VA Class:IM100

ATC Class:J0BB04

AHFS Class:

• Vaccines 80:12

Generic Name(s):

• Hepatitis B Vaccine

• Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined

• Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine

• Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine

Hepatitis B vaccine is an inactivated (recombinant) vaccine containing hepatitis B surface antigen (HBsAg) and is used to stimulate active immunity to hepatitis B virus (HBV) infection.132,133,213,281 Hepatitis B vaccine is commercially available in the US as monovalent vaccines (Engerix-B^®, Recombivax HB^®).132,133 Hepatitis B vaccine also is commercially available in a fixed-combination vaccine with Haemophilus influenzae type b (Hib) vaccine (Hib-HepB; Comvax^®),251 in a fixed-combination vaccine with hepatitis A virus vaccine (HepA-HepB; Twinrix^®),262 and in a fixed-combination vaccine that contains diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®).104

Hepatitis B vaccine (recombinant) is used to stimulate active immunity to hepatitis B virus (HBV) for prevention of HBV infection in susceptible individuals, including those considered at risk of potential exposure to HBV or hepatitis B surface antigen-positive (HBsAg-positive) materials (e.g., blood, plasma, serum).105,125,130,132,133,213,241,269,281,282

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) recommend that all neonates and infants and all previously unvaccinated children and adolescents through 18 years of age receive routine primary immunization against HBV infection with hepatitis B vaccine, unless contraindicated.105,112,213,241,281 In addition, the ACIP, AAFP, American College of Obstetricians and Gynecologists (ACOG), and American College of Physicians (ACP) recommend preexposure vaccination with hepatitis B vaccine for all susceptible adults with medical, occupational, behavioral, or other factors that put them at risk for HBV infection and for any other susceptible adult requesting protection from HBV.280,281

Postexposure prophylaxis using combined active immunization with hepatitis B vaccine and passive immunization with hepatitis B immune globulin (HBIG) is used to prevent perinatal HBV infection in neonates born to HBsAg-positive women and also is used to prevent HBV infection in certain susceptible individuals exposed to HBV or HBsAg-positive material (e.g., blood, plasma, serum).105,213,233,269,281,282,290 (See Uses: Postexposure Prophylaxis.)

Successful prevention of HBV infection, either by primary or preexposure vaccination with hepatitis B vaccine or postexposure prophylaxis with hepatitis B vaccine and HBIG, generally will also prevent hepatitis D virus (HDV) infection (delta virus infection).105,133 HDV infection occurs only as a coinfection or superinfection in patients with HBV infection.105 HDV is dependent on HBV for replication; therefore, individuals immune to HBV also should be immune to HDV infection.105 Routes of transmission of HDV are similar to those for HBV, and HDV infection in the US most commonly affects individuals at high risk for HBV, particularly parenteral drug abusers and individuals receiving plasma-derived clotting factor concentrates.156,157,158,159,161,162,163 Individuals who are carriers of HBsAg are at risk of HDV infection, especially if they are at high risk of repeated exposure to HBV (e.g., parenteral drug abusers, homosexuals); however, there currently is no effective means for preexposure or postexposure prophylaxis of HDV infection in HBsAg carriers.105

With the exception of HDV,105,133 monovalent hepatitis B vaccine will not prevent hepatitis caused by other viruses known to infect the liver, including hepatitis A virus (HAV), hepatitis C virus (HCV), or hepatitis E virus (HEV).105,132,133

Primary immunization against HBV can be integrated with age-appropriate primary immunization against diphtheria, tetanus, pertussis, hepatitis A, Haemophilus influenzae type b (Hib), human papillomavirus (HPV), influenza, measles, mumps, rubella, pneumococcal disease, meningococcal disease, poliomyelitis, rotavirus, and varicella.105,112,213,216,259,260 (See Drug Interactions: Vaccines.)

Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens

Hepatitis B vaccine is commercially available in a fixed-combination vaccine with Haemophilus influenzae type b (Hib) vaccine (Hib-HepB; Comvax^®),251 in a fixed-combination vaccine with hepatitis A virus vaccine (HepA-HepB; Twinrix^®),262 and in a fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®).104 When indicated based on the age and vaccination status of the individual and when there are no contraindications to any of the individual components, these combination vaccines can be used instead of separate injections.104,105,213,251,262

The commercially available fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®) can be used in infants and children 6 weeks through 6 years of age born to HBsAg-negative women when doses of poliovirus vaccine inactivated (IPV), diphtheria and tetanus toxoids adsorbed and acellular pertussis vaccine adsorbed (DTaP), and hepatitis B vaccine are indicated and there are not contraindications to any of the individual components.104,112,213 The ACIP states that this fixed-combination vaccine also may be used to complete the hepatitis B vaccine series in infants 6 weeks of age or older born to HBsAg- positive women†.213 Pediarix^® should not be used for the initial dose of hepatitis B vaccine that is indicated in neonates.104,105,213 (See Neonates and Infants under Uses: Primary Immunization.)

The commercially available fixed-combination vaccine containing Haemophilus influenzae type b (Hib) and hepatitis B vaccine (Hib-HepB; Comvax^®) can be used whenever a dose of Hib vaccine and a dose of hepatitis B vaccine are both indicated in an infant 6 weeks to 15 months of age born to an HBsAg-negative woman.213,251 The ACIP states that this fixed-combination vaccine also may be used to complete the hepatitis B vaccine series in infants 6 weeks to 15 months of age born to HBsAg-positive women†.213 Comvax^® should not be used for the initial dose of hepatitis B vaccine that is indicated in neonates.105,213 (See Neonates and Infants under Uses: Primary Immunization.)

When vaccination against both hepatitis A and hepatitis B infection is indicated in adults 18 years of age or older, the commercially available fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) can be used.213,262,281

Past and Current Considerations Regarding Hepatitis B Vaccine Recommendations

Hepatitis B vaccines have been available in the US since 1981.282 Although early hepatitis B vaccines were plasma-derived vaccines (no longer commercially available in the US), vaccines produced using recombinant DNA technology became available in 1986.282 Initially (from 1981-1991), the strategy for HBV prevention in the US consisted of selective vaccination of individuals in high-risk groups and serologic screening of all pregnant women for HBsAg with vaccination of neonates born to HBsAg-positive mothers.214,238,282 This limited strategy was successful only in reducing the risk of acquiring infection through occupational exposure, a group that accounts for only approximately 4% of cases of HBV infection, and failed to effectively target the majority of high-risk groups.214,282 In addition, it became evident that screening pregnant women for HBsAg and active and passive immunization of their neonates prevented only a small percentage of HBV infections that occurred annually in the US and had little impact on the control of HBV and its sequelae.214

Therefore, the ACIP and AAP expanded their recommendations in 1991 and 1992 to include universal primary immunization of all neonates (regardless of the HBsAg status of the mother).214,238,282 This recommendation was based on the belief that universal immunization of all neonates has an immediate impact on reducing vertical transmission of HBV infection from mothers to neonates and would diminish or eliminate horizontal transmission between preschool-age children within 5 years.214 In 1995, a comprehensive vaccination strategy was adopted by the ACIP, AAP, and AAFP that included universal immunization for all adolescents not vaccinated previously.222,238,241 This expansion of recommendations to include immunization of older children was based on the fact that most individuals infected with HBV in the US acquired their infection while they were adolescents or young adults241 and efforts aimed at universal immunization of neonates were not likely to substantially affect the incidence of acute disease in the US for 20-30 years.222 Therefore, targeting neonates and adolescents was expected to result in a more rapid decline in the incidence of HBV infection.222,241 To encourage vaccination of children and adolescents, the ACIP, AAP, and AAFP beginning in 1999 recommended that all children and adolescents through 18 years of age who had not previously received hepatitis B vaccine begin the primary immunization series during any routine health care visit.238,250

As a result of these strategies, the incidence of acute HBV reported in the US declined 78% during 1990-2005 and the greatest decline (96%) occurred among children and adolescents younger than 19 years of age.281 As of 2004, more than 92% of US children 19-35 months of age had received 3 doses of hepatitis B vaccine213 and data from 2003 indicate the vaccine coverage rate is 50-60% among adolescents 13-15 years of age.213,281

The vaccination rate among adults, however, has remained low and adults accounted for approximately 95% of new HBV infections reported in 2005.281 Although the incidence of acute HBV infection among adults decreased 35% during 2002-2005, the highest incidence of acute HBV infection occurred among adults 25-45 years of age.281,282 Data indicate that ongoing HBV transmission occurs principally among unvaccinated adults with risk behaviors for HBV transmission and among household contacts and sexual partners of individuals with chronic HBV infection.281,282 Therefore, in 2006, the ACIP updated guidelines regarding hepatitis B vaccination in adults in an attempt to increase vaccination coverage in this age group.281 The ACIP now recommends hepatitis B vaccine (inactivated) for all unvaccinated adults at risk for HBV infection and for all unvaccinated adults who request protection from HBV.281 It is hoped that expanded use of the vaccine in adults in conjunction with routine use of the vaccine in neonates, children, and adolescents will ultimately result in the elimination of HBV transmission in the US.281

