIP recommends that states, counties, and communities with existing selective preexposure hepatitis A vaccination programs for children 2 through 18 years of age maintain these programs.192 In such areas, new efforts focused on routine vaccination of children at 1 year of age should enhance, not replace, ongoing programs directed at a broader population of children.192 In areas without existing selective vaccination programs, catch-up vaccination of unvaccinated children 2 through 18 years of age may be considered.192 Catch-up vaccination programs may especially be warranted in the context of rising incidence or ongoing outbreaks of HAV among children or adolescents.192

HIV-infected Individuals

Because hepatitis A vaccine is an inactivated vaccine, it can be used safely in immunocompromised individuals, including individuals with human immunodeficiency virus (HIV) infection;60,159 however, the fact that the vaccine may be less immunogenic in immunocompromised individuals than in immunocompetent individuals should be considered.60,159,187,192 (See Pharmacology: Response to Hepatitis A Virus Vaccine Inactivated.)

Recommendations for use of hepatitis A vaccine in HIV-infected individuals are the same as those for individuals without HIV infection.197,198 HIV-infected individuals with chronic liver disease (including those coinfected with HBV or HCV) are at risk of fulminant hepatic failure if they acquire HAV.197 The ACIP, AAP, CDC, National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and others recommend that HAV-susceptible, HIV-infected adults, adolescents, and children receive hepatitis A vaccine.197,198 Because the response to the vaccine may be reduced in those with CD4⁺ T-cell counts less than 200 cells/mm³, some experts suggest delaying vaccination until the patient is receiving antiretroviral therapy and the CD4⁺ T-cell count is greater than 200 cells/mm³.197

Travelers

Travelers to areas with intermediate to high levels of endemic HAV are at risk of exposure to the disease.13,22,59,63,74,76,84,90,97,110,167,171,176,192,196 (See Travelers, under Uses: Risks of Exposure and Infection.) Clinicians should be alert to opportunities to provide vaccination for all travelers whose plans might include travel at some time in the future to an area of high or intermediate HAV endemicity, including those whose current medical evaluation is for travel to an area where hepatitis A vaccination is not recommended.167

The ACIP, CDC, World Health Organization (WHO), and other clinicians state that all susceptible individuals traveling to or working in areas with intermediate to high levels of endemic HAV should receive preexposure vaccination with hepatitis A vaccine or, alternatively, preexposure prophylaxis with IGIM prior to departure.22,59,74,132,167,176,192,196 A complete schedule of HAV vaccination at the age-appropriate dose is preferable to prophylaxis with IGIM in children 12 months of age and older, adolescents, and adults because of the longer duration of immunity conferred by the vaccine, especially for individuals planning to travel repeatedly to, or reside for long periods in, areas with intermediate or high levels of endemic HAV infection.22,74,75,107,167,192,196 Travelers who are allergic to a vaccine component or younger than 12 months of age and travelers electing not to receive the vaccine should receive preexposure prophylaxis with IGIM since it provides protection for up to 3 months; if travel will be more prolonged, a high dose of IGIM should be given initially or repeated (if travel will exceed 5 months) during travel.107,128,132,167,192,196

Administration of a primary and second (booster) dose of hepatitis A vaccine prior to possible HAV exposure ensures the highest antibody titers.1,2,8,9,10,11,12,22,33,35,46,47,48,49,62,171 Unvaccinated individuals should receive the first dose of hepatitis A vaccine as soon as travel to countries with high or intermediate HAV endemicity is considered.167,196 Protection can be assumed if a single vaccine dose is administered at least 4 weeks prior to possible exposure to HAV.1,13,59,148,154,158,167,171,176,192 Although the degree of protection provided 2-4 weeks after an initial dose of hepatitis A virus vaccine is unknown,192 data from a study that evaluated the relative efficacy of a single dose of monovalent hepatitis A vaccine or a single dose of IGIM for postexposure prophylaxis in susceptible individuals 12 months to 40 years of age (see Clinical Experience under Uses: Postexposure Prophylaxis) suggest that a single vaccine dose administered at any time before departure can provide adequate protection for most healthy individuals 12 months to 40 years of age.196

For optimal protection in travelers at greatest risk for HAV (older adults or individuals with altered immunocompetence, chronic liver disease, or other chronic medical condition) who are planning to depart to an area of HAV risk within 2 weeks should receive the initial dose of hepatitis A vaccine and also should receive simultaneously (at a different site) a dose of IGIM.167,196 Completion of the recommended vaccine series is necessary for long-term protection.196

Whenever the vaccine is contraindicated or cannot be used (e.g., in travelers younger than 12 months of age) or when travelers elect not to receive the vaccine, a single dose of IGIM should be administered prior to travel since it provides effective protection against HAV for up to 3 months.167,196

Data are not available regarding the possible efficacy of the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) for preexposure vaccination of travelers who will depart prior to 2 weeks after receipt of the vaccine.196 The ACIP states that the fixed-combination vaccine should not be used in such situations.192,196 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Individuals who receive a dose of hepatitis A vaccine within 2 weeks of departure and who do not receive IGIM (e.g., by choice or because of limited availability) will be at lower risk for infection than those who do not receive the vaccine or IGIM.167 Although at least 80% of healthy adults develop protective levels of anti-HAV within 15 days of a single 1440-unit dose of Havrix^® vaccine,1,2,8,22,47,48,49,110,148,158 and 69% of healthy adults develop protective levels of anti-HAV within 2 weeks of a single 50-unit dose of Vaqta^®,171 a second dose 6-12 months later is necessary for long-term protection.192 In addition, other data indicate that up to 50% of vaccinees may not be protected at 14 days after receiving an initial dose of vaccine.172 (See Pharmacology: Response to Hepatitis A Virus Vaccine Inactivated.) For individuals with imminent departure dates (e.g. less than 4 weeks after the initial vaccine dose) who require both immediate and long-term protection, the vaccine and IGIM can be administered simultaneously at different sites; if only short-term protection is required, IGIM can be used alone.35,60,107,110,111,128,132,167,192

For travelers older than 40 years of age, adult travelers who were born in or resided for extensive periods in geographic areas with a high or intermediate level of endemic hepatitis A, and certain older adolescent and adult travelers (e.g., those from certain high-risk populations such as Native Americans and Alaskans, Hispanics), prevaccination serologic testing for susceptibility to HAV can be considered.144,167,192 (See Uses: Serologic Testing.)

Individuals at Risk of Exposure Because of Their Sexual Practices

Male homosexuals and bisexuals are at high risk of exposure to HAV infection secondary to their sexual practices.63,73,74,76,81,126,171,192 Therefore, the ACIP, CDC, and manufacturers recommend that all sexually active male adolescents and adults who have sex with men (homosexual, bisexual) receive preexposure vaccination with hepatitis A vaccine.2,110,132,179,192 Primary-care clinicians and those in specialty medical settings should offer hepatitis A vaccine to male adolescents and adults who have sex with men; strategies to increase coverage (e.g., use of standing orders) should be considered.192 Prevaccination serologic testing for susceptibility to HAV may be cost effective in certain men who have sex with men since the prevalence of HAV infection is likely to be high.179,192 The ACIP recommends that prevaccination serologic testing be considered for older adults of this group, but may not be indicated for adolescents.132,140,141,142,192

Illicit Drug Users

Individuals who illicitly use injectable or noninjectable drugs may be at increased risk of exposure to HAV infection.63,74,76,97,192 (See Uses: Types of Exposure.) The ACIP and CDC recommend preexposure vaccination with hepatitis A vaccine for illicit users of injectable or noninjectable drugs.132,192 Prevaccination serologic testing for HAV susceptibility may be considered for adults in this group, but testing is not indicated for adolescents.132,140,141,142,192 In addition, the need for prevaccination serologic testing may also depend on the specific characteristics of a particular population of drug users (e.g., type and duration of drug use).192 Clinicians should obtain a complete history to identify individuals who might benefit from hepatitis A vaccination (e.g., those who use illicit drugs or who are at increased risk for such drug use).192 Clinicians should consider implementing strategies to increase vaccine coverage in these patients (e.g., use of standing orders).192

Recipients of Blood Products and Plasma-derived Preparations

The extent to which recipients of blood products (e.g., whole blood, packed red blood cells, plasma) and plasma-derived preparations (e.g., albumin human, antihemophilic factor [human], anti-inhibitor coagulant complex, factor IX [human], factor IX complex) may be at high risk of HAV exposure is unclear,138,139,165,166,168,169 but certain populations (e.g., individuals with hemophilia receiving solvent/detergent-treated plasma-derived preparations) appear to be at increased risk of exposure to the virus via such preparations.102,168,192 Several outbreaks of HAV infection have been reported in Europe in individuals with hemophilia receiving chemically (solvent/detergent) treated antihemophilic factor (human) preparations that presumably were contaminated from plasma of donors who were incubating HAV at the time of donation.64,65,66,67,70,138,139,165,166,168,169,192 Data from one serologic study in the US suggest that individuals with hemophilia may be at increased risk for HAV infection.192 In addition, HAV seroconversion has been reported in a few recipients of similar plasma-derived preparations marketed in the US and in at least one patient who received a factor IX (human) product inactivated by a chemical (solvent/detergent) process.168,169,192 However, more effective viral inactivation procedures, high HAV vaccine coverage, and improved donor screening have decreased the risk for HAV transmission from clotting factors.192 Analysis of serosurveillance data from 140 participating hemophilia treatment centers obtained during May 1998 through July 2002, indicates that there were no new cases of HAV infection attributable to blood products during this period.192 Because HAV can be transmitted via blood products and plasma-derived products including antihemophilic factor (human), the ACIP recommends that all susceptible individuals receiving plasma-derived clotting-factor concentrates receive preexposure vaccination with the vaccine.195 The National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) recommends that all individuals with hemophilia or other congenital bleeding who are HAV-seronegative should receive age-appropriate preexposure vaccination with hepatitis A vaccine.18,61 This is especially important for those who have HCV infection.18 Although postvaccination serologic testing to confirm immunity is not usually indicated because of the high rate of vaccine response, MASAC strongly recommends such testing following HAV vaccination in adults and children with hemophilia.18 (See Cautions: Precautions and Contraindications.)

Individuals with Occupational Risk

ACIP recommends preexposure vaccination with hepatitis A vaccine in workers handling HAV-infected nonhuman primates (born in the wild) and workers in contact with live HAV in a research laboratory setting.67,99,108,110,132,192 Routine immunization with the vaccine currently is not recommended for other occupational groups in the US.192 (See Occupational Risk, under Uses: Risks of Exposure and Infection.)

The ACIP and the Hospital Infection Control Practices Advisory Committee (HICPAC) state that routine preexposure vaccination with hepatitis A vaccine or routine use of IGIM in health-care personnel providing care to patients with HAV infection is not indicated.132,178,192 Instead, hygienic practices should be emphasized and health-care personnel should be made aware of the risk of exposure to HAV and precautions regarding direct contact with potentially infective materials.132,178,192 In documented outbreaks of HAV infection, postexposure prophylaxis with IGIM may be indicated in health-care workers and others who have close contact with the infected individuals.132,178 (See Hepatitis A Virus Infection under Uses: Immune Globulin IM, in Immune Globulin 80:04.) The usefulness of hepatitis A vaccine in controlling outbreaks in health-care settings has not been investigated.178

Individuals with Chronic Liver Disease

Although individuals with chronic liver disease are not at increased risk of acquiring HAV infection, data indicate that such individuals are at increased risk of severe consequences of HAV infection, including fatal fulminant hepatitis and hepatic failure.16,74,103,110,132,192 The ACIP and AAP recommend that susceptible individuals with chronic liver disease and those who are awaiting or have undergone liver transplantation receive preexposure vaccination with hepatitis A vaccine.132,192

Although some clinicians have recommended that hepatitis A vaccine be used for preexposure vaccination in susceptible individuals with HBV or HCV infection, autoimmune hepatitis, or primary biliary cirrhosis,1,177 the ACIP states that data do not support routine vaccination of individuals with chronic HBV or HCV infection who do not have evidence of chronic liver disease.192

Food Handlers

Individuals employed as food handlers can become infected with HAV and may possibly transmit HAV to patrons.84,177,192 Food-source outbreaks often are associated with contamination of food during preparation by an HAV-infected food handler; a single infected food handler can transmit HAV to numerous, possibly hundreds of patrons through contaminated food.192 However, analysis of US economic data indicates that routine use of hepatitis A vaccine in all food handlers is not economically feasible from a societal or food industry perspective.84,177,192 However, HAV vaccination of restaurant employees may be considered in areas where the state and local health authorities or private employers have determined that such vaccination is indicated to decrease the frequency of evaluations of food handlers for HAV and the need for postexposure prophylaxis of restaurant patrons.84,177,192 Under these circumstances, a record of HAV vaccination should be provided to vaccinated food handlers and those not vaccinated should be informed of the signs and symptoms of HAV infection.192 In addition, all food handlers should receive instruction on food preparation practices that reduce the risk for fecal contamination.192 Occasionally, vaccination of foodhandlers may be considered during a community outbreak.110,177,192

Outbreak Control

Prior to widespread use of hepatitis A vaccine, HAV infection was transmitted from direct contact through the fecal-oral route within households and extended family settings during communitywide epidemics.192 Such HAV epidemics often persisted for 1-2 years, were difficult to control, typically spread throughout the community, and could not generally be attributed to a single risk factor or group.192 Children played a key role in sustaining HAV transmission during these epidemics since they often have asymptomatic or undiagnosed infections.192 In the context of increasing HAV incidence or ongoing outbreaks among children or adolescents in areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children 2 through 18 years of age should be considered.192

The frequency of large communitywide outbreaks has decreased considerably following implementation of recommended childhood hepatitis A vaccination programs.192 Universal childhood vaccination with hepatitis A vaccine for all children should further reduce the occurrence of outbreaks.192 In the event of a communitywide outbreak, accelerated vaccination programs may be considered as an additional control measure.192 The decision to initiate an outbreak-control vaccination program should take into account the feasibility of rapidly vaccinating the target population of children, adolescents, or young adults, and the costs associated with such a program.192 Routine vaccination of children in affected communities should continue in order to maintain high levels of immunity and prevent future epidemics.192 Prevaccination serologic testing for HAV susceptibility generally is not indicated for routine or “catch-up” vaccination of children in such populations.192 (See Children Who Reside in High-Risk Areas under Uses: Preexposure Vaccination in High-risk Groups.)