Risks of Exposure and Infection

HBV is transmitted by percutaneous or mucosal exposure to hepatitis B surface antigen-positive (HBsAg-positive) blood, serum, plasma, semen, or saliva from individuals who have acute HBV infection or individuals who are carriers of the virus.105,130,213,269,281,282,291 The principal sources of HBV are blood (plasma or serum) and serous fluids.130,269 Lower concentrations are found in saliva, semen, vaginal secretions, and wound exudates.130,282 Although saliva can be a vehicle of HBV transmission through bites, other types of exposure to saliva (e.g., kissing) are unlikely modes of transmission.282 Transmission of HBV does not appear to occur via tears, sweat, urine, feces, or droplet nuclei and the virus is not transmitted via the fecal-oral route.282

HBV can be transmitted perinatally from mother to infant at birth, usually as the result of blood exposures during labor and delivery.105,213,282,291 In utero transmission of HBV is rare.105 Without postexposure HBV prophylaxis in the neonate, the risk for perinatal transmission of the virus and chronic infection is 5-20% if the mother is HBsAg-positive and hepatitis B e antigen-negative (HBeAg-negative) and about 70-90% if the mother is positive for both HBsAg and HBeAg.105,213,282 Up to 90% of infants who become infected perinatally will become HBV carriers.105,282

In the US, the primary risk factors for HBV infection in adults and adolescents are unprotected sex with an infected partner, unprotected sex with more than one partner, men who have sex with men, history of other sexually transmitted diseases (STDs), and illicit injection drug use.130,282 The US Centers for Disease Control and Prevention (CDC) states that individuals considered at high risk of exposure to HBsAg-positive material include immigrants or refugees from areas of high HBV endemicity, residents in institutions for the developmentally disabled, users of illicit parenteral drugs, homosexually active men, hemodialysis patients, and household contacts of HBV carriers.282 Those considered at intermediate risk include male prisoners, health-care workers who have frequent blood contact, staff of institutions for the developmentally disabled, and heterosexuals with multiple partners.282

Transmission from infected health-care personnel to patients is uncommon, but has been documented during certain invasive, exposure-prone procedures (e.g., certain oral, cardiothoracic, colorectal, or obstetric/gynecologic surgery).182,183,184,195,211 HBsAg-positive health-care personnel need not be restricted from patient contact unless they have been associated epidemiologically with transmission of HBV; adherence to recommended surgical and dental techniques, compliance with universal precautions for the prevention of blood-borne pathogens in health-care settings, and recommendations for sterilization/disinfection minimize the risk of transmission.211,233 However, health-care personnel who are HBeAg-positive should not perform exposure-prone procedures unless they have sought the advice and guidance of experts and have a clear understanding of the risks, associated precautions, and circumstances under which such procedures can continue to be performed.211,233

Presence of HBeAg indicates a high degree of infectivity of body fluids.282 Individuals exposed to body fluids that are positive for HBsAg, HBeAg, and HBV-specific DNA polymerase are more likely to develop HBV infection than individuals exposed to body fluids that are positive for HBsAg and anti-HBe but negative for HBeAg and DNA polymerase.282 The development of the HBV carrier state generally is associated with high serum titers of HBsAg and persistent, high serum titers of antibody to hepatitis core antigen (anti-HBc); HBeAg may also be present.282

Acute HBV infection may be self-limited resulting in production of antibody to HBsAg (anti-HBs) and immunity against reinfection; however, it may also progress to chronic HBV infection (especially in infants or young children, immunocompromised individuals, patients with diabetes).105,213,281,282 The case fatality rate is 0.5-1.5% among those with acute HBV infection,213,281,290 and the highest fatality rates are in adults older than 60 years of age.213,281 Chronic HBV infection develops in 90% or more of infants infected perinatally, 25-50% of children infected at 1-5 years of age, and less than 5% of those infected at 5 years of age or older.105,213,281,282,290,291 Chronic infection is associated with persistent HBV replication in the liver and may result in liver cirrhosis, liver cancer, liver failure, and death.105,213,281,282,290 Data from 2006 indicate that approximately 800,000-1.4 million people in the US have chronic HBV infection.291

The risk of HBV infection for international travelers generally is low, except for certain travelers in countries with intermediate or high HBV endemicity (i.e., prevalence of HBsAg 2% or greater).125,282 The prevalence of chronic HBV infection is low (less than 2%) in the general populations of the US, Canada, Northern and Western Europe, Australia, New Zealand, Mexico, and southern South America.105,125,282 The prevalence of chronic HBV infection is intermediate (2-7%) in South Central and Southwest Asia, Israel, Japan, Eastern and Southern Europe, Russia, and most areas surrounding the Amazon River basin, Honduras, and Guatemala.125 However, the prevalence of chronic HBV infection is high (8% or more) in all socioeconomic groups in certain areas, including all of Africa; Southeast Asia, including China, Korea, Indonesia, and the Philippines; the Middle East, except Israel; southern and western Pacific islands; the interior Amazon Basin; and certain parts of the Caribbean, such as Haiti and the Dominican Republic.125,274 In China, Southeast Asia, most of Africa, most Pacific islands, parts of the Middle East, and the Amazon Basin, most individuals acquire the disease at birth or during childhood, and 8-15% of the population is chronically infected.274,282

Primary Immunization

Neonates and Infants

Hepatitis B vaccine is used to stimulate active immunity to HBV in neonates and infants.105,132,133,213,221 The ACIP, AAP, and AAFP recommend that all neonates and infants receive primary immunization against HBV with hepatitis B vaccine regardless of the HBsAg status of the mother.105,112,213 Special efforts should be made to ensure that infants in populations with current or previously high rates of childhood HBV infection (e.g., native Alaskans, Asian-Pacific Islanders, infants who reside in households of first-generation immigrants from Asia, Africa, or other regions with intermediate or high endemic rates of HBV) are completely vaccinated by 6-12 months of age.105,213,222

Medically stable neonates weighing 2 kg or more at birth should receive the first dose of hepatitis B vaccine at birth, prior to discharge from the hospital; only monovalent hepatitis B vaccine should be used for this dose.105,112,213 On a case-by-case basis and only in rare circumstances, administration of the first dose may be delayed until hospital discharge in neonates weighing 2 kg or more provided the mother is HBsAg- negative .213 If the first dose is not given before hospital discharge to infants born to HBsAg- negative mothers, it should be administered no later than 2 months of age.213

Neonates born to women who are HBsAg positive should receive the first dose of hepatitis B vaccine within 12 hours of birth (in conjunction with passive immunization with HBIG), regardless of gestational age or birthweight, and the second and third doses of vaccine at 1-2 and 6 months, respectively.105,112,213,282 (See Prevention of Perinatal Hepatitis B Virus Infection, in Uses.)

For neonates born to HBsAg- negative women, the first dose optimally should be administered at birth (but may be given at birth to 2 months of age); the second dose optimally should be administered at 1-2 months of age (but may be given at 1-4 months of age or at least 4 weeks after the first dose); and the third dose should be given at 6-18 months of age.105,112

If the mother's HBsAg status is unknown at the time of delivery, the neonate or infant should receive the dosage of hepatitis B vaccine recommended for those born to HBsAg-positive women within 12 hours of birth and the mother should be screened for HBsAg as soon as possible to determine the subsequent management of the infant, including the need to administer HBIG.105,112,213 If it is unlikely that the HBsAg status of the mother can be determined within the first 12 hours, the AAP recommends that preterm neonates weighing less than 2 kg receive a dose of HBIG (in addition to a dose of vaccine) within 12 hours of birth since the vaccine may be less immunogenic in these infants.105 (See Premature and Low-birthweight Neonates under Primary Immunization: Neonates and Infants, in Uses.) If the mother of a full-term neonate or preterm neonate weighing more than 2 kg at birth is subsequently found to be HBsAg-positive, these infants should receive a dose of HBIG as soon as possible, but within 7 days of birth.105,112

The ACIP and AAP recommend routine serologic screening of all pregnant women during an early prenatal visit (e.g., first trimester) to determine their HBsAg status, even if they have previously been tested or received hepatitis B vaccine.105,112,213 Women who are not tested prenatally, those who engage in behaviors that put them at high risk for HBV (e.g., more than one sex partner in the previous 6 months, an HBsAg-positive sex partner, evaluation or treatment for a STD, recent or current injection drug abuse), and those with clinical hepatitis should be tested at the time of admission to the hospital for delivery.213 Routine serologic testing to confirm the immune response to the vaccine is not necessary in infants born to HBsAg- negative women.105,213 However, all infants born to HBsAg- positive women should undergo serologic testing 9-18 months after completion of the vaccine series (usually at the next well-child visit).105,213 (See Uses: Pre-and Postvaccination Serologic Testing.)

Premature and Low-birthweight Neonates

There is some evidence that the seroconversion rate is lower in low-birthweight neonates when the initial dose of hepatitis B vaccine is administered shortly after birth than when it is administered when the neonate is older or weighs more than 2 kg.105,131,213,221 By 1 month of age, medically stable preterm infants (regardless of initial birthweight or gestational age) have a response to vaccination that is comparable to that of full-term neonates.213

The ACIP and AAP recommend that neonates born to HBsAg-positive women receive a dose of hepatitis B vaccine and HBIG as soon as possible after birth (within 12 hours of birth), regardless of gestational age or birthweight.105,213,221 However, for neonates weighing less than 2 kg, this dose should not be counted toward completion of the vaccine series; the usual 3-dose series should be initiated when the infant is 1 month of age.105,213,282

If the maternal HBsAg status is unknown at birth, preterm infants should receive the first dose of hepatitis B vaccine within 12 hours of birth.105,213 The mother's HBsAg status should be determined as quickly as possible and, if positive, HBIG should be administered as soon as possible, but within 7 days of birth.105 For neonates weighing less than 2 kg, if the mother's HBsAg status cannot be determined within 12 hours of birth, HBIG should be given within 12 hours of birth, and the birth dose of vaccine should not be counted toward completion of the vaccine series.105,213

For premature neonates born to HBsAg-negative women, the AAP recommends that those weighing less than 2 kg at birth receive the first dose of hepatitis B vaccine at 1 month of age.105,213 However, those with low birthweight who are medically stable and showing consistent weight gain when discharged from the hospital before 1 month of age may receive the first vaccine dose at the time of discharge.105,213

Children and Adolescents

The ACIP, AAP, and AAFP recommend that all previously unvaccinated children and adolescents through 18 years of age receive primary immunization with hepatitis B vaccine.105,112,213,222,250

For most children in the US, the risk of HBV infection is low until adolescence, and immunization before or as these children approach adolescence will provide age-appropriate protection against infection.105 However, younger children of certain population groups with high rates of childhood HBV infection (e.g., native Alaskans, Asian-Pacific Islanders, children of immigrants from countries in which HBV infection is endemic) are at high risk of infection from person-to-person transmission.105 Because of the high risk of chronic HBV infection during the first 5 years of life, vaccination of this age group in these populations should be a high priority.105 Children in institutions for the developmentally disabled also are at high risk of HBV infection and should be vaccinated.105

As a strategy to ensure immunization of adolescents, the ACIP, AAP, AAFP, and other clinicians recommend that hepatitis B vaccination be initiated or completed at a routine preadolescent preventive health-care visit at 11-12 years of age.222,233,241 This routine health-care visit provides an opportunity to initiate protection against HBV before the adolescent begins high-risk behaviors and facilitates administration of other vaccines recommended at this age (e.g., measles, mumps, and rubella virus vaccine live (MMR), human papillomavirus [HPV] vaccine, varicella virus vaccine live, meningococcal vaccine).105,241

Hepatitis B vaccine should be administered to all children and adolescents 13 through 18 years of age or older (without regard to degree of risk) if they have not previously received the vaccine.241,250 The ACIP and AAP state that HBV immunization should be emphasized for adolescents with the major risk factors for acquisition of HBV infection.105,213 This includes adolescents who have multiple sexual partners (more than one in 6 months) or STDs; are sexually active homosexual or bisexual males; sexual or regular household contacts of individuals positive for HBsAg; IV drug abusers; employees, volunteers, or trainees in jobs that involve contact with blood or blood-contaminated body fluids; residents of institutions for the developmentally disabled; recipients of clotting factors; or living in areas with increased rates of parenteral drug abuse, teenage pregnancy, and/or STD.105,213,241 Adolescents can be vaccinated against HBV in various settings, including school-based clinics, community health centers, family planning clinics, clinics for the treatment of STDs, and special adolescent clinics.213,241

Internationally Adopted Children and Other Immigrants

The number of children adopted from outside the US has increased substantially in recent years and the immune status of such children may be difficult to determine based on country of origin and medical records.105 To complete an international adoption and bring an infant or a child to the US, prospective parents must fulfill requirements of the Bureau of Citizenship and Immigration Services (BICS), the foreign country in which the infant or child resides, and, possibly, the state of residence of the adoptive parents.125 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 Schedule or the US Recommended Adult Immunization Schedule ).125,131 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.105,125

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) also should be considered.131 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 schedule.105,131 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).131 Although vaccines with inadequate potency have been produced in other countries, most vaccines used worldwide are immunogenic and produced with adequate quality control standards.105,131

When the immune status of an internationally adopted child is uncertain, the ACIP and the AAFP recommend that health-care providers either repeat vaccinations (since this usually is safe and avoids the need to obtain and interpret serologic tests) and/or use selective serologic testing to determine the need for immunizations (helps avoid unnecessary injections).105,131 Internationally adopted children should be tested for HBsAg and those found to be HBsAg-positive should be monitored for the development of liver disease.125,131 Regardless of vaccination status, individuals born in Asia, Pacific Islands, Africa, or other regions where HBV is highly endemic should be tested for HBsAg.131 The ACIP states that the age-appropriate hepatitis B vaccine series should be initiated or completed if the child's vaccination history is uncertain or less than 3 vaccine doses were given previously.131 If a child's prior vaccination record indicates receipt of 3 or more doses of hepatitis B vaccine, additional vaccine doses are not necessary provided at least 1 of the prior doses were administered at 6 months of age or older;131 however, if the child's vaccination record indicates that the last dose of the hepatitis B vaccine series was given when the child was younger than 6 months of age, the ACIP recommends that an additional vaccine dose should be given when the child is at least 6 months of age.131 The AAP recommends that serologic testing for HBsAg be performed in all internationally adopted children and that the hepatitis B vaccine series should be given if such testing is not available and vaccination history is uncertain.105

Adults

The ACIP recommends that all unvaccinated adults at risk for HBV infection receive primary immunization with hepatitis B vaccine and states that any unvaccinated adult who requests protection from HBV can receive primary immunization with the vaccine.280,281,282

In settings in which a high proportion of individuals are likely to be at risk for HBV, ACIP recommends universal vaccination for all adults who have not completed the vaccine series.281,282 Standing orders should be implemented to administer hepatitis B vaccine as part of routine services to all susceptible individuals who visit these settings.281,282 This includes facilities that test and treat STDs and human immunodeficiency virus (HIV), drug abuse treatment and prevention facilities, health-care settings targeting services for injection drug abusers, health-care settings targeting men who have sex with men, correctional facilities281,282 , end-stage renal disease programs, facilities for chronic hemodialysis patients, and institutions and nonresidential daycare facilities for persons with developmental disabilities.280 In addition, because not all adults with HBV risk factors visit these settings, ACIP recommends that primary care and specialty medical settings (e.g., physicians' offices, community health centers, family planning clinics, liver disease clinics, travel clinics) also implement standing orders to identify susceptible adults and provide hepatitis B vaccine whenever indicated or requested as part of regular preventive care.281,282 (See Uses: Preexposure Vaccination in High-risk Groups.)

Individuals with Altered Immunocompetence

Recommendations regarding use of hepatitis B vaccine in individuals with altered immunocompetence generally are the same as those for individuals who are not immunocompromised.220,278,279 Therefore, if indicated, hepatitis B vaccine may be used in HIV-infected individuals; individuals severely immunocompromised because of congenital immunodeficiency, leukemia, lymphoma, generalized malignancy, or therapy with alkylating agents, antimetabolites, radiation, or corticosteroids; individuals with solid organ transplants or receiving chronic immunosuppressive therapy; or those with asplenia, renal failure, diabetes, alcoholism, or alcoholic cirrhosis.220,278,279 However, the immunologic response to the vaccine may be lower in immunocompromised patients, including HIV-infected patients, than in immunocompetent individuals.101,127,128,129,212,220,278,279

HIV-infected Individuals

The ACIP, AAP, CDC, National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society, and others state that recommendations for use of hepatitis B vaccine in HIV-infected individuals are the same as those for individuals who are not HIV-infected.278,279 Therefore, all HIV-infected neonates, children, adolescents, and adults should receive hepatitis B vaccine according to the usually recommended childhood and adult immunization schedules.278,279

Some HIV-infected individuals may not have a satisfactory response to hepatitis B vaccine.101,127,128,129,212,220 Lower antibody responses to the vaccine may occur in HIV-infected children, especially older children or those with CD4⁺ T-cell counts less than 200/mm³.279 Following vaccination with hepatitis B vaccine, the seroconversion rate in HIV-infected adults is 18-72% compared with 90% or greater in healthy adults who are not infected with HIV.278 In addition, mean antibody titers are lower and decline faster in HIV-infected individuals than in those who are not infected with HIV.101,127,128,129,212,220,278 There is some evidence that doses of hepatitis B vaccine twice the usual dose may result in higher seroconversion rates in HIV-infected individuals with CD4⁺ T-cell counts greater than 350/mm³.278 Administration of an additional vaccine dose in HIV-infected individuals also may result in a higher antibody response or higher seroconversion rate.278 However, the ACIP, AAP, CDC, NIH, and other experts state that data are insufficient to make recommendations regarding use of higher or additional doses of hepatitis B vaccine in HIV-infected children or adults.101,147,148,153,160,220,278,279

Because there is some evidence that the immunologic response to hepatitis B vaccine may be better in adults with CD4⁺ T-cell counts greater than 350/mm³, the ACIP, AAP, CDC, NIH, and others recommend early use of the vaccine in HIV-infected patients before the CD4⁺ T-cell counts decreases to less than 350/mm³.278 However, vaccination should not be deferred until the CD4⁺ T-cell count increases to greater than 350/mm³.278

Because HIV-infected individuals (especially children with CD4⁺ T-cell counts less than 200/mm³ or adults with CD4⁺ T-cell counts less than 350/mm³) may have an inadequate response to hepatitis B vaccine, postvaccination serologic testing should be done 1-2 month after the vaccine series is completed to determine whether an adequate anti-HBs response was attained.220,278,279 (See Postvaccination Serologic Testing under Uses: Pre- and Postvaccination Serologic Testing.) If there is no response to the initial vaccine series, revaccination should be considered.220,278,279 Some clinicians might delay revaccination until the patient has had a sustained increase in CD4⁺ T-cell count in response to antiretroviral therapy.278