Limited HAV outbreaks, especially those involving adults at increased risk (e.g., illicit drug users, men who have sex with men) continue to occur and may be expected until higher rates of vaccination are achieved in these populations.192 Vaccination programs in these risk groups to control such outbreaks have been difficult to implement.192 Some success in vaccine coverage has been achieved in programs to control HAV outbreaks among illicit drug users (e.g., methamphetamine users) that focused on vaccination in county jails and judicial diversion programs.192 Efforts to control and prevent HAV outbreaks among adults in such populations at increased risk should generally focus on initiating and maintaining routine vaccination programs in these individuals.192

Child-care center outbreaks have decreased considerably since the implementation of childhood hepatitis A vaccination programs and further decreases are expected now that universal childhood vaccination against HAV is recommended.192 ACIP does not recommend routine preexposure vaccination with hepatitis A vaccine for personnel in child-care centers.192 However, postexposure prophylaxis is recommended in all previously unvaccinated staff and attendees of child-care centers or homes if one or more cases of HAV are recognized in children or employees or if HAV is recognized in 2 or more households of center attendees.196 If an outbreak occurs in a child-care center (i.e., HAV in 3 or more families), postexposure prophylaxis should also be considered for members of households that have diapered children attending the center.196 (See Uses: Postexposure Prophylaxis.)

ACIP does not recommend routine preexposure vaccination with hepatitis A vaccine in hospitals, schools, and institutions for the developmentally disabled because the frequency of outbreaks in these institutions is not high enough to warrant such recommendations.192 Outbreaks involving student-to-student transmission in primary and secondary schools are rare in developed countries, but outbreaks have been documented;32,132,161,192 in developing countries, outbreaks among children in primary schools is more common.7,151,161 If an epidemiologic investigation indicates HAV transmission has occurred among students in a school or among patients or between patients and staff in a hospital, postexposure prophylaxis should be administered to individuals who have close contact with index patients.107,132,192,196 (See Uses: Postexposure Prophylaxis.)

Postexposure Prophylaxis

Hepatitis A vaccine is used for HAV postexposure prophylaxis†.132,178,179,192,196 Unvaccinated individuals with recent (within 2 weeks) exposure to HAV should receive postexposure prophylaxis with a single dose of hepatitis A vaccine and/or a dose of IGIM as soon as possible.132,178,179,192,196 The choice of active immunization with the vaccine or passive immunization with IGIM should take into account the magnitude of risk associated with the exposure and characteristics of the patient that are associated with more severe manifestations of HAV (e.g., older age, chronic liver disease).132,196 Although IGIM was traditionally the recommended regimen for postexposure prophylaxis of HAV since it is 80-90% effective in preventing clinical HAV if administered within 2 weeks of exposure196 (see Uses: Hepatitis A Virus Infection, in Immune Globulin 80:04), there is limited evidence that hepatitis A vaccine administered within 2 weeks of exposure may be as effective as IGIM in healthy individuals 1-40 years of age.196,199 Because the vaccine offers certain advantages over IGIM (induces active immunity and longer protection, more readily available, easier to administer, greater patient acceptance),196,199 the ACIP updated their recommendations regarding postexposure prophylaxis of HAV in June 2007 to include use of the vaccine for postexposure prophylaxis in certain individuals.196

When HAV postexposure prophylaxis is indicated in healthy individuals 12 months to 40 years of age, the ACIP states that an age-appropriate dose of monovalent hepatitis A vaccine should be used and is preferred to IGIM.196 In adults older than 40 years of age, the ACIP states that IGIM is preferred for HAV postexposure prophylaxis since data are not available to date regarding efficacy of the vaccine for prophylaxis in this age group and because these individuals are at risk of more severe manifestations of HAV; however, the vaccine can be used if IGIM cannot be obtained.196 IGIM should be used for postexposure prophylaxis in children younger than 12 months of age, in immunocompromised individuals, individuals with chronic liver disease, and whenever the vaccine is contraindicated.196

When HAV postexposure prophylaxis is indicated, it should be administered as soon as possible.192,196 Data are not available regarding efficacy of hepatitis A vaccine or IGIM for postexposure prophylaxis of HAV if administered more than 2 weeks after exposure.196

Whenever hepatitis A vaccine is used for postexposure prophylaxis†, a monovalent vaccine (Havrix^®, Vaqta^®) should be used.196 The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) should not be used for HAV postexposure prophylaxis196 .192,196 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Combined active immunization with hepatitis A vaccine and passive immunization with IGIM (using different syringes and different injection sites) is recommended by the ACIP for individuals with recent HAV exposure in whom providing long-term protection is indicated.1,36,42,48,84,171,192,196 If a dose of hepatitis A vaccine is used with or without IGIM for HAV postexposure prophylaxis, a second (booster) dose of the vaccine should be administered according to the usually recommended schedule to ensure long-term protection.196

Routine screening of contacts for serologic markers of HAV infection prior to administration of HAV postexposure prophylaxis is not recommended.107,132,192 However, because HAV infection cannot be diagnosed reliably by clinical presentation alone, serologic confirmation of HAV in the index case is recommended before treatment of contacts.42,86,132,192 (See Uses: Serologic Testing.)

Postexposure Prophylaxis in Close Personal Contacts

HAV postexposure prophylaxis with hepatitis A vaccine or IGIM should be administered within 2 weeks to all previously unvaccinated household and sexual contacts of individuals with serologically confirmed HAV.196 Consideration also should be given to administering postexposure prophylaxis with the vaccine or IGIM to individuals with other types of ongoing, close personal contact (e.g., regular babysitting) with a person with HAV.196

Contacts who have shared illicit drugs with an individual with serologically confirmed HAV within the last 2 weeks should receive postexposure prophylaxis with the hepatitis A vaccine or with both the vaccine and IGIM administered simultaneously (at separate sites).196

Postexposure Prophylaxis in Child-care Centers

HAV postexposure prophylaxis with hepatitis A vaccine or IGIM should be administered to all previously unvaccinated staff and attendees of child-care centers or homes if one or more cases of HAV are recognized in children or employees or if HAV is recognized in 2 or more households of center attendees within the last 2 weeks.196 In centers that do not provide care to children who wear diapers, postexposure prophylaxis with the vaccine or IGIM needs to be administered only to classroom contacts of the index patient.196

When an outbreak occurs (i.e., HAV in 3 or more families), postexposure prophylaxis with hepatitis A vaccine or IGIM should also be considered for members of households that have diapered children attending the center.196

Postexposure Prophylaxis in Common-source Exposures

If HAV is diagnosed in a food handler, the ACIP recommends postexposure prophylaxis with hepatitis A vaccine or IGIM within 2 weeks for other food handlers at the same establishment.196 Postexposure prophylaxis for patrons typically is not indicated since common-source transmission to patrons is unlikely.196 However, postexposure prophylaxis for patrons may be considered if the food handler directly handled uncooked or cooked foods and had diarrhea or poor hygienic practices during the time when they were likely to be infectious and if patrons can be identified and treated within 2 weeks after the exposure.196 Settings where repeated HAV exposure might have occurred (e.g., institutional cafeterias) warrant stronger consideration of postexposure prophylaxis for patrons.196

If a common-source outbreak of HAV occurs, the ACIP states that postexposure prophylaxis should not be provided to exposed individuals after cases have begun to occur because the 2-week period after exposure during which the vaccine or IGIM is known to be effective will have been exceeded.196

Postexposure Prophylaxis in Schools, Hospitals, and Work Settings

The ACIP states that routine HAV postexposure prophylaxis is not indicated when a single HAV case occurs in an elementary or secondary school or an office or other work setting if the source case is outside the school or work setting.196

When an individual with HAV is admitted to a hospital, staff members do not need to receive routine postexposure prophylaxis; careful hygienic practices should be emphasized in such situations.196

If an epidemiologic investigation indicates that HAV transmission has occurred among students in a school or among patients or between patients and staff members in a hospital, the ACIP recommends that postexposure prophylaxis with hepatitis A vaccine or IGIM should be administered in individuals who have close contact with index patients.196

Clinical Experience

Efficacy of hepatitis A vaccine for postexposure prophylaxis† of HAV has been evaluated in a randomized, double-blind, noninferiority trial in susceptible individuals 2-40 years of age who were household or child-care center contacts of index patients with HAV (study NCT00139139).199 Individuals were randomized to receive a single dose of monovalent hepatitis A vaccine (age-appropriate dose of Vaqta^®) or IGIM (0.02 mL/kg) within 14 days after exposure to a laboratory-confirmed index case of HAV.199 The primary end point was laboratory-confirmed symptomatic HAV occurring between 15-56 days after exposure.199 In the per-protocol analyses, HAV was confirmed in 4.4% of those who received the vaccine and 3.3% of those who received IGIM.199 The relative risk of HAV among vaccine recipients was noninferior to that reported for IGIM recipients.199

In a study in Naples, Italy where HAV infection is endemic, hepatitis A vaccine (Havrix^®) was administered to family contacts of individuals with primary HAV infection (index cases) for postexposure prophylaxis†.185 The vaccine was administered to family contacts who were 1-40 years of age (1440-unit dose in adolescents and adults and 720-unit dose in children 1-11 years of age) and was given within 8 days of symptom onset in the index cases.185 During 45 days of follow-up, secondary cases of HAV infection occurred in 13.3% of households in the unvaccinated group and 2.8% of households in the vaccinated group; the protective efficacy of the vaccine was 79%.185

Serologic Testing

HAV infection confers lifelong immunity to HAV and presumably against subsequent reinfection.16,32,57,132,153,192,203 Although high rates of HAV seropositivity are present in some populations for whom HAV vaccination is recommended, vaccination of an individual with preexisting immunity is not associated with any unusual risk.192,203 Therefore, prevaccination testing for susceptibility to HAV generally is not indicated unless such testing would be less costly than unnecessarily vaccinating an individual who is already immune.140,145,149,192,203 If prevaccination testing is indicated, commercially available tests that measure total anti-HAV (i.e., both IgG and IgM anti-HAV) should be used.7,9,11,23,37,42,57,76,84,87,140,141,142,192,203 A positive result indicates that the individual is immune to HAV as the result of past infection or vaccination.203

The ACIP and AAP state that prevaccination serologic testing is not recommended in children132,192 because of their expected low prevalence of prior infection.140,141,192 For adults, the possibility of prior infection and resultant immunity is the basis for considering testing.123,140,141,145,179,192 Factors to consider include the cost of vaccination versus the cost of serologic testing (including the cost of an additional visit), the expected prevalence of immune individuals, and the likelihood that prevaccination testing will not interfere with completion of the vaccine series if vaccination is indicated.76,140,167,179,192 For example, if the cost of screening (including laboratory and office visit costs) is one-third the cost of the vaccine series, then screening of potential recipients from populations with a prevalence of HAV infection of 33% should be cost-effective.140,192

The ACIP also states that populations for whom prevaccination serologic testing is likely to be most cost-effective include adults who were born or lived for extensive periods in geographic areas with high endemicity for HAV infection, older adolescents and adults in certain groups with a high prevalence of infection (e.g., Native Americans, Alaska Natives, Hispanics), adults over 40 years of age, adult men who have sex with men, and adults who illicitly use injectable or noninjectable drugs.140,141,144,145,149,192,203

Based on epidemiologic evidence from the National Health and Nutrition Examination Survey (NHANES), the anti-HAV prevalence among adults older than 40 years of age in the US generally exceeds 33% regardless of race/ethnicity or income level.120,192 Therefore, prevaccination serologic testing for any adult older than 40 years of age is likely to be cost-effective, assuming that the cost of screening is one-third the cost of the vaccination series.140,192

Prevaccination serologic testing before routine or “catch-up” vaccination of children, including adolescents, generally is not indicated.192 Prevaccination testing also is not routinely indicated for adolescent homosexual or bisexual males nor for adolescent illicit drug users, although it may be warranted for older adults.192 However, prevaccination testing in populations that have expected high rates of HAV infection may be cost-effective.192 (See Uses: Preexposure Vaccination in High-Risk Groups.)

Serologic testing of contacts of an HAV-infected individual for possible preexisting immunity prior to administration of postexposure prophylaxis with IGIM is not recommended since screening is more costly than IGIM and would delay its administration, thus potentially compromising prophylactic efficacy.32,107,132,192 However, because HAV infection cannot be diagnosed reliably by clinical presentation alone, serologic confirmation of HAV in the index case is recommended before HAV postexposure prophylaxis is initiated in contacts.42,86,132,192

Postvaccination serologic testing is not recommended because of the high rate of vaccine response among adults and children and the lack of an approved, commercially available assay in the US with sensitivity to detect low anti-HAV concentrations.132,192,203 (See Pharmacology.) However, the National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) strongly recommends such testing following hepatitis A vaccination in adults and children with hemophilia.18

Administration

Hepatitis A virus vaccine inactivated (hepatitis A vaccine) is administered by IM injection.1,171 The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) also is administered by IM injection.186 These vaccines should not be administered IV, intradermally, or subcutaneously.1,171,186

To ensure delivery of vaccine into the muscle, IM injections of hepatitis A vaccine should be made at a 90-degree angle to the skin using a needle size that is appropriate for the individual's age and body mass, thickness of adipose tissue and muscle at the injection site, and injection technique.60,206,207 Anatomic variability, especially in the deltoid, should be considered and clinical judgment should be used to avoid inadvertent underpenetration or overpenetration of muscle.206,207 Depending on the age of the patient, the IM injection should be made into the deltoid muscle or anterolateral thigh.1,60

For toddlers 1-2 years of age, the IM injection should preferably be administered into the anterolateral thigh;1,60 the deltoid muscle is an alternative if the muscle mass is adequate.60 For children 3 years of age or older, adolescents, and adults, the deltoid muscle is preferred,1,60 although the anterolateral thigh is an alternative for those 3-18 years of age.60

Generally, muscles of the buttock should not be used for administration of vaccines in children because of the well-documented potential for injection-associated injury to the sciatic nerve.60 In addition, studies in adults indicate that a suboptimal response may occur when hepatitis A vaccine is injected into the gluteal rather than the deltoid muscle; therefore, the deltoid region is the preferred site for IM injection of the vaccine in adults.1,60

Although some experts state that aspiration (i.e., pulling back on the syringe plunger after needle insertion and before injection) can be performed to ensure that a blood vessel has not been entered, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) state that this procedure is not required because large blood vessels are not present at the recommended IM injection sites.60,132

When multiple vaccines are administered during a single visit, administration of each preparation at a different anatomic site is preferred.60 In younger children, the thigh is the preferred injection site when more than 2 vaccines must be administered into a single limb.60 Injection sites should be separated by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.60 The deltoid muscle may be used in older children and adults when more than one vaccine must be administered.60

Before withdrawing a dose of monovalent hepatitis A vaccine or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine, the vial should be shaken well to obtain a uniform, slightly turbid, white suspension;1,171,186,200 the vaccine should be discarded if a homogenous suspension does not result.171,200

Since syncope may occur following vaccination, vaccinees should be observed for approximately 15 minutes after the vaccine dose is administered.60 If syncope occurs, the patient should be observed until symptoms resolve.60 Syncope after vaccination occurs most frequently in adolescents and young adults.60

Hepatitis A vaccine may be given simultaneously with other age-appropriate vaccines during the same health-care visit (using different syringes and different injection sites).60,132,192 (See Drug Interactions: Vaccines.) In addition, hepatitis A vaccine may be given simultaneously with immune globulin IM (IGIM), using different syringes and different injection sites, when passive immunization is considered necessary in addition to active immunization with the vaccine (e.g., in travelers who will depart within 2 weeks).1,60,132,171,192,196

Dosage

The recommended dose and dosing schedule for hepatitis A vaccine vary according to the individual's age and specific vaccine administered (Havrix^® or Vaqta^® monovalent vaccines or Twinrix^® fixed-combination vaccine).1,171,186 Dosage recommendations for the specific preparation used should be followed.192

Whenever possible, the monovalent vaccine chosen for the initial dose should be used for subsequent doses in the same individual.192 However, because there is evidence from several studies in adults that vaccination schedules that alternated doses of both monovalent formulations of hepatitis A vaccine resulted in protective antibody levels similar to those attained with a dosage schedule that used a single vaccine formulation,171,192 the ACIP and AAP state that the commercially available formulations of monovalent hepatitis A vaccine may be considered interchangeable.60,132,192

When vaccination against both hepatitis A virus (HAV) and hepatitis B virus (HBV) infection is indicated in adults 18 years of age or older, the commercially available fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine(HepA-HepB; Twinrix^®) can be used.186,192

Primary Immunization against Hepatitis A Virus Infection

Havrix®

If Havrix^® is used for primary immunization, an initial dose of the age-appropriate preparation should be given followed by a second (booster) dose 6-12 months after the initial dose.1,3,132,192 Children and adolescents 12 months through 18 years of age should receive 720-unit doses and adults 19 years of age or older should receive 1440-unit doses.1

The ACIP, AAP, and the American Academy of Family Physicians (AAFP) recommend that the initial dose be given routinely to all children at 1 year of age (i.e., 12 through 23 months of age) and that the second dose be given at least 6 months after the initial dose.3,132 Children not fully vaccinated by 2 years of age can be vaccinated at subsequent health-care visits.3,132 Catch-up vaccination should be considered for children 2 through 18 years of age in areas without existing selective preexposure hepatitis A vaccination programs.192

If a different hepatitis A vaccine (e.g., Vaqta^®) was used for the initial dose, a second (booster) dose of Havrix^® may be given 6-18 months after the initial dose of the other vaccine;132,192 however, whenever possible, the formulation chosen for the initial dose should be used for subsequent doses in the same individual.132,192

The need for subsequent doses after the initial and additional (booster) dose has not been fully determined.1,2,6,7,23,33,41,46,49,74,76,77,84,145,149,150,155,192 Subsequent booster doses are not recommended.192

Vaqta®

If Vaqta^® is used for primary immunization, an initial dose of the age-appropriate preparation should be given followed by a second (booster) dose 6-12 months after the initial dose.3,132,171,192 Children and adolescents 12 months through 18 years of age should receive 25-unit doses and adults 19 years of age or older should receive 50-unit doses.171

The ACIP, AAP, and AAFP recommend that the initial dose be given routinely to all children at 1 year of age (i.e., 12 through 23 months of age) and that the second dose be given at least 6 months after the initial dose.3,132 Children not fully vaccinated by 2 years of age can be vaccinated at subsequent health-care visits.3,132 Catch-up vaccination should be considered for children 2 through 18 years of age in areas without existing selective preexposure hepatitis A vaccination programs.192

If a different hepatitis A vaccine (e.g., Havrix^®) was used for the initial dose, a second (booster) dose of Vaqta^® may be given 6-12 months after the initial dose of the other vaccine;132,171,192 however, whenever possible, the formulation chosen for the initial dose should be used for subsequent doses in the same individual.132,192

The need for subsequent doses after the initial and second (booster) dose has not been fully determined.2,6,7,23,33,41,46,49,74,76,77,84,145,149,150,155,171,192 Subsequent booster doses are not recommended.192

HepA-HepB (Twinrix®)

If the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) is used for primary immunization in adults 18 years of age or older, three 1-mL doses, administered at 0, 1, and 6 months, should be given.186 Alternatively, if an accelerated dosing schedule is needed, three 1-mL doses, administered at 0, 7, and 21-30 days, may be given, followed by a booster dose given at 12 months.167,186,203 Each 1-mL dose of the fixed-combination vaccine contains 720 units of hepatitis A viral antigen and 20 mcg of hepatitis B surface antigen (HBsAg).186 Safety and efficacy of the fixed-combination vaccine in children younger than 18 years of age have not been established.186

Preexposure Vaccination and Outbreak Control

When hepatitis A vaccine is indicated for preexposure vaccination in individuals who are or will be at high risk of exposure to HAV (e.g., international travelers, individuals at risk because of their sexual practices, individuals with potential occupational exposure, military personnel, illicit drug users, recipients of blood products, individuals with chronic liver disease) and any other unvaccinated individual desiring protection from HAV infection or to prevent or control HAV outbreaks in certain populations that have high or intermediate rates of infection, the recommended vaccine regimens are the same as the age-specific regimens recommended for primary immunization.132,171,192,195 Administration of the recommended initial and second (booster) dose before an expected exposure to HAV ensures the highest level of protection.1,148,158,171,192,196 However, individuals who have received at least 1 dose of hepatitis A vaccine 1 month prior to an exposure probably will be protected.167,192,196 (See Pharmacology: Response to Hepatitis A Virus Vaccine Inactivated.)

For individuals who plan to travel or work in areas with intermediate to high levels of endemic HAV, the first dose of hepatitis A vaccine should be given as soon as travel is considered.167,196 For most healthy children, adolescents, and adults 40 years of age and younger, a single dose will provide adequate protection regardless of the scheduled departure date.167,196 To ensure protection in adults older than 40 years of age, immunocompromised individuals, or those with chronic liver disease or other chronic medical conditions who plan to depart within 2 weeks, the ACIP recommends that a single dose of IGIM (0.02 mL/kg) be given concurrently with the initial vaccine dose using a different syringe and different injection site.167,196

Postexposure Prophylaxis

For postexposure prophylaxis† of HAV in unvaccinated healthy individuals 12 months to 40 years of age, a single dose of age-appropriate hepatitis A vaccine can be given alone or in conjunction with IGIM (0.02 mL/kg).196 Although IGIM is preferred for postexposure prophylaxis in unvaccinated individuals older than 40 years of age, a single age-appropriate dose of hepatitis A vaccine can be used if IGIM cannot be obtained.196 Efficacy of HAV postexposure prophylaxis has not been established if given more than 2 weeks after exposure.196

If hepatitis A vaccine is administered in conjunction with IGIM for postexposure prophylaxis in previously unvaccinated individuals to provide long-term protection against HAV, the recommended vaccine regimens are the same as the age-specific regimens recommended for primary immunization.1,107,111,128,171,192 The first dose of vaccine can be administered simultaneously with IGIM but at a separate anatomic site using different syringes.1,107,111,128,171,192 (See Dosage and Administration: Dosage, in Immune Globulin 80:04.) IGIM should be administered as soon as possible after confirmed HAV exposure, but preferably no later than 2 weeks after exposure.107,132,192 Administration of IGIM later than 2 weeks after HAV exposure may only attenuate rather than prevent clinical manifestations of HAV infection.107,132 Individuals who have received at least 1 dose of hepatitis A vaccine at least 1 month prior to the HAV exposure do not need to receive postexposure prophylaxis with IGIM.179,192

Confirmation of Immunity

Serologic confirmation of immunity against HAV following vaccination with hepatitis A vaccine is not necessary in most individuals because of the high rate of vaccine response among adults and children and because of the lack of an approved, commercially available test with the sensitivity to detect the anti-HAV levels necessary for protection.109,132,142,145,192

Duration of Response

The duration of protection and the need for subsequent doses after primary and additional (booster) doses of hepatitis A vaccine has not been fully determined.1,2,6,7,23,33,41,46,49,74,76,77,84,132,145,149,150,155,171,192 Antibodies induced by hepatitis A vaccine decline steadily with time and geometric mean antibody titers (GMTs) generally decrease by 50% in 48 months in adult vaccinees receiving three 720-unit doses of Havrix^® hepatitis A vaccine at 0, 1, and 6 months, although anti-HAV levels considered protective were still maintained 8 years after the first dose.62,172 In a small study in adults who received three 720-unit doses of Havrix^® hepatitis A vaccine at 0, 1, and 6 months, vaccinees maintained anti-HAV levels greater than 15 mIU/mL 12 years after the first dose.192 All the adults in a larger study who received two 1440-unit doses of Havrix^® hepatitis A vaccine maintained anti-HAV levels considered protective 10 years after vaccination.192 Of children who received Vaqta^® hepatitis A vaccine, 99% maintained anti-HAV levels considered protective 5-6 years after vaccination.192 In addition, there were no cases of HAV infection reported from surveillance data in children who were followed 9 years after vaccination.192 Some estimates based on kinetic modeling suggest that protective antibody levels may persist for 25 years or longer in adults and 14-20 years or longer in children (see Pharmacology: Response to Hepatitis A Virus Vaccine Inactivated);2,62,132,192 however, the ACIP states that the long-term protective efficacy of hepatitis A vaccine must be determined in ongoing postvaccination studies and future postmarketing surveillance before recommendations can be made regarding the need, if any, for additional booster doses of the vaccine.192

Hepatitis A virus vaccine inactivated (hepatitis A vaccine) generally is well tolerated,1,2,7,8,9,11,13,23,33,35,36,61,110,112,120,145,150,151,152,155,157,171,192 and reported adverse reactions to the vaccine have been infrequent, mild, and transient.2,7,8,23,35,171,192 No serious adverse effects have been definitely attributed to the commercially available preparations of hepatitis A vaccine.171,192 In a postmarketing safety study involving 42,110 children, adolescents, and adults who received 1 or 2 doses of Vaqta^®, there were no serious vaccine-related adverse events and diarrhea/gastroenteritis requiring an outpatient visit to a health-care provider was determined to be the only vaccine-related nonserious adverse event.171 There were no vaccine-related adverse effects identified in this postmarketing study that had not been reported in earlier clinical studies of the vaccine.171 In 2 other postlicensure studies of Vaqta^®, one involving 11,417 children and 25,023 adults and the other involving 2000 children and adults, there were no serious vaccine-related adverse effects reported.192

Of 6136 adverse effects reported to the Vaccine Adverse Event Reporting System (VAERS) in hepatitis A vaccine recipients (with or without the concurrent use of other vaccines) since FDA approval, the most frequently reported effects included fever, injection-site reaction, rash, and headache;192 serious adverse effects reported in 871 vaccinees included Guillain-Barré syndrome, transaminitis, idiopathic thrombocytopenic purpura, and seizures (among children).192 The safety of hepatitis A vaccine will continue to be evaluated through ongoing monitoring of data from VAERS and other surveillance systems;192 it is possible that increased clinical use of hepatitis A vaccine may reveal rare, unreported adverse effects.1,2,10,171

Among adults, the most common adverse effects of hepatitis A vaccine occurring within 3 days of vaccination for Havrix^® or 5 days for Vaqta^® are local effects at the site of injection (soreness for Havrix^® and tenderness, pain, and warmth for Vaqta^®)1,2,7,8,9,11,13,23,35,36,110,112,120,151,152,155,156,157,171,192 and headache.1,2,7,8,10,12,13,35,36,110,120,152,155,192 With the exception of fever, the frequency and severity of adverse effects tend to decrease with successive doses of hepatitis A vaccine.7,160 Among children, the most frequently reported adverse effects of Havrix^® were soreness at the injection site, feeding problems, headache, and induration at the injection site,192 and of Vaqta^® were local pain, tenderness, and warmth.192 Adverse effects appear to be similar for Havrix^® and Vaqta^®.192

The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) generally is well tolerated and adverse effects reported with the vaccine have been mild and transient (usually persisting for no longer than 48 hours).186 In adults, adverse effects reported with the fixed-combination vaccine were similar to those reported when monovalent hepatitis A vaccine and monovalent hepatitis B vaccine were administered alone or concurrently at different sites.186,192 No increase in the frequency of adverse effects has been reported with successive doses of the fixed-combination vaccine.186 In addition, adverse effects reported with an accelerated vaccination regimen of Twinrix^® (doses at 0, 7, and 21-30 days and a booster dose at 12 months) have been similar to those reported with the usual 3-dose regimen (doses at 0, 1, and 6 months).186

Local Effects

Local reactions are the most common adverse effects with either formulation of monovalent hepatitis A vaccine,1,2,7,171,192 with soreness/pain at the injection site1,2,7,8,9,10,11,12,13,35,36,110,112,120,145,151,152,155,156,157,171 being reported in 56% of adults (1440-unit doses)1,2 and 21% of children (720-unit doses) receiving primary immunization with the Havrix^® vaccine1,2 and in 6.4% of children (25-unit dose) receiving primary immunization with Vaqta^® vaccine.171 In adults or children receiving one or more doses of Vaqta^®, pain was reported in 51 or 19% of vaccines, respectively.171,192 However, of those individuals reporting soreness, less than 0.5% described it as severe.1