Although transient increases in HIV RNA concentrations have been reported following use of hepatitis B vaccine in HIV-infected individuals, this does not appear to be clinically important and there is no evidence of accelerated HIV disease progression in vaccinated individuals.236,237,239,278,279

Preexposure Vaccination Against Hepatitis B Virus (HBV) Infection in High-risk Groups

Hepatitis B vaccine is used for preexposure vaccination in previously unvaccinated children, adolescents, or adults at risk of exposure to HBsAg-positive materials (e.g., blood, plasma, serum).130,132,133,233 The ACIP recommends preexposure vaccination for all unvaccinated adults in settings in which a high proportion of individuals are likely to be at risk for HBV infection.130,132,133,233 This includes health-care personnel, selected patients and patient contacts, populations with high risk of infection, individuals at risk because of their sexual practices, military personnel identified as being at increased risk, and other individuals at risk of exposure (e.g., injection drug abusers).130,132,133,233

In settings in which a high proportion of individuals are likely to be at risk for HBV, the ACIP recommends universal vaccination for all adults who have not completed the vaccine series and suggests standing orders to administer hepatitis vaccine as part of routine services to all susceptible individuals who visit these settings.281 This includes facilities that test and treat sexually transmitted diseases (STDs) and HIV facilities that provide drug abuse treatment and prevention, health-care facilities targeting services for injection drug abusers or men who have sex with men, and correctional facilities.281

Health-care Personnel

HBV infection is a major infectious occupational hazard for health-care personnel.180,181,182,183,185,206,233 Health-care personnel at risk of exposure to blood, blood-contaminated body fluids, other body fluids, and/or needles that might be contaminated with HBsAg are at risk of HBV infection and should be vaccinated against HBV.180,181,182,183,185,206,233,269,282,290 Among susceptible health-care personnel, the risk for HBV infection after a needlestick injury involving an HBV-positive source is 23-62%.290 Many HBV infections that occurred before widespread vaccination of health-care personnel probably resulted from unapparent exposures (e.g., inoculation into cutaneous scratches, lesions, or mucosal surfaces).290 Generally, regardless of institutional experience and institutional differences, individuals (e.g., health-care personnel and public-safety workers) exposed to blood, blood products, body fluids or tissues are at substantial risk of exposure to HBV infection,280 and the risk of acquiring HBV infection from occupational exposure depends on the frequency of percutaneous or permucosal exposures.233

The ACIP and the Hospital Infection Control Practices Advisory Committee (HICPAC) recommend use of hepatitis B vaccine in all health-care personnel who, because of their occupation and work environment, are at risk of exposure to blood, blood-contaminated body fluids, other body fluids, and/or needles that might be contaminated with HBsAg.233 This includes individuals who provide health-care to patients or work in institutions that provide patient care (e.g., clinicians, nurses, emergency medical personnel, dental professionals and students, medical and nursing students, phlebotomists, medical and laboratory technicians, hospital volunteers, and administrative and support staff in health-care institutions).233 Hepatitis B vaccine should be administered to health-care personnel, including students, prior to beginning work in a high-risk environment.233 Because risks for health-care professionals vary during the training and working career of each individual but often are highest during professional training, ACIP and HICPAC recommend that vaccination be completed during training in schools of medicine, dentistry, nursing, laboratory technology, and other allied health professions before exposure to a high-risk environment.233

Prevaccination serologic screening for previous infection is not indicated for individuals being vaccinated because of occupational risk, unless the health-care facility considers such screening cost-effective.233,269 However, ACIP and HICPAC recommend postvaccination testing to confirm an anti-HBs response in health-care personnel who have blood or patient contact and are at ongoing risk for percutaneous or mucosal exposure to blood or body fluids (e.g., physicians or physician assistants, nurses or nurse practitioners, dentists or dental hygienists, phlebotomists, emergency medical technicians, first responders, laboratory technologists or technicians, acupuncturists, and students of these professions).233,281 Most experts recommend postvaccination testing to document a response 1-2 months after completion of the primary vaccine series233,253,255,281 and consider additional periodic testing and booster vaccination of health-care workers unnecessary in those who responded to the primary series.233,253,255

Recipients of Blood Products and Plasma-derived Preparations

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 HBV, the manufacturers, the ACIP, and the National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) recommend that all seronegative individuals who receive frequent and/or large volume transfusions of blood, blood products, or plasma-derived preparations (e.g., individuals with hemophilia or thalassemia) be vaccinated with hepatitis B vaccine.100,101,132,133,288 The risk for transmission of recognized blood-borne viruses in blood and plasma-derived preparations is considered to be low because donors are screened for HBV.288 In addition, most commercially available plasma-derived preparations undergo heat-treatment, filtration, and/or chemical (solvent/detergent) procedures to reduce viral infectious potential.288 Studies using plasma-derived coagulation factor preparations indicate that improved donor screening practices and viral inactivation procedures have resulted in plasma-derived preparations with greatly reduced risk for transmission of HBV.288 However, the possibility of transmission of HBV with available viral-inactivated, plasma-derived products still remains.288 For further information on precautions related to transmissible agents in plasma-derived preparations, see Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications, in Antihemophilic Factor (Human) 20:12.16.

MASAC considers immunization against HBV essential for all seronegative patients with hemophilia or other congenital bleeding disorders.100,288 If immunization against HBV was not initiated at birth, it should be initiated at the time of diagnosis of hemophilia or other congenital bleeding disorder.288 Although postvaccination serologic testing to confirm immunity is not usually indicated after routine vaccination of infants, children, or adolescents, MASAC recommends that such testing be performed following completion of the hepatitis B vaccine series (see Uses: Pre- and Postvaccination Serologic Testing) in individuals with hemophilia100,288 and that nonresponders receive 1 or more additional doses of the vaccine.100 MASAC states that subsequent booster doses or additional serologic testing to assess antibody levels is not necessary in immunocompetent children and adults.100

Certain Patients and Patient Contacts

Patients and staff of hemodialysis, organ transplant, or oncology wards are at high risk of exposure to HBsAg-positive material and should be vaccinated against HBV.101,220 Although a decrease in the rate of HBV infection in hemodialysis wards can occur with environmental control measures alone (e.g., serologic screening of staff and patients, segregation of carriers, environmental hygiene), the manufacturers and the ACIP recommend use of hepatitis B vaccine in these individuals.101,133,220 While seroconversion rates and anti-HBs titers induced are lower in patients undergoing hemodialysis than in healthy individuals, for those patients who do respond, vaccination will provide protection against HBV infection and reduce the need for frequent serologic screening.101,203,204,220 In addition, the ACIP recommends that potential candidates for hepatitis B vaccination be identified as early as possible in the course of their renal disease since there is some evidence that higher seroconversion rates and antibody titers can be achieved in uremic patients when they are vaccinated before requiring dialysis.101,199,220

Residents and staff of institutions for the developmentally disabled, including those in small (group) residential settings, are at high risk of exposure to HBsAg-positive material and should be vaccinated.101 Risk of exposure to HBsAg-positive material in these institutions is associated not only with exposure to blood or blood products, but commonly results from bites or contact with open skin lesions (e.g., those due to impetigo, scabies, or scratched insect bites), saliva, or other infective secretions or excretions.125 Therefore, the manufacturers and ACIP recommend use of hepatitis B vaccine in susceptible residents and staff of institutions for the developmentally disabled.132,133,281 Residents and staff who live or work in smaller (group) residential settings with known HBsAg carriers also should be vaccinated.101 In addition, residents discharged from residential institutions into community settings should be screened for HBsAg so that appropriate measures can be taken to prevent transmission in the community; such measures include both environmental controls and appropriate vaccination.101

Classroom contacts (principally teachers but also classmates) of aggressive, deinstitutionalized developmentally disabled individuals are at high risk of exposure to HBsAg-positive material.101,186 Use of hepatitis B vaccine in classroom contacts of these individuals may be necessary.133 Vaccination of classroom contacts of a HBsAg carrier is strongly encouraged when the carrier is aggressive or has special medical problems that increase the risk of exposure to their blood or serous secretions.101,186 In addition, staff of nonresidential day-care programs (e.g., schools, sheltered workshops for the developmentally disabled) attended by known HBsAg carriers have a risk of infection comparable to that among health-care personnel and therefore should be vaccinated.101,200,205 Vaccination of other enrollees in such day-care programs also should be considered.101,205

Spouses and nonsexual household and sexual contacts of HBsAg carriers are at high risk of exposure to HBsAg-positive material;101 however, sexual contacts appear to be at the greatest risk of exposure to HBV infection or virus.101,281 When carriers are identified through routine screening of donated blood, diagnostic testing in hospitals, prenatal screening, screening of refugees from certain areas, or other screening programs, they should be notified of their HBsAg status.101 Although some unvaccinated spouses and nonsexual household and sexual contacts of HBsAg carriers may develop immunity against HBV infection during continuous, long-term exposure, all such contacts be tested and those who are susceptible should receive hepatitis B vaccine.101

Prisoners

Prisoners may be at high risk of exposure to HBV and should be vaccinated against HBV.132,133 In addition, initiation of vaccination programs in prisoners provides an opportunity to potentially affect transmission of HBV in the parenteral drug abuser population.101