Adverse local effects at the injection site following administration of hepatitis A vaccine that occur with 1-10% of doses1 include induration,1,2,10,36,151,152 erythema,1,2,7,9,10,36,145,152,171 warmth,171 and swelling.1,2,7,9,145,171 Although tenderness also was reported in 1-10% of doses of Havrix^®,1 it was reported in up to 53% of adults receiving Vaqta^® and in up to 17% of children receiving this vaccine.171,192 Hematoma or ecchymosis was reported at the injection site with less than 2% of doses of the vaccine.1,171 With Vaqta^® vaccine, adverse local effects were reported more commonly in adults than in children.171,192

In children 11-25 months of age who received Havrix^® hepatitis A vaccine, local effects reported within 4 days after the initial or booster dose included pain in 15-21%, erythema in 16-22%, and swelling in 8%.1 In children 11-25 months of age who received Vaqta^® hepatitis A vaccine (with or without other routine childhood immunizations administered concurrently at a different site), local effects reported within 5 days after the initial or booster dose included pain, tenderness, and/or soreness in 3.1-3.5%, erythema in 1.3-1.6%, swelling in 1.3-1.6%, ecchymosis in 1%, and warmth in 0.8-0.9%.171

Adverse local reactions reported in adults receiving the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) include soreness (37-41%), erythema (8-11%), and swelling (4-6%).186

Systemic Effects

Adverse dermatologic effects have been reported with less than 1% of hepatitis A vaccine doses and include urticaria,1,171 pruritus,1,171,180 and rash.1,7,171 Erythema multiforme also has been reported with Havrix^® and generalized erythema and dermatitis have been reported with Vaqta^®, but these effects have not been directly attributed to the vaccine.1,171,192

Mild adverse systemic effects have been reported in about 14% of patients receiving primary immunization with Havrix^® hepatitis A vaccine.1 Headache,1,2,7,8,10,110,180 the most frequently reported adverse systemic effect with Havrix^®, occurred in 14% of adults2 and less than 9% of children receiving primary immunization with the vaccine;1,2 headache was reported in 16% of adults and in up to 2.3% of children receiving Vaqta^®.171,192

In children 11-25 months of age who received Havrix^® hepatitis A vaccine, adverse systemic effects reported within 4 days after the initial or booster dose included irritability in 24-36%, loss of appetite in 16-19%, drowsiness in 15-17%, and fever (exceeding 39.5°C) in up to 2%.1 In children 11-25 months of age who received Vaqta^® hepatitis A vaccine (with or without other routine childhood vaccines given concurrently at a different site), adverse systemic effects reported within 14 days after the initial or booster dose included irritability in 10.8%, crying in 1.8%, rash in 4.5% (measles-like, rubella-like, or varicella-like in about 1%), fever (exceeding 38°C) in 9.1-11.3%, fever (exceeding 38.9°C) in 3.1-3.8%, diarrhea in 5.9%, vomiting in 4%, and anorexia in 1.2%.171

Adverse systemic effects occurring with up to 10% of Havrix^® doses1,21 or Vaqta^® vaccinees171 in adults and children include fatigue/asthenia,112,120,151,155,157,171 feeding problems, fussiness,10 lethargy,10,152 fever1,7,112,120,171,180 (37.5°C or higher, low-grade fever lasting 1 day),10 malaise,1,2,7,110,120,145,152 anorexia,1,2,10,145 and nausea.1,2,145,151,152 The frequency of fever does not appear to diminish with successive doses of the vaccine.7 Other adverse systemic effects occurring occasionally with hepatitis A vaccine include pharyngitis,1,171 upper respiratory tract infection,1,171 nasal congestion,171 abdominal pain,1,171,180 diarrhea,1,171 vomiting,1,35,152,171 arthralgia,1 elevation of creatine kinase (CK, creatine phosphokinase, CPK),1 elevation of liver enzymes,180 myalgia,1,145,157,171,180 arm or back pain,171 stiffness,171 lymphadenopathy,1 hypertonia,1 insomnia,1,7 menstrual disorder,171 ocular irritation or itching,171 photophobia,1 and vertigo.1

Somnolence,1 syncope,1 thrombocytopenia,1,127,171,180 possible vasculitis,180 idiopathic thrombocytopenic purpura,180 purpura,180 Kawasaki disease,1 autoimmune hemolytic anemia,180 jaundice,1 hepatitis,1 diabetes mellitus,180 pancreatitis,180 transient hypertension,180 pericarditis,180 rhabdomyolysis,180 hyperhidrosis,1 angioedema,1 dyspnea,1 encephalitis,171 seizures,171 febrile seizure in a child 18 months of age,1 cerebellar ataxia,171 encephalopathy,1,121,192 dizziness,1 neuropathy (brachial plexus),1,192 myelitis (transverse),1,192 paresthesia,1 Guillain-Barré syndrome,1,2,171,180,192 multiple sclerosis,1,192 congenital abnormality1 and death180 have been reported rarely in individuals receiving Havrix^® or Vaqta^® hepatitis A vaccine.1,180 Most of these rare effects have been postlicensure reports in adults from over 1.3 million vaccinees who received Havrix^® in Europe and Asia, and about one-third of cases have occurred in individuals receiving other vaccines concurrently or in adults or children who received Havrix^® or Vaqta^® in the US or outside the US, and about 40% of cases have occurred in those receiving at least one other vaccine concurrently;180,192 therefore, a definite causal relationship to hepatitis A vaccine has not been established.1,171,180,192 In addition, for serious adverse effects for which background incidences are known (e.g., Guillain-Barré syndrome, brachial plexus neuropathy), the rates among vaccinees are no higher than would be expected among an unvaccinated population.192

In the US, more than 6.5 million doses of hepatitis A vaccine were administered from 1995-1998, including over 2.3 million pediatric doses.172 During this period, 247 adverse events were reported in individuals receiving hepatitis A vaccine, including 80 in children and adults younger than 19 years old and 167 in adults; of these events, approximately 33% occurred in individuals receiving at least one other vaccine concurrently.172 Serious adverse events, including neurologic, hematologic, and autoimmune syndromes were reported in 13 children (0.6/100,000 vaccine doses distributed) and 85 adults (1.4/100,000 vaccine doses distributed); however, these serious events could not be definitively attributed to hepatitis A virus (HAV) vaccination and the rates of these serious adverse events were not higher than reported background rates for which incidence data are available.172 For example, published background incidence rates for Guillain-Barré syndrome have ranged from 0.5-2.4 cases per 100,000 person-years.172 The 5 Guillain-Barré cases among adult recipients of hepatitis A vaccine represent an estimated incidence of 0.2 cases per 100,000 person-years.172

While the risk of sensitivity reactions to hepatitis A vaccine appears to be low,7 anaphylaxis and anaphylactoid manifestations have been reported rarely in patients receiving the vaccine.1,2,192 Bronchoconstriction,171 asthma,171 and wheezing have been reported in less than 1% of vaccinees.171 Additional data and experience are needed to define more precisely the frequencies of uncommon reactions.10,127 If a hypersensitivity reaction occurs, it should be treated appropriately and additional doses of the vaccine should not be administered.1,171

Precautions and Contraindications

Hepatitis A vaccine is contraindicated in individuals who are hypersensitive to any ingredient in the respective formulation, including neomycin.1,2,60,171 The vaccine also is contraindicated in individuals with previous hypersensitivity or severe allergic reactions (e.g., anaphylaxis) to any hepatitis A vaccine.1,171,192

The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) is contraindicated in individuals hypersensitive to any ingredient in the vaccine, including the hepatitis A vaccine component (Havrix^®), the hepatitis B vaccine component (Engerix-B^®), yeast, or neomycin.186 The vaccine is contraindicated in individuals with previous hypersensitivity reactions to Twinrix^® or monovalent hepatitis A or hepatitis B vaccines.186

Prior to vaccine administration, the patient and/or the patient's parent or guardian should be informed of benefits and risks of immunization and should be provided with a copy of the appropriate Vaccine Information Statement (available at the CDC website [Web]).186,192,202 Patients and/or patient's parent or guardian also should be instructed to report any severe or unusual adverse reactions to their healthcare provider.186 Clinicians or individuals can report any adverse reactions that occur following vaccination to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].1,171

Sensitivity Reactions

Prior to administration of monovalent hepatitis A vaccine (Havrix^®, Vaqta^®) or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) all known precautions should be taken to prevent adverse reactions, including a review of the patient's history with respect to possible hypersensitivity to the vaccine or to similar vaccines;1,186 epinephrine and other appropriate agents should be readily available for immediate treatment of anaphylaxis or an anaphylactoid reaction if such a reaction should occur.1,60,171,186 Patients experiencing hypersensitivity reactions after a vaccine dose should not receive further injections of the vaccine.1,60,171

Both the monovalent hepatitis A vaccine (Havrix^®) and the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) contain trace amounts of neomycin sulfate.1,186 Manufacturers state that these vaccines are contraindicated in individuals hypersensitive to neomycin.1,186 Neomycin allergy usually results in delayed-type (cell-mediated) hypersensitivity reactions manifested as contact dermatitis.60,132 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) state that vaccines containing trace amounts of neomycin should not be used in individuals with a history of anaphylactic reaction to neomycin, but use of such vaccines may be considered in those with a history of delayed-type neomycin hypersensitivity if benefits of vaccination outweigh risks.60,132

Some packaging components (e.g., needle cover, syringe plunger) of the single-dose prefilled syringes of Havrix^® contain dry natural latex; the stopper on the vial of Havrix^® does not contain latex.1 In addition, some packaging components (e.g., vial stopper, syringe plunger) of Vaqta^® contain dry natural latex.171 Some individuals may be hypersensitive to natural latex proteins found in a wide range of medical devices, including such packaging components, and the level of sensitivity may vary depending on the form of natural rubber present;60,189,190,191 rarely, hypersensitivity reactions to natural latex proteins have been fatal.60,189,190,191 Health-care professionals should take appropriate precautions if these preparations are administered to individuals with a history of latex sensitivity.60,189,190,191 Preparations packaged with components containing dry natural latex should not be administered to individuals with a history of serious hypersensitivity reaction (anaphylaxis) to latex, unless the benefit of vaccination outweighs the risk for a potential severe hypersensitivity reaction.60

Individuals with Altered Immunocompetence

Hepatitis A vaccine may be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.60,159,167,192 However, active immunization against HAV may be less effective in immunocompromised individuals and in individuals receiving immunosuppressive therapy since the immune response to the vaccine may be decreased.1,14,60,132,159,167,171,186,192

Recommendations regarding use of hepatitis A vaccine in individuals with human immunodeficiency virus (HIV) infection are the same as those for individuals who are not infected with HIV.197,198 Because HIV-infected individuals with chronic liver disease (including those coinfected with hepatitis B virus [HBV] or hepatitis C virus [HCV]) are at risk of fulminant hepatic failure if they acquire HAV, the US Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the Infectious Diseases Society of America (IDSA) recommend that such individuals be vaccinated against HAV.197,198 Because the response to the vaccine may be reduced in those with CD4⁺ T-cell counts less than 200 cells/mm³, some experts suggest delaying vaccination until the patient is receiving antiretroviral therapy and the CD4⁺ T-cell count is greater than 200 cells/mm³.197 These experts also recommend that the antibody response to the vaccine be assesed 1 month after vaccination and that nonresponders be revaccinated.197

Concomitant Illness

The decision whether to administer or delay administration of hepatitis A vaccine or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine in an individual with a current or recent acute illness depends largely on the severity of symptoms and etiology of the illness.60 The ACIP states that minor acute illness, such as mild upper respiratory infection (with or without fever) or mild diarrhea, usually does not preclude vaccination.60 However, vaccination of individuals with moderate or severe acute illness generally should be delayed until they have recovered from the acute phase of the illness.60,171,186 This precaution avoids superimposing adverse effects of the vaccine on the underlying illness or mistakenly concluding that a manifestation of the underlying illness resulted from vaccination.60 The manufacturer states that hepatitis A vaccine may be given to individuals with acute infection or febrile illness if withholding the vaccine poses greater risk to the patient.171

Individuals with Bleeding Disorders

Hepatitis A vaccine and the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine should be administered with caution to individuals with thrombocytopenia or a bleeding disorder (e.g., hemophilia) or individuals receiving anticoagulant therapy, since bleeding may occur following IM administration of the vaccines in such individuals.18,60,169,171,186 The ACIP and the National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) state that a vaccine may be given IM to individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient's bleeding risk determines that the vaccine can be administered with reasonable safety.18,60 In these cases, a fine needle (23 gauge or smaller) should be used to administer the vaccine and firm pressure should be applied to the injection site (without rubbing) for at least 2 minutes.18,60 In individuals with a bleeding disorder who are receiving antihemophilic factor or other similar therapy, IM vaccination can be scheduled shortly after a dose of such therapy to minimize the risk of bleeding.18,60 The individual and/or their family should be instructed concerning the risk of hematoma from the injection.18,60,171

Use of Fixed Combinations

Whenever the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) is used, the contraindications and precautions related to both antigens should be considered.186

Although an accelerated dosing schedule of the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) can be used when necessary (e.g., for travelers), a booster dose of the vaccine is necessary 1 year later.167,186 The ACIP states that this fixed-combination vaccine should not be used for preexposure vaccination of travelers who will depart within 2 weeks after receipt of the vaccine196 since this vaccine contains less HAV antigen and data are not available regarding efficacy in this situation.192,196

The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) should not be used for HAV postexposure prophylaxis196 since this vaccine contains less HAV antigen and data are not available regarding efficacy in this situation.192,196

Limitations of Vaccine Effectiveness

The possibility that unrecognized HAV infection may be present in some individuals at the time of vaccination (since the infection has a long incubation period of 15-50 days) and that hepatitis A vaccine may not prevent infection in such individuals should be considered.1,167,171 In addition, the possibility that hepatitis A vaccine may not prevent infection in any individual who does not achieve protective antibody titers should be considered, although the lowest titer needed to confer protection has not been established.1,171

The monovalent hepatitis A vaccines (Havrix^® or Vaqta^®) provide protection only against HAV.1,171,192 The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) provides protection only against HAV and HBV.186,192 These vaccines do not provide protection against other infectious agents (e.g., HCV, HEV).171,186,192

Passively acquired anti-HAV (e.g., acquired from IGIM administration or from maternal transfer) may interfere with the active antibody response to hepatitis A vaccine.35,36,58,192,183,188 Reduced titers have been observed in adults receiving concurrent IGIM and primary immunization with the vaccine,1,35,36,58,192 and vaccine immunogenicity also is reduced in infants with anti-HAV passively acquired through maternal transfer.188,192 However, the clinical importance of the reduced immunogenicity is yet to be determined, since seroconversion levels are greater than levels considered to be protective.192 When concomitant administration of other vaccines or IGIM is required, they should be given with different syringes and at different injection sites.1,60,111,171,192

Following the initial dose, immunogenicity of hepatitis A vaccine (Havrix^®) in adults with chronic liver disease of various etiologies (e.g., chronic HBV, chronic HCV, moderate chronic liver disease, alcoholic cirrhosis, autoimmune hepatitis, chronic hepatitis/cryptogenic cirrhosis, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis) was lower than in healthy subjects.1 However, 1 month after the second (booster) dose at month 6, seroconversion rates were similar among both groups.1 Relevance of these data to the duration of protection afforded by hepatitis A vaccine (Havrix^®) is unknown.1

Travelers to areas with intermediate to high levels of endemic HAV who are 40 years of age or older, immunocompromised, or have chronic liver disease or other chronic medical conditions who receive preexposure vaccination with a dose of monovalent hepatitis A vaccine given within 2 weeks of departure also should receive passive immunization with a dose of IGIM to ensure optimal protection.196

The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) should not be used for preexposure vaccination in travelers who will depart within 2 weeks and should not be used for postexposure prophylaxis against HAV.196 (See Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and reduced immune response in vaccinees.60,200

Single antigen hepatitis A vaccine (Havrix^®, Vaqta^®) or fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) that has been mishandled or has not been stored at the recommended temperature should not be administered.60,200 (See Chemistry and Stability: Stability.)

All vaccines should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.60,200 If there are concerns about mishandling, the manufacturer or state or local health departments should be contacted for guidance on whether the vaccine is usable.60,200

Pediatric Precautions

Safety and efficacy of hepatitis A vaccine have not been established in infants younger than 12 months of age.1,171 In young infants, passively-acquired maternal anti-HAV antibody may interfere with the active immune response to hepatitis A vaccine.188,192 Passively-acquired antibody declines to undetectable levels in most infants by 1 year of age, and the vaccine is highly immunogenic in children who begin the vaccine series after 1 year of age (regardless of maternal anti-HAV status).192 Data regarding the use of the vaccine in neonates and infants younger than 12 months of age are limited;1,171 the optimal dose and vaccination schedule in this age group as well as the effect of passively acquired maternal antibody on vaccine immunogenicity remain to be more fully elucidated.77,172 (See Infants Younger than 12 Months of Age under Pharmacology: Response to Hepatitis A Virus Vaccine Inactivated.)

Safety and efficacy of the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) have not been established in children younger than 18 years of age.186

Geriatric Precautions

Clinical studies of Havrix^® hepatitis A vaccine did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently from younger patients; however, other clinical experience has revealed no evidence of age-related differences.1

Clinical studies to date evaluating Vaqta^® hepatitis A vaccine have included 68 vaccinees 65 years of age or older and 10 of these were 75 years of age or older.171 In addition, postmarketing safety studies have included 4769 individuals 65 years of age or older, including 1073 who were 75 years of age or older.171 Although no overall differences in immunogenicity or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the vaccine cannot be ruled out.171

Clinical studies of the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) did not include sufficient numbers of individuals 65 years of age or older to determine whether geriatric individuals respond differently than younger adults.186

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of hepatitis A vaccine or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®).1,171,186

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with hepatitis A vaccine or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®), and it is not known whether the vaccines can cause fetal harm when administered to pregnant women or can affect reproductive capacity.1,171,186,192 The vaccines should be used during pregnancy only if clearly needed.1,171

Because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to the fetus is expected to be low.60,203 The ACIP, AAP, American Academy of Family Physicians (AAFP), American College of Obstetricians and Gynecologists (ACOG), and the American College of Physicians (ACP) state that the vaccine may be used in pregnant women when indicated for preexposure vaccination in high-risk groups (including travelers) or for postexposure prophylaxis.195,201 However, if only short-term protection against HAV infection is needed during pregnancy, passive immunization with IGIM should be considered as an alternative to active immunization with hepatitis A vaccine.107,128,132,192

Hepatitis A vaccine and the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine should be used in pregnant women only when clearly needed,1,171,186 weighing the risk of vaccination against the risk of infection.60,167,192 Clinicians are encouraged to register pregnant women who receive the fixed-combination vaccine with the manufacturer's vaccination pregnancy registry at 888-452-9622.186

Fertility

It is not known whether hepatitis A vaccine or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) affect fertility.1,171,186

Lactation

Hepatitis A vaccine and the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine should be used with caution, but are not contraindicated, in nursing women.1,60,171,186 Because inactivated vaccines do not multiply within the body, they should not pose any unusual problems for lactating women or their infants.60,167

Anti-infective Agents

Concurrent use of anti-infective agents generally does not affect the immune response to inactivated vaccines, including hepatitis A virus vaccine inactivated (hepatitis A vaccine) or the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®).60

Immune Globulin

Passively acquired antibody to hepatitis A virus (anti-HAV) from administration of immune globulin IM (IGIM) appears to interfere with the active immune response produced by hepatitis A vaccine; however, because vaccine-induced titers generally are so much higher than antibody levels considered protective, the reduced immunogenicity associated with passively acquired antibody may not be clinically important.35,36,58,111,125,192 Adults receiving IGIM concurrently with the initial dose of hepatitis A vaccine developed the same rate of protective antibodies as adults who received the vaccine alone; however, geometric mean titers were lower (2488 versus 3614 mIU/mL, respectively) 1 month after three 720-unit doses of Havrix^® vaccine were administered.36,58,192 The effect of reduced geometric mean titers on long-term protection has not been determined following concurrent use of IGIM and the initial dose of hepatitis A vaccine.192 Since adequate antibody levels are achieved when hepatitis A vaccine and IGIM are administered concomitantly, the 2 can be given simultaneously but in different syringes and at separate injection sites.1,60,111,125,171,192

The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that the development of a protective antibody response to hepatitis A vaccine should not be impaired when used concurrently or at any interval before or after administration of an antibody-containing preparation.60 If combined active immunization with hepatitis A vaccine and passive immunization with IGIM is used (e.g., for postexposure prophylaxis), the first dose of vaccine should be administered concurrently with IGIM (using different syringes and different injection sites).1,60,107,111,128,171,192

Immunosuppressive Agents

Individuals receiving immunosuppressive therapy (e.g., alkylating agents, antimetabolites, corticosteroids, cytotoxic agents, radiation) may require additional doses of hepatitis A vaccine to develop circulating HAV antibody levels considered protective.1,60,171 Vaccines generally should be administered 2 weeks prior to initiation of immunosuppressive therapy or deferred until at least 3 months after such therapy is discontinued.14,60

Vaccines

Since hepatitis A vaccine is a noninfectious, inactivated preparation, concurrent use of hepatitis A vaccine and other killed or live vaccines is not likely to cause interference with the immune response to these vaccines.60,167,192 Studies conducted in infants 18 months of age or younger indicate that concurrent use of hepatitis A vaccine with diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP), Haemophilus influenzae type b (Hib) vaccine, hepatitis B vaccine, measles, mumps, and rubella virus vaccine live (MMR), or inactivated poliovirus (IPV) vaccine does not affect the immunogenicity and reactogenicity of these vaccines.192 The ACIP, American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) state that primary immunization with hepatitis A vaccine can be integrated with primary immunization against diphtheria, tetanus, pertussis, Haemophilus influenzae type b (Hib), hepatitis B, influenza, measles, mumps, rubella, meningococcal disease, pneumococcal disease, poliomyelitis, and varicella.3,132,192 However, hepatitis A vaccine should be administered at a different site using a separate syringe.1,132,171

Diphtheria and Tetanus Toxoids and Pertussis Vaccines

Hepatitis A vaccine may be given concurrently with DTaP using different syringes and different injection sites.1,132,192

In one study in children who received Havrix^® hepatitis A vaccine at 15-18 months of age concurrently with diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP; Infanrix^®) and Hib polysaccharide conjugate (tetanus toxoid conjugate) vaccine (PRP-T; OmniHIB^® [not commercially available in the US]) at different sites, the immune response to Havrix^® was the same as that reported when Havrix^® is given alone.1 However, there was a higher incidence of some adverse effects (e.g., irritability, drowsiness, loss of appetite) in those who received Havrix^® concurrently with DTaP and PRP-T than in those who received Havrix^® alone.1 In addition, the manufacturer of Havrix^® states that data are insufficient to date to assess the immune response to a fourth dose of DTaP when the dose is administered concurrently with Havrix^®.1

Vaqta^® hepatitis A vaccine has been administered in children 18 months of age concomitantly with DTaP (Tripedia^®) at different sites without a decrease in the antibody response to hepatitis A vaccine;171 however, immunogenicity data were insufficient to assess the antibody response to DTaP in these children.171

Haemophilus b Vaccine

Hepatitis A vaccine may be given concurrently with Hib vaccine using different syringes and different injection sites.1,60,132

In one study in children who received Havrix^® hepatitis A vaccine at 15-18 months of age concurrently with Hib polysaccharide conjugate (tetanus toxoid conjugate) vaccine (PRP-T; OmniHIB^® [not commercially available in the US]) and DTaP at different sites, the immune response to Havrix^® and the immune response to the Hib vaccine was the same as that reported when the vaccines are given alone.1 However, there was a higher incidence of some adverse effects (e.g., irritability, drowsiness, loss of appetite) in those who received Havrix^® concurrently with PRP-T and DTaP than in those who received Havrix^® alone.1

The manufacturer of Vaqta^® hepatitis A vaccine states that data are not available to date regarding concurrent administration of the vaccine and Hib conjugate vaccines.171

Hepatitis B Vaccine

Studies have shown that monovalent hepatitis A vaccine and monovalent hepatitis B vaccine can be administered simultaneously at different sites using separate syringes without interfering with the immune response or increasing the frequency of adverse effects to either vaccine.104,145,146,192 In addition, studies in adults indicate that immune responses and adverse effects reported in individuals who received a 3-dose series of the fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) are similar to those reported in individuals who received a 2-dose series of monovalent hepatitis A vaccine (Havrix^®) and a 3-dose series of monovalent hepatitis B vaccine (Engerix-B^®) given concurrently in opposite arms.186 Data are not available to date regarding concomitant administration of Twinrix^® and other vaccines.186

Measles, Mumps, and Rubella Virus Vaccine Live

Hepatitis A vaccine can be administered concurrently at a separate site with measles, mumps, and rubella virus vaccine live (MMR).171

Pneumococcal Vaccine

Hepatitis A vaccine may be given concurrently with pneumococcal vaccine using different syringes and different injection sites.1,60,132

Concomitant administration of pneumococcal 7-valent conjugate vaccine (PCV7; Prevnar^®) and Havrix^® hepatitis A vaccine in children 15 months of age did not affect the immune response to either vaccine.1

Varicella Virus Vaccine Live

Vaqta^® hepatitis A vaccine has been administered concurrently with varicella virus vaccine live at a different site without a decrease in the antibody response to the hepatitis A vaccine; however, immunogenicity data to date are insufficient to assess the response to the varicella vaccine.171

Typhoid and Yellow Fever Vaccines

The ACIP states that hepatitis A vaccine may be given concomitantly (using different syringes and different injection sites) with yellow fever vaccine.204

The manufacturer of Vaqta^® hepatitis A vaccines states that the vaccine may be administered concurrently with typhoid and yellow fever vaccines.171 Although lower anti-HAV geometric mean antibody titers (GMTs) were observed in vaccinees who received Vaqta^® concurrently with typhoid and yellow fever vaccines compared with those who received Vaqta^® alone, similar anti-HAV GMTs were observed in vaccinees after a booster dose of Vaqta^® was administered.171

Limited data indicate that the concurrent administration of hepatitis A vaccine with typhoid (IM or oral) or yellow fever vaccines at different sites in adults does not affect the immunogenicity or adverse effect profile of the vaccines.192 In one study, hepatitis A vaccine did not appear to affect the immune response or adverse reactions to parenteral inactivated typhoid vaccine (Typhim Vi^®).205 In another study, hepatitis A vaccine was administered concurrently on the same day or within the 4-week period before administration of typhoid or yellow fever vaccines without evidence of impaired antibody response to any of the vaccines.174

Other Vaccines

Limited data from adults indicate that the concurrent administration of hepatitis A vaccine with cholera vaccine (not commercially available in the US), Japanese encephalitis virus vaccine, IPV or poliovirus vaccine live oral (OPV; no longer commercially available in the US), or rabies vaccines does not affect the immunogenicity or adverse effect profile of the vaccines.192 Hepatitis A vaccine has been administered concurrently on the same day or within the 4-week period before administration of various other vaccines used in travelers, including vaccines against Japanese encephalitis, poliovirus, and rabies.174 There was no evidence that concurrent administration of any of these vaccines impaired the antibody response to hepatitis A vaccine.174 In addition, there was a 100% response rate to vaccines against Japanese encephalitis and rabies.174

In individuals initially seronegative who received one dose of OPV (no longer commercially available in the US) concurrently with hepatitis A vaccine, the seroconversion rate was lower for poliovirus type 3 (39%) than for poliovirus types 1 or 2 (67%).174

Laboratory Test Interferences

Serologic Tests Used in the Diagnosis of Hepatitis A Virus Infection

Individuals who have received hepatitis A virus vaccine inactivated (hepatitis A vaccine) and who are being evaluated for suspected hepatitis A virus (HAV) infection by serology to detect immunoglobulin M (IgM) anti-HAV to confirm a specific diagnosis of HAV infection may have a positive test result in the absence of infection, especially if the test is performed soon after vaccine administration.172,192 In adults who received a single dose of hepatitis A vaccine, IgM anti-HAV was detected 2-3 weeks after vaccine administration;172,192 however, only 1% of vaccinees had detectable IgM anti-HAV 1 month after vaccination.172

Pharmacology

Hepatitis A virus vaccine inactivated (hepatitis A vaccine) stimulates active immunity to hepatitis A virus (HAV) infection by inducing production of HAV-specific immunoglobulin G (IgG) and M (IgM) antibodies (anti-HAV), resulting in humoral immunity.1,2,6,7,8,9,10,11,13,23,32,47,57,155,171,192 Protection is provided only against HAV and not against other infectious agents (e.g., hepatitis B virus [HBV]; hepatitis C virus [HCV], hepatitis E virus [HEV]).171