Populations with High Endemicity of Infection

Individuals of certain US population groups (e.g., native Alaskans, Pacific Islanders, refugees from HBV-endemic areas) have high rates of infection with HBV (high endemicity) and should be vaccinated against HBV.101,105,213,222 Initiation of the hepatitis B vaccine series at birth and completion of the series by 6-12 months of age is particularly important in these population groups since transmission occurs principally during childhood in such populations.105,213,222 In addition, more extensive vaccination programs of other pediatric age-groups in these populations should be considered if resources are available, so that reductions in transmission can be achieved more rapidly.101

Prevaccination serologic testing is recommended for all foreign-born individuals (e.g., immigrants, refugees, asylum seekers, internationally adopted children) born in areas with high endemicity of HBV (e.g., Africa, Asia, the Pacific Islands).281 All susceptible household contacts of HBsAg carriers identified by such screening should be vaccinated.101 Because of the high rate of interfamily transmission among children in these populations, vaccination also is indicated for all susceptible children and adolescents who have at least one parent who was born in a highly endemic area.105,281

Individuals at Risk of Exposure Because of Their Sexual Practices

Individuals at high risk of HBV because of their sexual practices include men who have sex with men, individuals with more than 1 sexual partner in the previous 6 months, sexual partners of HBsAg-positive individuals,101,130,132,133,281 female prostitutes,132,133 and individuals seeking evaluation or treatment for a STD.130,132,281,282 All such individuals should be vaccinated against HBV.130,132,133 Hepatitis B vaccine is recommended in all susceptible adolescent and adult men who have sex with men (homosexual, bisexual), regardless of their age or duration of such sexual practices.130,132,133,282 Because of the prevalence of HBV infection in this population, serologic screening prior to vaccination may be cost effective, depending on the relative costs of laboratory testing and vaccine.130,281

Military Personnel at Increased Risk of Exposure

Military personnel identified as being at increased risk of exposure to HBV should be vaccinated with hepatitis B vaccine.132,133 (See Individuals Wounded in Mass Casualty Settings under Uses: Postexposure Prophylaxis.)

Travelers

Travelers to areas with levels of endemic HBV that are intermediate (2-7%) or high (8% or greater) are at risk of exposure to the disease.101,125,274 The ACIP, CDC, and others state that hepatitis B vaccine is indicated for previously unvaccinated travelers (neonates, infants, adolescents, adults) who are traveling to areas where the prevalence of chronic HBV infection is intermediate or high.101,125,274 (See Uses: Risks of Exposure and Infection.) This includes individuals who anticipate sexual contact with the local population, those who will live in rural areas and/or have daily physical contact with the local population, and those who are likely to seek medical, dental, or other treatment at local facilities during their stay in these areas.125,274 Individuals, including infants and young children, who will stay for 6 months or longer in areas highly endemic for HBV infection may be at risk of direct exposure to blood from the local population because of continuous close contact with local inhabitants who have open skin lesions (impetigo, scabies, scratched insect bites), exposure to unsterilized needles (or other medical or dental equipment) in local health facilities or tattoo parlors, or receipt of blood transfusions not screened for HBsAg.125,274 In addition, travelers should be advised not to use IV drugs, share needles for any purpose, or receive medications from multidose vials that may have been contaminated by used needles.125 Previously unvaccinated health-care workers who plan to work in health-care fields (e.g., medical, dental, laboratory) for any duration in areas with intermediate or high levels of endemic HBV are strongly advised to receive hepatitis B vaccine prior to travel.125

Ideally, vaccination should begin 6 months prior to travel in order to complete the full primary series of 3 doses.125 Although optimal protection is conferred by the complete 3-dose vaccine series, a partial series will offer some protection against HBV infection and the vaccine series should be initiated even if it cannot be completed before travel.101,125 Alternatively, the CDC suggests that travelers who will depart before the usual primary 3-dose series can be completed may receive an optional accelerated schedule† (doses given at 0, 7, and 21 days and a booster dose at least 1 year after the start of the series).125 (See Dosage and Administration: Dosage.)

Other Individuals at Risk of Exposure

Morticians and embalmers are at high risk of exposure to HBsAg-positive material, and the manufacturers recommend use of hepatitis B vaccine in these individuals.132,133

Public-safety personnel (e.g., police, fire department personnel) also may be at risk for occupational exposure to HBV, depending on the tasks performed; if contact with blood or blood-contaminated body fluids is involved, such personnel should be vaccinated.281

Individuals with chronic hepatitis C virus (HCV) infection may be at increased risk for HBV exposure and should receive hepatitis B vaccine.132,133 However, the optimal vaccination regimen for this group has not been determined since individuals with chronic HCV infection may have a reduced response to hepatitis B vaccine.267,268 (See Individuals with Hepatitis C Virus Infection under Pharmacology: Response to Hepatitis B Vaccine [Recombinant].)

Individuals addicted to parenterally administered drugs are at high risk of exposure to HBsAg-positive material.133 Hepatitis B vaccine should be used in these individuals as soon as possible after their drug use is identified.133

Individuals in casual contact with HBsAg carriers in settings such as schools, offices, and business environments are at minimal risk of exposure to HBV infection or virus; therefore, the ACIP does not recommend routine use of hepatitis B vaccine in these individuals.101 At child-care centers (other than those for the developmentally disabled), HBV transmission between children or between children and staff has rarely been documented.101 Unless special circumstances (e.g., behavior problems such as biting or scratching, medical conditions such as severe skin disease) that might facilitate transmission exist, the ACIP states that vaccination of contacts of carriers in child care is not necessary.101

Prevention of Perinatal Hepatitis B Virus (HBV) Infection

A regimen that includes active immunization with hepatitis B vaccine and passive immunization with HBIG is used to prevent perinatal HBV infection in neonates born to HBsAg- positive women.105,112,132,133,213 This regimen is 85-95% effective in preventing acute and chronic HBV infection in infants born to women positive for both HBsAg and HBeAg.105,213

The ACIP and AAP recommend routine serologic screening of all pregnant women during an early prenatal visit (e.g., first trimester) to determine their HBsAg status, even if they were tested previously or have already been vaccinated against HBV.105,112,213 (See Neonates and Infants under Uses: Primary Immunization.)

To prevent perinatal HBV infection, the ACIP and AAP recommend that all neonates born to HBsAg- positive women receive a dose of hepatitis B vaccine and a dose of HBIG as soon as possible after birth (within 12 hours of birth), regardless of gestational age or birthweight, followed by a second and third dose of hepatitis B vaccine given at 1-2 and 6 months, respectively.105,112,213,289

If maternal HBsAg status is unknown at birth, the neonate should receive the first dose of hepatitis B vaccine (within 12 hours of birth)105,112,213 and the mother's HBsAg status should be determined as quickly as possible and, if positive, the infant should receive a dose of HBIG as soon as possible (no later than 7 days of age).105,112 (See Neonates and Infants under Uses: Primary Immunization.)

Postexposure Prophylaxis of Hepatitis B Virus (HBV) Infection

Hepatitis B vaccine is used for postexposure prophylaxis in certain individuals exposed to HBV or HBsAg-positive materials (e.g., health-care personnel, sexual assault victims, sexual or intimate contacts of HBsAg-positive individuals).101,130,269,281,290 Depending on the exposure circumstances, the postexposure prophylaxis regimen may include combined active immunization with the vaccine and passive immunization with HBIG.101,130,269,281,290 Active immunization with hepatitis B vaccine in conjunction with passive HBIG immunization can provide both short- and long-term protection.282 Recommendations concerning postexposure prophylaxis are based on available efficacy data and on the likelihood of future exposure to HBV in the individual requiring postexposure therapy.101 For further information on the use of hepatitis B vaccine in conjunction with HBIG for postexposure prophylaxis (see Uses: Postexposure Prophylaxis of Hepatitis B Virus [HBV] Infection, in Hepatitis B Immune Globulin 80:04).

Postexposure prophylaxis is not necessary in individuals who previously received primary immunization with hepatitis B vaccine and have serologic evidence of adequate levels of anti-HBs (10 mIU/mL or greater).269 In addition, postexposure prophylaxis is not necessary in individuals previously infected with HBV; such individuals are immune to reinfection.269,282

The major determinant of postexposure prophylaxis effectiveness is early administration of the initial dose of hepatitis B vaccine or HBIG; postexposure prophylaxis is less effective depending on how long it has been since the exposure.290 Studies are limited regarding the maximum interval after exposure during which postexposure prophylaxis is effective, but postexposure prophylaxis is unlikely to be effective if initiated 7 days or longer after percutaneous (e.g., needlestick) exposures.290

Health-care Personnel Following Occupational Exposure

Hepatitis B vaccine is used in susceptible, unvaccinated health-care personnel following occupational exposures to blood and other body fluids that might contain HBV.269 All health-care personnel at risk of exposure to blood, blood-contaminated body fluids, other body fluids, and/or needles that might be contaminated with HBsAg should receive preexposure vaccination against HBV infection.101,233,269 (See Health-care Personnel under Uses: Preexposure Vaccination in High-risk Groups.) In addition, vaccination may be indicated as part of postexposure prophylaxis in individuals who have not previously received the vaccine or in individuals who have an inadequate or unknown antibody response to the vaccine.269 (See Table 1.) When both HBIG and hepatitis B vaccine are required for postexposure prophylaxis, they can be given simultaneously at separate sites.269,282

If an occupational exposure to HBV occurs, the vaccination status and vaccine-response status (if known) of the exposed individual and the HBsAg status of the source should be reviewed.269 If the exposed individual was not previously vaccinated, the hepatitis B vaccine series should be initiated as soon as possible (preferably within 24 hours).269 In addition, if the source is found to be HBsAg-positive, a single dose of HBIG should be given as soon as possible (preferably within 24 hours); HBIG is unnecessary if the source is found to be HBsAg-negative or the source is unknown or not available for testing.269

If the exposed individual was previously vaccinated and is a known responder (serum anti-HBs 10 mIU/mL or greater), no postexposure prophylaxis is necessary.269

If the exposed individual was previously vaccinated but is a known nonresponder (serum anti-HBs less than 10 mIU/mL), no postexposure prophylaxis is necessary if the source is HBsAg-negative.269 However, if the source is HBsAg-positive or the source is known to be high-risk for HBV, a single dose of HBIG should be given and a second hepatitis B vaccine series should be reinitiated with the first vaccine dose given as soon as possible after exposure.269 A 2-dose regimen of HBIG (without the vaccine) is preferred in individuals who already previously failed to respond to a second vaccine series.269

If the immune status of the exposed individual is unknown, they should be tested for anti-HBs prior to initiation of postexposure prophylaxis.269 If the exposed individual is found to be a responder, no treatment is necessary.269 If they are found to be a nonresponder (serum anti-HBs less than 10 mIU/mL) and the source is HBsAg-positive, a single dose of HBIG and a booster dose of hepatitis B vaccine should be administered.269 If they are found to be a nonresponder and the source is unknown or not available for testing, a booster dose of hepatitis B vaccine should be given and the antibody titer rechecked in 1-2 months.269

Sexual Assault Victims

The CDC and ACIP recommend postexposure vaccination with hepatitis B vaccine in susceptible adult, adolescent, and child victims of sexual assault.130,281 Trichomoniasis, genital chlamydial infection, gonorrhea, and bacterial vaginosis are the STDs most commonly diagnosed in women following sexual assault, and many experts recommend routine empiric anti-infective prophylaxis (i.e., a 3-drug regimen of IM ceftriaxone, oral metronidazole, and either oral azithromycin or oral doxycycline) in adult and adolescent victims of sexual assault.130 In addition, postexposure hepatitis B vaccination (without HBIG) is recommended.130 Unless the offender is HBsAg-positive, HBIG is not required.130 Individuals who have previously received the complete vaccine series are fully protected and do not need further doses of hepatitis B vaccine after a sexual assault; those who have received some, but not all, doses of the vaccine series should receive the remaining required doses as scheduled.130 If the victim is unvaccinated or incompletely vaccinated and the perpetrator is HBsAg-positive, a single dose of HBIG should be given within 14 days of the assault (preferably within 24 hours) and the hepatitis B vaccine series should be initiated or completed.130,281 For further information on anti-infective prophylaxis in sexual assault victims, see Uses: Prophylaxis in Sexual Assault Victims, in Ceftriaxone 8:12.06.12.

Contacts of Individuals with Acute HBV Infection

The ACIP and CDC recommend that previously unvaccinated sexual partners of individuals with acute HBV infection receive postexposure prophylaxis with both HBIG and hepatitis B vaccine as soon as possible, preferably within less than 24 hours.130,281 Studies are limited on the maximum interval after exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 14 days for sexual exposures.130,281 Completion of the hepatitis B vaccine series confers long-term protection in case the individual with acute HBV infection becomes chronically infected.130,281 Prevaccination serologic testing (anti-HBc) of sexual partners can be considered as long as it does not delay postexposure vaccination beyond 14 days.130

The AAP recommends that postexposure prophylaxis in children follow the ACIP guidelines for adults.105 In addition, because infants have a high risk of becoming chronic HBV carriers following acute infection, unvaccinated infants younger than 12 months of age who have close contact with a primary caregiver or family member with acute HBV infection should receive combined passive immunization with HBIG and active immunization with hepatitis B vaccine.105 If the infant has previously received a single dose of hepatitis B vaccine, the second vaccine dose should be administered if the interval is appropriate or, if it is too early to give a vaccine dose, the infant should receive a dose of HBIG.105 HBIG is not required if, at the time of exposure, the infant has already received at least 2 doses of hepatitis B vaccine.105

Other nonsexual household contacts of individuals with acute HBV infection are not at increased risk for infection unless they have other risk factors or are exposed to the blood of the infected patient (e.g., by sharing a toothbrush or razor).105,130 However, all household contacts of patients with acute HBV infection should be encouraged to complete primary immunization with hepatitis B vaccine.105,130 If the patient with acute HBV infection becomes chronically infected (i.e., remains HBsAg-positive after 6 months), all household contacts should be vaccinated with hepatitis B vaccine.130

Contacts of Individuals with Chronic HBV Infection

Sexual or needle-sharing partners and nonsexual household contacts of individuals with chronic HBV infection are at risk for HBV infection through percutaneous or mucosal exposures to blood or infectious body fluids (e.g., sharing a toothbrush or razor, contact with exudates from dermatologic lesions, contact with HBsAg-contaminated surfaces).281 The ACIP states that postexposure vaccination with hepatitis B vaccine is recommended for such individuals.281 A dose of HBIG also may be indicated if the most recent sexual exposure to an HBsAg-positive individual occurred within the last 14 days.130

Although efficacy of postexposure vaccination has not been evaluated for contacts of chronic HBV patients, such vaccination is expected to provide protection based on efficacy demonstrated in perinatal postexposure prophylaxis.130 The ACIP state that postvaccination serologic testing (anti-HBs) should be considered in sexual contacts of individuals with chronic HBV infection.281 Although most are expected to respond to vaccination, nonresponders should receive a second complete vaccine series.130 Those who do not respond to a second vaccine series should be counseled about abstinence and use of other methods to protect themselves from HBV via sexual transmission.281

Individuals Wounded in Mass Casualty Settings

Postexposure vaccination with hepatitis B vaccine (without HBIG) may be indicated after bombings or other mass casualty situations because of the high concentration of HBV in the blood of infected individuals, the durability of HBV in the environment, and the efficacy and relative ease of administration of the vaccine.290

In a mass casualty setting, the CDC states that use of hepatitis B vaccine generally is warranted in individuals who are unvaccinated or have an uncertain vaccination history if they have wounds (penetrating injuries), nonintact skin, or mucous membranes that may have been exposed to blood or body fluids from other individuals.290 In these situations, failure to provide hepatitis B vaccination could result in preventable illness, whereas unnecessary vaccination is unlikely to cause harm.290 If postexposure vaccination with hepatitis B vaccine is indicated in a mass casualty setting, a vaccine dose should be given as soon as possible (preferably within 24 hours) and not later than 7 days after the event, unless contraindicated.290 The age-appropriate vaccine series should then be completed at the time of discharge or during follow-up health-care visits.290 If the vaccine is in short supply, the fact that children younger than 17 years of age and health-care personnel are more likely to have previously received the vaccine than other individuals should be considered.290

Responders and other personnel in mass casualty settings should be managed using HBV postexposure prophylaxis regimens recommended for occupational exposures to HBV.290 (See Table 1.)

Pre- and Postvaccination Serologic Testing

Prevaccination Serologic Testing

Prevaccination testing for serologic markers of HBV infection are not usually necessary for individuals in populations with low prevalence of HBV serologic markers, including infants, children, or adolescents receiving routine vaccination or health-care personnel undergoing vaccination during their training years.105,130,233,269,282 However, prevaccination serologic testing is recommended for all foreign-born individuals (e.g., immigrants, refugees, asylum seekers, internationally adopted children) born in Africa, Asia, the Pacific Islands, or other regions with high HBV endemicity (i.e., prevalence of HBsAg 8% or greater).281,282 In addition, prevaccination serologic screening is recommended for individuals in risk groups with high rates of HBV infection, including HIV-infected individuals, injection drug abusers, incarcerated individuals, men who have sex with men, individuals born in countries with intermediate HBV endemicity (i.e., prevalence of HBsAg 2-7%), and household, sexual, and needle-sharing contacts of HBsAg-positive individuals.105,130,213,281,282

A decision to use prevaccination serologic testing to determine whether an individual was previously infected with HBV generally is based on whether such testing is less costly than unnecessarily vaccinating an individual who already is immune.130,281,282 For routine testing, a single test (anti-hepatitis core antigen; anti-HBc) or a panel of tests (HBsAg and anti-HBs) should be used.130,213,281 Anti-HBc identifies individuals with previous HBV infection, including those with chronic HBV infection.130,213,281 Individuals who are anti-HBc-negative are susceptible and should be vaccinated against HBV.213,281 In addition, anti-HBc-positive individuals should be tested for HBsAg.213,281

Postvaccination Serologic Testing

Postvaccination serologic testing to confirm an adequate anti-HBs response following the hepatitis B vaccine series is not necessary in most individuals because of the high rate of immunologic response among children, adolescents, and adults.105,130,282 However, postvaccination serologic testing is recommended in health-care personnel who have blood or patient contact and are at ongoing risk for percutaneous or mucosal exposure to blood or body fluids (e.g., physicians or physician assistants, nurses or nurse practitioners, dentists or dental hygienists, phlebotomists, emergency medical technicians, first responders, laboratory technologists or technicians, acupuncturists, and students of these professions).105,233,269,281,282 Postvaccination serologic testing also is recommended in infants born to HBsAg- positive women,105,112,213,282 chronic hemodialysis patients,105 HIV-infected individuals105,220,282,278 or other immunocompromised individuals,105,282 individuals with hemophilia,100 and sexual or needle-sharing partners of HBsAg-positive individuals.130,282