Protection against HAV infection is virtually complete in individuals who develop adequate antibody levels after immunization with hepatitis A vaccine.4,7,8,9,10,11,12,13,15,21,22,32,33,47,48,49,57,58,61,62,63,76,110,192 Because HAV infection does not induce a chronic carrier state6,16,21,32,37,42,92,110,132 and no known animal reservoir exists, high levels of population immunization with hepatitis A vaccine should reduce substantially the incidence of infection.10,11,15,16,21,23,80,120,192 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) does not recommend postvaccination testing for serologic response because vaccine immunogenicity has been very high in clinical studies, the absolute lower limit of antibody required to prevent HAV infection has not been defined, and the lack of an approved, commercially available assay with the sensitivity to detect the anti-HAV concentrations associated with protection (although modifications of these assays successfully have measured low levels of antibodies under research conditions [e.g., lower detection limits of 10-12 mIU/mL]).63,109,192 In most clinical trials, seroconversion levels of anti-HAV of 20 mIU/mL or greater, or in more recent clinical trials, 33 mIU/mL or greater, measured by modified enzyme immunoassays have been used to define a protective antibody response for Havrix^® vaccine4,7,8,9,10,11,12,13,33,35,36,46,49,192 and levels of 10 mIU/mL or greater measured by modified radioimmunoassay have been used for Vaqta^® vaccine.171,192 Clinical trial data regarding the minimum protective level of anti-HAV have been limited because of high vaccine-induced levels of anti-HAV following vaccination and the fact that diagnosis of HAV infection in vaccinees has been uncommon.192 Because the lower detection limit of unmodified (standard) immunoassays currently is approximately 100 mIU/mL, ACIP states that detection by such assays of any level of anti-HAV (i.e., seropositivity) after immunoprophylaxis indicates protection with either vaccine; likewise, individuals who are anti-HAV negative by such assays may still have protective levels of anti-HAV since the lower detection limit exceeds levels considered protective.109,192 Evidence from primate studies indicates that while antibody levels less than 10 mIU/mL may not prevent infection by the virus, they do prevent the development of clinical hepatitis and viral shedding.192

Hepatitis A vaccine has been shown to be effective in preventing infection when employed for preexposure vaccination.1,7,8,9,110,171,192 Unlike immune globulin IM (IGIM), hepatitis A vaccine is not approved for use in postexposure prophylaxis.192 Primate studies suggest that administration of hepatitis A vaccine soon after HAV exposure may prevent HAV infection.192 In addition, the fact that HAV infection was not reported 17 days or more following vaccination during a clinical trial also suggests possible postexposure benefit since the incubation period of HAV infection can be as long as 50 days.192 While administration of the vaccine during the incubation period of infection (i.e., after exposure to HAV but prior to onset of clinical manifestations such as jaundice) also may prevent HAV infection if given shortly after exposure,40 definitive studies have not been conducted to compare the postexposure efficacy of hepatitis A vaccine with that of IGIM to determine if hepatitis A vaccine without IGIM can provide effective postexposure protection.7,74,80,116,192

The active immune response produced by hepatitis A vaccine appears to be decreased by IGIM when administered concomitantly at a separate site.1,2,8,22,35,36,47,80,110,111,125,171,192 Reduced titers have been observed in adults receiving concurrent IGIM and primary immunization with either monovalent formulation of hepatitis A vaccine,1,171,192 but the degree of interference by IGIM generally does not affect the rate of seroprotection (i.e., antibody levels still generally exceed those considered protective by several fold) and therefore is unlikely to be clinically important.8,35,36,47,111,161,192 (See Drug Interactions: Immune Globulin.) The active immune response to hepatitis A vaccine may be reduced in infants with maternally acquired antibody.192 (See Pharmacology: Response to Hepatitis A Virus Vaccine Inactivated.) Immunogenicity of the vaccine also may be reduced in individuals with human immunodeficiency virus (HIV) infection, resulting in decreased protection rates and geometric mean antibody titers (GMTs).159,187,192 It remains to be determined whether other factors (e.g., age, obesity, smoking) associated with decreased response with other vaccines also may be associated with decreased responses to hepatitis A vaccine.8,192 Limited data indicate that the immunogenicity of hepatitis A vaccine may be reduced in older individuals; although the rates of protection in adults older than 40 years of age were similar to those in younger vaccinees, GMTs were lower.192

Hepatitis A Virus and Infection

Hepatitis A virus (HAV) is an RNA virus that is classified as a member of the Hepatovirus genus within the Picornaviridae family.1,2,4,6,21,23,32,37,57,106,132,192,203 Only one serotype of HAV among the various human strains isolated worldwide has been described.4,15,16,23,32,37,57,120 While minor differences in monoclonal antibody-binding patterns exist between human and simian HAV strains, they appear to elicit cross-protective immunity.4,15,23 Neither nucleotide similarity nor serologic cross-reactivity has been observed between HAV and non-A viruses causing hepatitis.37,42

HAV replicates mainly in the liver and is shed in feces via biliary excretion.1,4,16,30,37,42,57,92,120,171,192,203 The incubation period for HAV infection following exposure to the virus is shorter than that following exposure to hepatitis B, ranging from 15-50 days and averaging about 1 month for HAV regardless of the route of infection; however, the greater the inoculum of virus the shorter the incubation period.1,4,6,19,21,27,32,37,110,120,132,167,171,192,203 The illness associated with HAV infection typically has an abrupt onset that can include fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice.120,132,145,167,192,203 The likelihood of symptomatic infection is age related, with about 70% of children younger than 6 years of age experiencing asymptomatic infection and, even when symptomatic, usually is not accompanied by jaundice.83,110,120,132,145,167,192,203 HAV infection usually is symptomatic in older children and adults, with jaundice occurring in greater than 70% of patients.120,132,192,203 Manifestations usually persist for less than 2 months, although 10-15% of patients develop prolonged or relapsing disease persisting up to 6 months.120,164,167 While a chronic carrier state does not exist for HAV,6,16,21,32,37,42,92,132,203 illness may be prolonged,32 and relapse of clinical illness17,20,37,74,86 with fecal viral shedding has been described.16,17,20,32,37,42,57,120,164,192 Data from individuals with HAV infection reported to the National Notifiable Diseases Surveillance System indicate that the overall case-fatality rate is approximately 0.3-0.6% and may be as high as 1.8% among adults older than 50 years of a 167,192,203 infected individuals with chronic liver disease are at increased risk for acute liver failure.192

The initial antibody response to HAV infection is detectable by the time clinical manifestations develop (e.g., anorexia, abdominal discomfort, dark urine, fever, malaise, nausea, elevated serum ALT [SGPT], jaundice) and consists of IgM, IgG, and immunoglobulin A (IgA), with 7S (IgA or IgG) antibodies generally being detectable as early as 2 days after the onset of illness.4,6,19,21,32,107,120,132 Peak viral shedding of HAV in feces of, and peak viremia in, infected individuals occurs during the 2-week period prior to the onset of clinical manifestations (e.g., jaundice); thus, patients are asymptomatic during the period of greatest infectivity.4,6,30,32,37,57,74,120,132,192 At the time the infection becomes symptomatic, anti-HAV almost always is present; in rare cases when it is not, interferon gamma is detectable before seroconversion.4 In adults, fecal excretion of the virus usually declines following the development of jaundice,37 but children may excrete the virus for longer periods (e.g., 10 weeks after the onset of symptoms).16,192,203 In one nosocomial outbreak, infants infected as neonates shed HAV for up to 6 months.192 With conventional assays, IgM anti-HAV usually becomes detectable 5-10 days before clinical manifestations are observed and remains detectable for up to 6 months after symptomatic disease subsides in most patients;4,19,57,74,107,120,130,132,151,192 however, the antibody occasionally may be detected in serum by sensitive immunoassay for 1 year or longer after acute hepatitis.6,19,42,192 In addition, there have been reports of false-positive test results in individuals without evidence of recent HAV infection.192 HAV infection cannot be differentiated from other types of viral hepatitis based on clinical or epidemiologic characteristics alone.42,86,120,192 HAV RNA is detectable in the blood and stool of most patients during the acute phase of infection by using nucleic acid amplification methods, and nucleic acid sequencing has been used in epidemiologic investigations to determine the relatedness of HAV isolates; however, only a limited number of research laboratories have the capacity to use these methods. 4,21,42,120,192 Although sensitive saliva tests for IgM and IgG anti-HAV have been developed, they are not commercially available in the US.192 Therefore, serologic detection of IgM anti-HAV generally is required to confirm a specific diagnosis of HAV.4,6,7,9,17,19,20,21,30,42,57,114,118,120,129,130,132,192,203

There are 2 serologic tests commercially available in the US for the detection of antibodies to HAV; one measures IgM anti-HAV and the other measures total anti-HAV (i.e., IgM and IgG anti-HAV).192,203 Measurement of total anti-HAV is used in epidemiologic studies to determine the prevalence of previous HAV infection or by clinicians to determine whether an individual in whom preexposure prophylaxis is being considered is already immune.132,192

During convalescence, the major class of antibody to HAV detectable in serum is IgG, and evidence indicates that anti-HAV IgG is the principal defense against reinfection,4,6,19,21,107,192 generally remaining detectable for the life of the individual and conferring lifelong immunity to illness from HAV and presumably against subsequent HAV infection.6,16,32,57,74,76,120,132,151,153,192 Detection of total anti-HAV (IgG and IgM) in serum is of limited value in diagnosing acute HAV infection because of the high seroprevalence rate in many populations19,20,21,42,92,109,120 (e.g., 31% of the US population has serologic evidence of prior HAV infection).192

Response to Hepatitis A Virus Vaccine Inactivated

Hepatitis A vaccine appears to be highly immunogenic in most individuals.1,2,7,8,9,10,11,12,23,33,35,36,47,48,49,57,58,61,62,110,112,120,149,150,151,152,153,154,155,156,157,171,192,203 The HAV epitopes that stimulate the formation of protective antibodies include 2 capsid polypeptides (VP₁ and VP₃).6,15,23,120,131 The presence of antibodies to HAV (anti-HAV) confers protection against HAV infection;1,2,6,9,15,32,33,171,192 however, the lowest titer conferring protection has not been established.1,2,33,107,128,192 Clinical trials evaluating Havrix^® vaccine generally have defined a protective anti-HAV response as 20 mIU/mL or greater as measured by modified enzyme immunoassays7,8,9,10,11,12,13,33,35,36,46,49,153,192 (recent studies have defined a protective response as greater than 33 mIU/mL)192 and clinical trials evaluating Vaqta^® vaccine generally have defined a protective anti-HAV response as 10 mIU/mL or greater as measured by radioimmunoassay.171,192 ACIP states that any level of anti-HAV detected by commercially available (i.e., unmodified) enzyme or radioimmunoassay can be considered protective since the lower antibody detection limits of such assays (i.e., about 100 mIU/mL) greatly exceed defined levels of protections; however, individuals who are anti-HAV negative by such assays may still have protective levels of anti-HAV.109,192

The protective efficacy of Havrix^® hepatitis A vaccine has been demonstrated in a double-blind, randomized controlled study in school children 1-16 years of age living in villages in Thailand with high endemic rates of HAV and thus considered at high risk of infection.1,7,110,192,203 Children receiving hepatitis A vaccine at 0, 1, and 12 months were observed after day 138 of the study for 8 months for protocol-defined manifestations of HAV infection (2 days or more absence from school, serum ALT concentration exceeding 45 U/mL, and a positive enzyme-linked immunosorbent assay [ELISA] test result).1,7 In the control group, 32 cases of HAV infection were demonstrated, while in the group receiving hepatitis A vaccine, 2 cases of HAV infection were positively identified and 3 additional illnesses that could neither be proven nor disproven to be caused by HAV were observed.1,7 The calculated efficacy rate for prevention of clinical HAV infection ranges from 84-94%, depending on inclusion or exclusion of the 3 unproven illnesses.7,110,192 In a double-blind, randomized controlled study in children 2-16 years of age residing in a New York community with a high rate of HAV, the protective efficacy of Vaqta^® hepatitis A vaccine in preventing clinical HAV infection was 100% of vaccinees beginning 18 days after a single dose.40,192,203

The protective efficacy of hepatitis A vaccine has also been evaluated in demonstration projects and through analysis of surveillance and vaccine coverage data that focused on communities with the highest historical rates of HAV infection (e.g., Native American and Alaskan communities).192 Such data indicate that when relatively high vaccination coverage is achieved and sustained, ongoing epidemics are interrupted and reduced HAV infection rates are sustained.192 A communitywide HAV epidemic in 1992-1993 among Native Alaskans in a rural community ended within 4-8 weeks of HAV vaccination of approximately 80% of children and young adults in the community.192 Following the ACIP recommendations for routine HAV vaccination of children in these high-risk areas in 1996, surveys indicated that vaccine coverage among preschool- and school-aged Native American and Alaskan children was 50-80%; the incidence of HAV infection among these populations by 2000 had decreased 97% compared with the beginning of the decade and was lower than the overall US rate of HAV infection.192 Such low rates of HAV infection continue to be maintained; the 2004 rate of HAV infection among Native Americans and Alaskans was 0.1 case per 100,000 population, the lowest rate of any US racial/ethnic population.192 Considerable reductions in the overall incidence of HAV infection have also been achieved in populations with consistently elevated rates of HAV infection following implementation of an ongoing routine childhood vaccination program that achieved fairly modest coverage (i.e., receipt of at least a single dose of hepatitis A vaccine in 66% of the approximately 45,000 eligible children older than 2 years of age).192 During this 6-year project, a 94% decline in HAV infection was observed in the population, and the number of cases reported during the final year of the project was the lowest number reported since HAV surveillance began in 1966.192

The most comprehensive evidence of the protective efficacy of hepatitis A vaccine is derived from analysis of trends in HAV infection rates following the implementation of the 1999 ACIP recommendations for selective routine vaccination of children residing in 17 states with consistently elevated rates of HAV infection.192 Rates of HAV infection in these states decreased approximately 88% from the baseline prevaccine period rate of 21.1 cases per 100,000 population to the 2003 rate of 2.5 cases per 100,000 population.192 US rates of HAV infection are similar among regions with and without statewide recommendations for routine childhood HAV vaccination.192 Compared with HAV infection rates during 1990-1997, rates decreased most dramatically among children 2-18 years of a rates among children decreased from 35 to 19%.192 However, because the incidence of HAV infection has been cyclic in the US, the precise contribution of routine childhood vaccination to the observed decrease in HAV infection rates has been difficult to measure.192 Modeling studies also suggest that during 1995-2001, an estimated 97,800 cases of HAV infection were prevented because of the direct effects of HAV immunization and resultant herd immunity.192

Infants Younger than 12 Months of Age

Few data are available evaluating the use of hepatitis A vaccine in infants younger than 12 months of age.1,171,192 Administration of hepatitis A vaccine to infants with passively acquired antibody (because of previous maternal HAV infection) appears to be associated with reduced vaccine immunogenicity.188,192 In most studies, all vaccinated infants developed protective anti-HAV levels, but the final geometric mean titers (GMT) were approximately 10-33% of that observed in infants vaccinated by the same schedule and born to mothers negative for anti-HAV.192 Infants with passively acquired antibody who received hepatitis A vaccine developed substantially lower levels of anti-HAV 6 years later compared with vaccinated infants with no passively acquired antibody.192 Despite lower antibody levels after the primary series, the majority of infants with passively acquired antibody had an anamnestic response to a booster dose administered 1-6 years later.192 Passively acquired antibody declines to undetectable levels in most infants by 1 year of age.192 Hepatitis A vaccine is highly immunogenic in children who begin the vaccine series after 1 year of age, regardless of maternal anti-HAV status.192

The immunologic response to a 2-dose regimen of Havrix^® (720-unit doses given at 5 and 11 months of age) was evaluated in healthy infants with and without maternal anti-HAV.183 One month after the primary dose, all infants born to anti-HAV-negative mothers had seroconverted and the GMT was 171 mIU/mL; the GMT in these infants increased to 3021 mIU/mL one month after the booster dose.183 In the group of infants with maternal anti-HAV (prevaccination GMT of 409 mIU/mL), 96% had seroconverted and the GMT was 225 mIU/mL one month after the primary dose; however, the GMT in these infants decreased to 62 mIU/mL prior to the booster dose and then increased to 399 mIU/mL one month after the booster dose.183

Children 1 through 2 Years of Age

In clinical studies evaluating the immunogenicity of a 2-dose regimen of Havrix^® hepatitis A vaccine (720 units given 6 months apart) in children 11-13 months of age, 15-18 months of age, and 23-25 months of age, similar vaccine response rates (99-100%) and GMTs (1461-1911 mIU/mL) were obtained among these age groups when the response was assessed 1 month after the second dose.1 Vaccine response was defined as seroconversion in children initially seronegative or maintenance of at least the prevaccination anti-HAV concentration in initially seropositive children.1

Vaqta^® hepatitis A vaccine also has been highly immunogenic when administered in a 2-dose regimen (25 units each dose) to initially seronegative children 12-23 months of age (with or without concurrent administration of other routine childhood vaccines) with 96% seroconverting 1 month after the first dose with a GMT of 48 mIU/mL and 100% seroconverting after the second dose with a GMT of 6920 mIU/mL.171

Older Children and Adolescents

Hepatitis A vaccine (Havrix^® and Vaqta^®) is highly immunogenic when administered to children and adolescents by various schedules; 97-100% of individuals 2-18 years of age develop protective levels of antibody 1 month after receiving the initial dose and 100% develop levels of antibodies well above protective levels 1 month after the second dose.192,203 After receiving the vaccine, children with Down syndrome developed levels of protective antibody that were similar to those observed in children without the syndrome.192

In clinical studies evaluating the immunogenicity of 360-unit doses of Havrix^® hepatitis A vaccine (Havrix^® preparations containing 360 units/0.5 mL are no longer commercially available in the US) in children and adolescents 1-18 years of age, essentially all children developed protective antibody levels (GMT of 433 [range: 197-660] mIU/mL) within 2 months after a second dose (360 units each at 0 and 1 month) of vaccine.1,8,10,151 One month after a third dose of 360 units of Havrix^® vaccine (administered at 6 months), the GMT increased to 3831 (range: 3388-4643) mIU/mL.1,10 At 12 months (6 months after the third dose), protective levels persisted in all children, although the GMT had declined to 1069 mIU/mL.112 In children and adolescents 2-18 years of age who received two 720-unit doses at 0 and 6 months, protective antibody levels developed in 99% of such children 1 month after the first dose and in all such children 1 month after the second dose (i.e., 7 months after the initial dose), with GMTs of 253 or 2576 mIU/mL at 1 or 7 months, respectively.172

When administered to children and adolescents 2-18 years of age in a variety of 2-dose schedules (25-units/dose), Vaqta^® also has been highly immunogenic, with 97-100% developing protective antibody levels 1 month after the first dose and 100% developing such levels after a second dose administered at 6, 12, or 18 months.171,192 In clinical studies evaluating the immunogenicity of Vaqta^® in this age group, 97% of such children seroconverted with a GMT of 43 mIU/mL within 1 month of a single 25-unit IM dose; seroconversion has persisted for up to 18 months after a single dose in vaccinees.171 After a second 25-unit dose of Vaqta^® administered at 18 months in children and adolescents who were still seropositive at this time (35 out of 39 vaccinees), an anamnestic response developed in 95% of these vaccinees.171 In children and adolescents who received a 25-unit booster dose at 6, 12, or 18 months after the primary dose, seroconversion was 100% and GMT was 10,433 mIU/mL 1 month after the 6-month booster, 100% and 12,308 mIU/mL, respectively, 1 month after the 12-month booster, and 100% and 9591 mIU/mL, respectively, 1 month after the 18-month booster.171

Adults

Hepatitis A vaccine (Havrix^® and Vaqta^®) is highly immunogenic when administered to adults by the recommended schedules; 94-100% of adults developed protective levels of antibody 1 month after receiving the initial dose and 100% had protective levels following the second dose.192 Limited data indicate that 54-62% or 94-100% of vaccinees who were evaluated developed serum neutralizing antibodies by 14 days or 1 month, respectively, after the initial dose.192

Data from several clinical studies show that at least 80% (range: 80-98%) of healthy adults develop protective levels of anti-HAV (GMT range: 264-339 mIU/mL) by day 15 after a single 1440-unit dose of Havrix^® hepatitis A vaccine.1,2,8,22,47,48,49 One month after vaccination with Havrix^®, the rate of protective antibody levels was 99% and the GMT increased to a range of 335-637 mIU/mL, and at 6 months approximately 95% of vaccinees had seroconverted with a GMT of 208 mIU/mL.1,2,8,49 The geometric mean serum titers of anti-HAV attained after 4 doses of Havrix^® hepatitis A vaccine (administered at 0, 1, 2, and 12 months) are 100- to 300-fold higher than those attained after passive immunization with immune globulin IM (IGIM) and are similar to levels after natural infection.32,33 The manufacturer of Havrix^® states that the GMTs of serum anti-HAV obtained after a single dose of hepatitis A vaccine are at least several times higher than those observed following administration of 2.5-5 times the standard dose of IGIM (standard dose = 0.02-0.06 mL/kg);1,120,128 the GMTs in individuals receiving such doses of IGIM were 146, 77, and 63 mIU/mL after 5 days, 1 month, and 2 months, respectively.1 Similar immunogenicity is provided in adults by Vaqta^® hepatitis A vaccine.171,192 One month after vaccination with a single 50-unit IM dose of Vaqta^® in clinical studies in adults, 95% of vaccinees had seroconverted with a GMT of 37 mIU/mL;171 seroconversion has persisted for up to 18 months after a single dose of Vaqta^® in adults.171 An amnestic response occurred in children and adolescents who received a booster dose 6-18 months after the initial dose and in adults who received a booster dose 6 or 12 months after the initial dose.171 After a second 50-unit dose of Vaqta^® administered at 6 months in adults, seroconversion was 98%, and had increased to 100% and 5987 mIU/mL, respectively, 1 month later.171 After a second 25-unit dose of Vaqta^® administered at 6 months in children and adolescents, seroconversion was 97% and GMT was 107 mIU/mL after the second dose, and had increased to 100% and 10,433 mIU/mL, respectively, 1 month later.171 Similar seroconversion rates and increases in GMT were observed in adults who received a second 50-unit dose 12 months after the initial dose and in children, and adolescents who received a second 25-unit dose 12 or 18 months after the initial dose.171

In adults receiving both an initial dose (1440 units) of Havrix^® hepatitis A vaccine and an additional (booster) dose (1440 units) 6 months later, protective antibody levels (defined as a serum anti-HAV level of at least 20 mIU/mL) developed in all vaccinees (GMT of 4383 [range: 3318-5925] mIU/mL) 1 month after the second dose (i.e., 7 months after the initial dose).1,2 The initial dose resulted in protective levels in 88% (GMT: 293 mIU/mL) of these adults at 15 days and in 99% (GMT: 466 mIU/mL) at 1 month after this dose.8 The second dose of Havrix^® hepatitis A vaccine induced an anti-HAV titer similar to levels seen several years after natural infection.1,2

Limited data from 3 small studies involving children and adults indicate that interruption of the recommended vaccination schedule and a delay in administration of the second dose of hepatitis A vaccine may result in an immune response similar to that attained in those who receive the vaccine according to the usually recommended schedule.192 In one study, 97% of adults 18 years of age or older had protective levels of anti-HAV 18 months after the first 50-unit dose of Vaqta^® and final antibody concentrations attained after the second dose were similar to those reported in vaccinees who were vaccinated according to the usual schedule.192 In another study, 27 months after receiving one dose of the age-appropriate dose of Havrix^®, 84% of individuals 1 month to 64 years of age had protective levels of anti-HAV and practically all vaccinees developed a marked increase in concentrations of anti-HAV after receiving the second vaccine dose.192 In a third study, 72% of adults developed anti-HAV levels of 10 mIU/mL or greater following an initial dose of hepatitis A vaccine (Havrix^®; 1440 units in adults) and all vaccinees experienced a substantial increase in anti-HAV levels following a second dose 4-8 years following the initial dose.192

Limited data indicate that the immune response to hepatitis A vaccine may be decreased in older individuals.192 In several efficacy studies, the proportion of individuals older than 40 years of age who developed a protective antibody response after receiving the vaccine was similar to that of individuals 40 years of age or younger, but final anti-HAV concentrations were lower in the older age group.192

Although adults or children with chronic liver disease of viral or nonviral etiology appear to develop similar rates of protection after receiving hepatitis A vaccine compared with those observed in healthy adults, final anti-HAV concentrations may be lower in patients with chronic liver disease.192

Additional factors associated with decreased immunogenicity to other vaccines (e.g., smoking and obesity) have not been evaluated with the commercially available formulations of hepatitis A vaccine.172 Data are not available to date regarding response rates following revaccination with hepatitis A vaccine in individuals who failed to respond to the primary vaccine series.192

HIV-infected Individuals

The usual recommended dosage and schedule of hepatitis A vaccine is immunogenic in certain HIV-infected children and adults.192 The immune response observed in adults with CD4⁺ T-cell counts of at least 300 cells/mm³ is similar to that observed in healthy adults; however, adults with lower CD4⁺ T-cell counts are less likely to acquire protective levels of anti-HAV antibodies.192 Protective levels of antibody were observed in 61-87% of HIV-infected adults and in 100% of HIV-infected children following vaccination with hepatitis A vaccine.192 At the time of vaccination, a low CD4⁺ T-cell count (not the CD4⁺ T-cell count nadir) was associated with a lack of immune response to the vaccine; this observation suggests that immunologic reconstitution with highly active antiretroviral therapy may restore the immune system's ability to respond to vaccination.192

The antibody response and GMTs achieved with hepatitis A vaccine in individuals with HIV infection may be decreased compared with that in noninfected individuals.8,159,171,187 In a limited number of HIV-infected or noninfected individuals who received three 720-unit doses of Havrix^® vaccine, the seroconversion rate was 77 or 100%, respectively, and the GMT was 636 or 1687 mIU/mL, respectively.8,69,159,170 In a study in HIV-infected adults who received 2 doses of hepatitis A vaccine, the seroconversion rate was 68% in those with CD4⁺ T-cell counts of 200/mm³ or greater but was only 9% in those with lower CD4⁺ T-cell counts.187 The vaccine was well tolerated in these HIV-infected patients and there was no evidence that the vaccine had any adverse effects on the course of HIV infection or plasma HIV RNA levels.187

Individuals with Chronic Liver Disease

In a study evaluating the immunogenicity of hepatitis A vaccine (Havrix^®) in adults with chronic liver disease of various etiologies (e.g., chronic HBV, chronic HCV, alcoholic cirrhosis, autoimmune hepatitis, chronic hepatitis/cryptogenic cirrhosis, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis), the GMT response and seroconversion rates to the initial 1440-unit dose of vaccine were lower in those with chronic liver disease than in healthy subjects.1 However, the seroconversion rates were similar in both groups 1 month after a second 1440-unit dose (booster dose) given 6 months after the initial dose.1 The relevance of these results to the duration of protection afforded by hepatitis A vaccine (Havrix^®) is unknown.1

Transplant Recipients

Conflicting data have been reported regarding immunogenicity of hepatitis A vaccine in liver transplant recipients.192 In one small study of 8 liver transplant patients, none responded to hepatitis A vaccine.172 In another study, only 26% of 23 liver transplant patients responded to hepatitis A vaccine.192 In a larger controlled study evaluating the immunogenicity of a 2-dose regimen of Havrix^® (1400-unit doses given 6 months apart) in liver and renal transplant patients, the seroconversion rate after the initial vaccine dose was low in both the liver and renal transplant patients (41 and 24%, respectively) compared with that attained in healthy controls (90%).182,192 However, the seroconversion rate one month after the second vaccine dose was 97% in those who received liver transplants, 72% in those who received renal transplants, and 100% in healthy controls.182,192 This study included transplant recipients 18 years of age or older who were seronegative for anti-HAV and also seronegative for HIV.182 The mean time interval since transplantation was 40 months among the liver transplant patients (41% had undergone transplantation because of chronic HBV or HCV infection) and 96 months among the renal transplant patients (10% had serologic evidence of chronic HBV infection and 28% had serologic evidence of chronic HCV infection).182 Most liver transplant patients were receiving either tacrolimus or cyclosporine; all renal transplant patients were receiving 2 or more immunosuppressive agents which possibly may have contributed to the lower seroconversion rate in these patients.182 Follow-up of these transplant recipients indicated that anti-HAV levels may decline more rapidly for both liver and kidney transplant recipients compared with observed rates of antibody decline in healthy individuals.192