All infants born to HBsAg- positive women should undergo serologic testing at 9-18 months of age (usually at the next well-child visit) to document whether the combined regimen of active immunization with hepatitis B vaccine and passive immunization with HBIG prevented perinatal HBV infection.105,112,213,282 Infants should not be tested before 9 months of age to avoid detecting anti-HBs passively acquired from the HBIG dose administered at birth and to maximize the likelihood of detecting late HBV infections.105 Serologic testing is not necessary in infants born to HBsAg- negative women.105,213

When postvaccination serologic testing is indicated in adults, adolescents, and children (not neonates), including HIV-infected individuals, it usually is done 1-2 months after completion of the hepatitis B vaccine series.105,130,219,233,253,255,269,278,279,281 Individuals who received a combined regimen of active immunization with hepatitis B vaccine and passive immunization with HBIG may have passively acquired anti-HBs present in serum for several months213,269 and this may interfere with postvaccination serologic tests that measure anti-HBs.269

A repeat hepatitis B vaccine series should be given to individuals who had an inadequate response to the initial vaccine series (i.e., anti-HBs less than 10 mIU/mL).105,213,269,278,279 Those who do not respond to the second series (i.e., total of 6 doses) are unlikely to respond to additional vaccine doses.105,213

Administration

Monovalent hepatitis B vaccine (recombinant) (Engerix-B^®, Recombivax HB^®) usually is administered by IM injection.132,133 Hepatitis B vaccine may be administered by subcutaneous injection, but only when necessary in individuals at risk of hemorrhage following IM injections (e.g., patients with thrombocytopenia or a bleeding disorder such as hemophilia).132,133 (See Individuals with Bleeding Disorders under Cautions: Precautions and Contraindications.) The vaccine should not be administered IV or intradermally;101,132,133 there is evidence that intradermal administration may be associated with reduced immunogenicity.101,207,209

The fixed-combination vaccine containing Haemophilus influenzae type b (Hib) and hepatitis B antigens (Hib-HepB; Comvax^®),251 the fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®),262 and the fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®)104 are administered by IM injection. These fixed-combination vaccines should not be given IV, intradermally, or subcutaneously.104,251,262

Prior to administration, the vaccine should be inspected visually for particulate matter and discoloration.104,133 The vaccine should be shaken well immediately prior to administration and should not be used if it contains particulates, appears discolored, or cannot be resuspended with thorough agitation.104,133

Monovalent hepatitis B vaccine or fixed-combination vaccines containing hepatitis B vaccine should not be diluted133 and should not be mixed with any other vaccine or solution.104

Depending on the age of the patient, the IM injection should be made into the deltoid or anterolateral thigh.101,105,131,132,133,213 To ensure delivery of vaccine into the muscle, IM injections should be made at a 90° angle to the skin using a needle size that is appropriate for the individual's age and body mass, the thickness of adipose tissue and muscle at the injection site, and the injection technique.131

In neonates and young children (up to 12 months of age), IM injections should be made into the anterolateral thigh.101,104,105,132,133,213,282 For children 1-2 years of age, IM injections should preferably be administered into the anterolateral thigh; the deltoid muscle is an alternative if the muscle mass is adequate.131 For adults, adolescents, and children 3 years of age or older, the deltoid is preferred, although the anterolateral thigh is an alternative.101,104,105,131,132,133,282

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.131 In addition, studies in adults indicate that the seroconversion rate may be lower when the vaccine is given into the buttocks rather than the deltoid.101,102,103,132,133,213,282 The vaccine should not be injected into or near blood vessels.132,133

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.105,131

Since syncope may occur following vaccination, vaccinees should be observed for approximately 15 minutes after the vaccine dose is administered.131 If syncope occurs, the patient should be observed until symptoms resolve.131 Syncope after vaccination occurs most frequently in adolescents and young adults.131

Monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) may be given simultaneously with hepatitis B immune globulin (HBIG) (using different syringes and different injection sites) when passive immunization is considered necessary in addition to active immunization with the vaccine (e.g., in neonates born to hepatitis B surface antigen-positive [HBsAg-positive] women, postexposure prophylaxis in certain individuals exposed to hepatitis B virus (HBV) or HBsAg-positive materials).105,112,131,213,281 Hepatitis B vaccine and HBIG should not be given in the same syringe and should not be injected at the same site.104

Hepatitis B vaccine may be given simultaneously with other age-appropriate vaccines during the same health-care visit (using different syringes and different injection sites).131,133,213 (See Drug Interactions: Vaccines.)

When multiple vaccines are administered during a single visit, administration of each preparation at a different anatomic site is preferred.131,213 In younger children, the thigh is the preferred injection site when more than 2 vaccines must be administered into a single limb.131,213 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.131,213 The deltoid may be used in older children and adults when more than one vaccine must be administered.131

Dosage

Dosage recommendations for hepatitis B vaccine vary depending on the specific preparation used, the recipient's age, the HBsAg status of the mother (for neonates), and the presence of underlying disease.105,125,132,133,213,217

Because the recommended doses for Recombivax HB® and Engerix-B® are different, dosage recommendations for the specific preparation used should be followed .101,105

Monovalent hepatitis B vaccines (Engerix-B^®, Recombivax HB^®) generally are considered interchangeable; therefore, if the hepatitis B vaccine series is started with one monovalent vaccine, it may be completed using a different vaccine given in the dosage recommended for that specific preparation.105,125,213

Only monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) should be used for the initial (birth) dose in neonates or infants younger than 6 weeks of age.105,112,213 However, the vaccine series can be completed using either a monovalent hepatitis B vaccine or an age-appropriate fixed-combination vaccine containing hepatitis B vaccine.105,112

The complete hepatitis B vaccine series must be administered to ensure optimal protection.105,213 Interruptions resulting in an interval between doses longer than recommended should not interfere with the final immunity achieved.104,105,213 In addition, it is not necessary to give additional doses or start the vaccination series over.104,105,213,282

If the hepatitis B vaccination series is interrupted after the initial dose, the second dose should be given as soon as possible (minimum interval between first and second dose is 4 weeks) and the third dose should be given at least 8 weeks after the second dose (minimum interval between first and third dose is 16 weeks).112,213,269,281,282 If only the third dose is delayed, it should be administered as soon as possible.213,269 Infants should receive the final dose at 24 weeks of age or older.112,213,282

Hepatitis B Vaccine (Engerix-B®)

Neonates and Infants

When Engerix-B^® is used in neonates and infants, primary immunization consists of 3 doses of the pediatric/adolescent formulation containing 10 mcg/0.5 mL.133,213

The manufacturer of Engerix-B^® recommends that 10-mcg doses be given at 0, 1, and 6 months of age.133 Alternatively, the manufacturer states that a 4-dose regimen consisting of 10-mcg doses given at 0, 1, 2, and 12 months can be used.133

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) recommend that full-term neonates born to HBsAg- positive women or women with unknown HBsAg status receive the initial 10-mcg dose of Engerix-B^® as soon as possible after birth (within 12 hours of birth) and the second and third 10-mcg doses at 1-2 and 6 months of age, respectively.105,112,213 The third dose should be given no earlier than 24 weeks of age.112,213 If the mother is known or found to be HBsAg-positive, the neonate also should receive a dose of HBIG as soon as possible after birth (within 12 hours of birth).105,112,213 (See Neonates and Infants under Uses: Primary Immunization.)

The ACIP, AAP, and AAFP recommend that full-term neonates born to HBsAg- negative women receive the initial 10-mcg dose of Engerix-B^® at birth (before hospital discharge) and the second and third 10-mcg doses at 1-2 and 6-18 months of age, respectively.105,112,213 If the vaccine is not given before hospital discharge, the initial dose should be given no later than 2 months of age.213 The third dose should be given no earlier than 24 weeks of age.112,213

Preterm neonates weighing less than 2 kg born to HBsAg- positive women or women with unknown HBsAg status should receive a dose of hepatitis B vaccine and a dose of HBIG as soon as possible after birth (within 12 hours of birth).105,213,221 This birth dose of hepatitis B vaccine should not be counted toward completion of the vaccine series; the usual 3-dose vaccine series should be initiated when the infant is 1 month of age.105,213,282

Preterm neonates weighing less than 2 kg born to HBsAg- negative women should be given the initial dose of hepatitis B vaccine at 1 month of a 105,213 however, the initial dose may be given at the time of hospital discharge (before 1 month of age) if the infant is medically stable and showing consistent weight gain.105,213 After the initial dose, the second and third doses of hepatitis B vaccine should be given at 1-2 and 6-18 months, respectively.213

Children 10 Years of Age or Younger

When Engerix-B^® is used in children 10 years of age or younger, primary immunization (including catch-up vaccination) usually consists of 3 doses of the pediatric/adolescent formulation containing 10 mcg/0.5 mL.133

The initial dose of 10 mcg should be given on a selected date and the second and third 10-mcg doses should be given at 1 and 6 months, respectively, after the initial dose.133 Alternatively, the manufacturer states that children 5-10 years of age can receive a 3-dose regimen consisting of 10-mcg doses given on a selected date and at 12 and 24 months after the initial dose or children 10 years of age or younger can receive a 4-dose regimen consisting of 10-mcg doses given on a selected dated and at 1, 2, and 12 months after the initial dose.133