Response to Hepatitis A Virus Vaccine Inactivated and Hepatitis B Vaccine (Recombinant)

Data from several studies in healthy adults (17-70 years of age) indicate that the immunogenicity of a 3-dose series (at 0, 1, and 6 months) of the fixed-combination vaccine (HepA-HepB; Twinrix^®) that contains the antigens of hepatitis A vaccine (Havrix^®) and hepatitis B vaccine (Engerix-B^®) is similar to that of a 2-dose series (at 0 and 6 months) of the monovalent hepatitis A vaccine (Havrix^®) and a 3-dose series (at 0, 1, and 6 months) of the monovalent hepatitis B vaccine (Engerix-B^®) administered concurrently at separate sites or administered alone.186,192 In adults who received a 3-dose series of the fixed-combination vaccine, 99.9% developed anti-HAV titers of at least 20 mIU/mL and 98.5% developed anti-HBsAg titers of at least 10 mIU/mL 1 month after completion of the vaccine series.186 In one US study in adults 18-70 years of age, serum anti-HAV titers of at least 20 mIU/mL and anti-HBsAg titers of at least 10 mIU/mL were observed in 99.6 or 95.1% of vaccinees, respectively, who received a 3-dose series (at 0, 1, 6 months) of the fixed-combination vaccine compared with 99.3 or 92.2%, respectively, of vaccinees who received the separate monovalent hepatitis A vaccine and monovalent hepatitis B vaccine concurrently.186 The GMT of anti-HAV measured 1 month after completion of the vaccine series was 4756 mIU/mL in vaccinees who received the fixed-combination vaccine versus 2948 mIU/mL in vaccinees who received both monovalent vaccines; this difference is not considered clinically important and has been attributed to the differences in the hepatitis A viral antigen content in the 2 regimens (3 doses of 720 units in the regimen compared to 2 doses of 1440 units in the monovalent regimen).186 The average GMTs of anti-HBsAg measured 1 month after completion of the vaccine series was 2099 mIU/mL in vaccinees who received the fixed-combination vaccine versus 1871 mIU/mL in vaccinees who received both monovalent vaccines.186

When an accelerated dosage regimen of the fixed-combination vaccine (HepA-HepB; Twinrix^®) was used (doses at 0, 7, and 21-30 days and a booster dose at 12 months) in healthy adults, the seroprotection rate for HBV and seroconversion rate for HAV at month 13 was noninferior to the rates reported with monovalent hepatitis A vaccine (Havrix^®) and monovalent hepatitis B vaccine (Engerix-B^®) administered at separate sites (i.e., Havrix^® at 1 and 12 months and Engerix-B^® at 0, 1, 2, and 12 months).186 On day 37 (after 3 doses of Twinrix^®), the seroprotection rate for HBV was 63.2% compared with 43.5% in the control group who had received 2 doses of Engerix-B^®; the HAV seroconversion rates were similar in both groups (98.5 or 98.6%, respectively).186 On day 90, the seroprotection rate for HBV was 83.2% in the Twinrix^® group and 76.7% in the control group; the HAV seroconversion rate was 100 or 95.6%, respectively.186 At month 12 (before the booster dose of Twinrix^®), the seroprotection rate for HBV was 82.1% in the Twinrix^® group and 77.8% in the control group; HAV seroconversion rates were 96.9 or 86.9%, respectively.186

Duration of Immunity

The duration of protection from HAV infection following administration of either commercially available monovalent formulation of hepatitis A vaccine and the need for additional booster doses have not been fully defined.1,2,6,7,23,33,41,46,49,74,76,77,84,132,145,149,150,167,171,192 All 31 adults who received three 720-unit doses (at 0, 1, and 6 months) of Havrix^® hepatitis A vaccine maintained anti-HAV levels of 15 mIU/mL or greater at 12 years following the first dose.192 After receiving two 1440-unit doses of Havrix^® hepatitis A vaccine, all 307 adults maintained anti-HAV levels exceeding 20 mIU/mL at 10 years following vaccination.192 Of 549 children who received Vaqta^® hepatitis A vaccine, 99% maintained protective levels of anti-HAV at 5-6 years following vaccination.192

In one study of antibody persistence in healthy adults, anti-HAV levels were maintained at a GMT of approximately 1500 mIU/mL 3 years after administration of a series of three 720-unit doses (at 0, 1, and 6 months) of Havrix^® hepatitis A vaccine.8,47 In one study in healthy adults who received a primary dose of Havrix^® followed by a booster dose given 6 or 12 months after the first dose, more than 99% of vaccinees still had detectable levels of anti-HAV antibodies 4 years after the second dose.184 In another study, the rate of decrease in anti-HAV titers calculated from the antibody decrease between months 6 and 12 and between months 13 and 18 in individuals vaccinated with 4 doses of hepatitis A vaccine suggests the duration of anti-HAV levels of at least 10 mIU/mL to be at least 10 years.33 After 18 months, anti-HAV titers were approximately 1200-8000 mIU/mL in this study; however, the rate of disappearance of protective antibodies was independent of the absolute titer, vaccine dose or strain, or vaccination schedule.33,46 Experience with Vaqta^® vaccine in vaccinees who were observed for 36 months also indicates that anti-HAV levels decline over time; however, protective levels persisted in 100% of vaccinees during this period.172 Studies have been initiated to evaluate persistence of immunity in healthy children, adolescents, and adults who have been vaccinated with Vaqta^® and to determine if additional booster doses will be required.171

In 2 studies evaluating antibody persistence in healthy adults following a 3-dose series (at 0, 1, and 6 months) of the fixed-combination vaccine (HepA-HepB; Twinrix^®) containing hepatitis A vaccine (Havrix^®) and hepatitis B vaccine (Engerix-B^®), anti-HAV and anti-HBsAg levels were maintained for at least 4 years.186

Estimates of antibody persistence derived from kinetic models of decline suggest that protective levels of anti-HAV may persist for 25 years or longer in adults and 14-20 years or longer in children.2,62,132,192,203 However, it has been suggested that the duration of antiviral protection induced by the vaccine may exceed persistence of measurable antibodies.7,33,46,107,109 For example, cellular memory (anamnestic antiviral response) may contribute to long-term protection.7,33,46,107,109,171,192 Additional long-term study and experience are needed and ongoing to elucidate more fully the duration of protective efficacy of currently recommended regimens of hepatitis A vaccine and the possible need for booster doses.1,2,6,7,23,33,41,46,49,84,171,192,203 Surveillance data and population-based studies are ongoing and data to date indicate that no cases of HAV infection have been detected among children followed for 9 years after receiving hepatitis A vaccine.192

Chemistry and Stability

Chemistry

Hepatitis A Virus Vaccine Inactivated

Hepatitis A virus vaccine inactivated (hepatitis A vaccine) is a noninfectious, sterile suspension of a cell culture-adapted, attenuated strain of hepatitis A virus (HAV).1,2,6,7,8,9,10,11,12,13,15,22,23,35,36,38,39,47,48,49,50,51,52,53,54,55,63,78,110,113,115,171,192 Hepatitis A vaccine is prepared from attenuated strains of the virus that have been propagated in MRC-5 human diploid fibroblasts, harvested and purified from cell lysates using a combination of physical (e.g., ultrafiltration) and chromatographic (e.g., exclusion gel chromatography, high-performance liquid chromatography [HPLC]) techniques, inactivated with formaldehyde, and then adsorbed onto an aluminum adjuvant.1,2,7,9,10,11,15,23,38,39,48,49,171,192 Hepatitis A vaccine commercially available in the US is prepared using either the attenuated virus strain HM175 (Havrix^®)1,2,6,7,8,9,10,11,12,13,15,22,23,25,35,36,38,39,47,48,49 or the attenuated virus strain CR326F' (Vaqta^®).6,7,38,40,45,50,63,78,110,113,115 Havrix^® and Vaqta^® do not contain thimerosal or any other preservatives.1,171

Commercially available hepatitis A vaccine meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration (FDA) and purity requirements of the World Health Organization (WHO) for vaccines prepared in human diploid cells.9,11,23,39 Viral antigen activity of hepatitis A vaccine prepared from the HM175 strain (Havrix^®) is referenced to a standard using an enzyme-linked immunosorbent assay (ELISA), and therefore is expressed in terms of ELISA units (ELU).1,4,8,23,192 This calibration reflects the presence of antigenic sites recognizable by neutralizing antibodies.23 Viral antigen activity of the vaccine prepared from the CR326F' strain (Vaqta^®) is referenced to a standard confirmed by amino acid analysis in which 1 unit (U) approximately equals 1 ng of viral protein antigen; therefore, potency of Vaqta^® is expressed in units (U) of HAV antigen.78,192

Each 0.5-mL pediatric or 1-mL adult dose of Havrix^® vaccine containing at least 720 or 1440 units of viral antigen, respectively, also contains 0.25 or 0.5 mg of aluminum (as aluminum hydroxide).1,2,8,11,15,48 Havrix^® also contains an amino acid supplement (0.3 mg/mL) in a phosphate-buffered saline solution, and polysorbate (Tween^®) 20 (0.05 mg/mL).1 Residual MRC-5 cellular proteins (not exceeding 5 mcg/mL), which represent 95% of the total protein in the vaccine,161 and trace amounts of formalin (not exceeding 0.1 mg/mL) also are present.1 Trace amounts (not exceeding 40 ng/mL) of neomycin may be present in Havrix^® since the aminoglycoside is included in the cell growth media used in the manufacture of the vaccine and trace amounts may remain following purification.1 Following thorough agitation, the vaccine is a uniform, slightly turbid, white suspension.1 The suspension has a pH of 6.8-7.5.162

Each 1-mL adult dose of Vaqta^® vaccine contains approximately 50 units of viral antigen, 0.45 mg of aluminum (as amorphous aluminum hydroxyphosphate sulfate), and 70 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.171 Each 0.5-mL pediatric dose of Vaqta^® vaccine contains approximately 25 units of viral antigen, 0.225 mg of aluminum (as amorphous aluminum hydroxyphosphate sulfate), and 35 mcg of sodium borate, in 0.9% sodium chloride.171 Within the limits of assay variability, each 1-mL of vaccine (50 units) also contains less than 0.1 mcg of nonviral protein, less than 4 × 10^-6 mcg of DNA, less than 10^-4 mcg of bovine albumin, and less than 0.8 mcg of formaldehyde.171 Other chemical residuals from the manufacturing process are present in a concentration of less than 10 parts per billion.171 Following thorough agitation, the vaccine appears as a slightly opaque, white suspension.171 The suspension has a pH of 5.5-7.5.173

Live attenuated hepatitis A virus vaccines (currently not commercially available in the US) also have been developed and tested in nonhuman primate models of HAV infection and human immunogenicity trials.15,32,37,38,39,40,43,44,56,192 In addition, a live attenuated hepatitis A vaccine (based on the H2 strain) has been tested in the People's Republic of China and is in use in that country.15,22,32,42,44,56,113,122 However, these vaccines have not been shown to offer distinct advantages over inactivated vaccines,15 and the US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that only inactivated hepatitis A virus vaccines have been evaluated in controlled clinical efficacy trials.192

Hepatitis A Virus Vaccine Inactivated and Hepatitis B Vaccine (Recombinant)

Hepatitis A virus vaccine inactivated and hepatitis B vaccine (recombinant) is a fixed-combination vaccine that contains both HAV and hepatitis B virus (HBV) antigens.186 The commercially available fixed-combination vaccine (HepA-HepB; Twinrix^®) is a sterile suspension containing the antigenic components used to produce Havrix^® hepatitis A vaccine and Engerix-B^® hepatitis B vaccine.186 Each antigenic component is adsorbed separately onto aluminum phosphate or aluminum hydroxide and then pooled to form the fixed-combination preparation.186

Each 1-mL dose of Twinrix^® contains 720 units of hepatitis A viral antigen and 20 mcg of hepatitis B surface antigen (HBsAg) and also contains 0.45 mg of aluminum (as aluminum hydroxide and aluminum phosphate).186 Each 1-mL dose of the vaccine also contains residual MRC-5 cellular (not exceeding 2.5 mcg), yeast proteins (not exceeding 50 mg), trace amounts of formaldehyde (not exceeding 0.1 mg), trace amounts of neomycin sulfate (not exceeding 0.02 mcg), and amino acids in a phosphate-buffered saline solution with polysorbate (Tween^®) 20.186 Twinrix^® does not contain any preservatives.186 The vaccine has a pH of 5.8-6.6.2 Following thorough agitation, Twinrix^® appears as a homogeneous, turbid, white suspension.186

Stability

Hepatitis A Virus Vaccine Inactivated

Hepatitis A vaccine should be refrigerated at 2-8°C and should not be frozen;1,60,171,200 if freezing occurs, the vaccine should be discarded.1 When stored as recommended, Havrix^® has an expiration date of 3 years after the date of manufacture.162 While refrigeration is the recommended storage and shipping condition for Havrix^® and Vaqta^® vaccines,1,171 the vaccines are reported to be thermally stable.192,203 Reactogenicity and immunogenicity of Havrix^® stored at 37°C for up to 1 week and Vaqta^® stored at 37°C for 12 months or longer does not differ from that reported for these vaccines when stored at 2-8°C.163,192,203

Hepatitis A Virus Vaccine Inactivated and Hepatitis B Vaccine (Recombinant)

The fixed-combination vaccine containing hepatitis A vaccine and hepatitis B vaccine (HepA-HepB; Twinrix^®) should be refrigerated at 2-8°C and should not be frozen;60,186 if freezing occurs, the vaccine should be discarded.186 When stored as recommended, the vaccine has an expiration date of 3 years after the date of manufacture.2

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. GlaxoSmithKline. Havrix^® (hepatitis A vaccine) prescribing information. Research Triangle Park, NC; 2009 Oct.

2. Krause DS. SmithKline Beecham Pharmaceuticals, Philadelphia, PA; Personal communication.

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