Adolescents 11-19 Years of Age

When Engerix-B^® is used in adolescents 11-19 years of age, primary immunization (including catch-up vaccination) usually consists of 3 doses of either the pediatric/adolescent formulation containing 10 mcg/0.5 mL or the adult formulation containing 20 mcg/mL.133

If the pediatric/adolescent formulation is used, the initial dose of 10 mcg should be given on a selected date and the second and third 10-mcg doses should be given at 1 and 6 months, respectively, after the initial dose.133 Alternatively, in those 11-16 years of age, the manufacturer states that 10-mcg doses can be given on a selected date and at 12 and 24 months after the initial dose.133

If the adult formulation is used, the initial dose of 20 mcg should be given on a selected date and the second and third 20-mcg doses should be given at 1 and 6 months, respectively, after the initial dose.133 Alternatively, the manufacturer states that adolescents 11-19 years of age can receive a 4-dose regimen consisting of 20-mcg doses given on a selected date and at 1, 2, and 12 months after the initial dose.133

Adults 20 Years of Age or Older

When Engerix-B^® is used in adults 20 years of age or older, primary immunization consists of 3 doses of the adult formulation containing 20 mcg/mL.133,280,281

The initial dose of 20 mcg should be given on a selected date and the second and third 20-mcg doses should be given at 1-2 and 4-6 months, respectively, after the initial dose.133,281 Alternatively, a 4-dose regimen can be used consisting of 20-mcg doses given on a selected date and at 1, 2, and 12 months after the initial dose.133,281

Adults Undergoing Hemodialysis

When Engerix-B^® is used in adult hemodialysis patients, primary immunization consists of four 40-mcg doses using the adult formulation containing 20 mcg/mL.133,281 Each 40-mcg dose may be given using 1 or 2 injections.133,281

An initial 40-mcg dose should be given on a selected date followed by additional 40-mcg doses at 1, 2, and 6 months after the initial dose.133,281

Hepatitis B Vaccine (Recombivax HB®)

Neonates and Infants

When Recombivax HB^® is used in neonates and infants, primary immunization consists of 3 doses of the pediatric/adolescent formulation containing 5 mcg/0.5 mL.132,213

The manufacturer of Recombivax HB^® recommends that 5-mcg doses be given at 0, 1, and 6 months of age.132

ACIP, AAP, and AAFP recommend that full-term neonates born to HBsAg- positive women or women with unknown HBsAg status receive the initial 5-mcg dose of Recombivax HB^® as soon as possible after birth (within 12 hours of birth) and the second and third 5-mcg doses at 1-2 and 6 months of age, respectively.105,112,213 The third dose should be given no earlier than 24 weeks of age.112,213 If the mother is known or found to be HBsAg-positive, the neonate also should receive a dose of HBIG as soon as possible after birth (within 12 hours of birth).105,112,213 (See Neonates and Infants under Uses: Primary Immunization.)

The ACIP, AAP, and AAFP recommend that full-term neonates born to HBsAg- negative women receive the initial 5-mcg dose of Recombivax HB^® at birth (before hospital discharge) and the second and third 5-mcg doses at 1-2 and 6-18 months of age, respectively.105,112,213 If the vaccine is not given before hospital discharge, the initial dose should be given no later than 2 months of age.213 The third dose should be given no earlier than 24 weeks of age.112,213

Preterm neonates weighing less than 2 kg born to HBsAg- positive women or women with unknown HBsAg status should receive a dose of hepatitis B vaccine and a dose of HBIG as soon as possible after birth (within 12 hours of birth).105,213,221 This birth dose of hepatitis B vaccine should not be counted toward completion of the vaccination series; the usual 3-dose vaccination series should be initiated when the infant is 1 month of age.105,213,282

Preterm neonates weighing less than 2 kg born to HBsAg- negative women should be given the initial dose of hepatitis B vaccine at 1 month of a 105,213 however, the initial dose may be given at the time of hospital discharge (before 1 month of age) if the infant is medically stable and showing consistent weight gain.105,213 After the initial dose, the second and third doses of hepatitis B vaccine should be given at 1-2 and 6-18 months, respectively.213

Children 10 Years of Age or Younger

When Recombivax HB^® is used in children 10 years of age or younger, primary immunization (including catch-up vaccination) consists of 3 doses of the pediatric/adolescent formulation containing 5 mcg/0.5 mL.132

The manufacturer recommends that the initial 5-mcg dose be given on a selected date and the second and third 5-mcg doses given at 1 and 6 months, respectively, after the initial dose.132

Adolescents 11-19 Years of Age

When Recombivax HB^® is used in adolescents 11-19 years of age, primary immunization (including catch-up vaccination) usually consists of 3 doses of the pediatric/adolescent formulation containing 5 mcg/0.5 mL.132 Alternatively, the manufacturer states that 2 doses of the adult formulation containing 10 mcg/mL can be used for primary immunization in adolescents 11-15 years of age.132

If the pediatric/adolescent formulation is used, the manufacturer recommends that the initial 5-mcg dose be given on a selected date and the second and third 5-mcg doses be given at 1 and 6 months, respectively, after the initial dose.132

If the adult formulation is used in adolescents 11-15 years of age, a 10-mcg dose should be given on a selected date and a second 10-mcg dose given 4-6 months later.132

Adults 20 Years of Age or Older

When Recombivax HB^® is used in adults 20 years of age or older, primary immunization consists of 3 doses of the adult formulation containing 10 mcg/mL.132

The initial dose of 10 mcg should be given on a selected date and the second and third 10-mcg doses should be given at 1-2 and 4-6 months, respectively, after the initial dose.132,281

Adults Undergoing Hemodialysis

When Recombivax HB^® is used in predialysis/dialysis patients, primary immunization consists of 3 doses of the dialysis formulation containing 40 mcg/mL.132,281

The initial 40-mcg should be given on a selected date and the second and third 40-mcg doses should be given at 1 and 6 months, respectively, after the initial dose.132,281

Preexposure Vaccination in High-risk Groups

Travelers

Individuals requiring primary immunization against HBV prior to travel to areas with intermediate or high levels of endemic HBV (see Travelers under Uses: Preexposure Vaccination in High-risk Groups) should receive an initial dose of the vaccine on a selected date and a second and third dose 1 and 6 months, respectively, after the initial dose.101,125 To ensure completion of the 3-dose hepatitis B vaccine series and to provide optimal protection against HBV, the vaccine series should be initiated 6 months prior to travel.101,125 Because a partial series offers some protection, the series should be initiated even if it cannot be completed before travel.101,125

Alternatively, the CDC states that international travelers with time constraints that preclude completion of the usual 3-dose vaccination regimen may receive an optional accelerated schedule† with doses given at 0, 7, and 21 days.125 The US Food and Drug Administration (FDA) has approved this accelerated schedule for the fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®), but not for the monovalent hepatitis B vaccines (Engerix-B^®, Recombivax HB^®).125 Individuals who receive hepatitis B vaccine using the optional accelerated schedule also should receive a booster dose at 1 year after the initial dose of the series to promote long-term immunity.125

Alternatively, a 4-dose regimen can be used.133,213,281 The initial dose should be given on a selected date and the other 3 doses given at 1, 2, and 12 months after the initial dose.133,213,281 This regimen induces immunity more rapidly than the usual 3-dose regimen and may be useful when there are time constraints; the first 3 doses should be administered before travel (i.e., at 0, 1, and 2 months).101

Prevention of Perinatal HBV Infection

Neonates Born to HBsAg-positive Women

Combined passive immunization with HBIG and active immunization with hepatitis B vaccine is indicated to prevent perinatal HBV infection in neonates born to HBsAg- positive women.105,112,132,133,213

Neonates born to HBsAg- positive women should receive the first dose of hepatitis B vaccine within 12 hours of birth in conjunction with a dose of HBIG using different syringes and different injection sites.105,112,213,221,282 Only monovalent hepatitis B vaccine should be used for the birth dose.105,112,213,221,282 The hepatitis B vaccine series should then be completed by giving second and third doses of hepatitis B vaccine at 1-2 and 6 months (24 weeks) of age, respectively.105,112,213,221,282 The final dose of the vaccine series should be given at 24 weeks of age or older.112,213

For preterm neonates weighing less than 2 kg at birth, the initial (birth) dose of hepatitis B vaccine should not be counted as part of the 3-dose vaccine series.105,213,282 In addition to the birth dose, 3 vaccine doses beginning at 1 month of age (total of 4 doses) should be given.105,130,213

After completion of the hepatitis B vaccine series, these neonates should undergo serologic testing at 9-18 months of age (usually at the next well-child visit) to evaluate the success or failure of postexposure prophylaxis.105,112,213 (See Postvaccination Serologic Testing under Uses: Pre- and Postvaccination Serologic Testing.) If HBsAg is not detected and anti-HB levels are at least 10 mIU/mL, the child is protected and does not need additional doses of hepatitis B vaccine.105,213 If the child has anti-HBs concentrations less than 10 mIU/ mL and is HBsAg-negative, the ACIP and AAP state that a second 3-dose series of hepatitis B vaccine should be administered (initial dose on a selected date and a second and third dose at 1-2 and 6 months, respectively, after the initial dose).105,213

If the mother's HBsAg status is unknown at the time of delivery, the neonate or infant should receive a dose of monovalent hepatitis B vaccine within 12 hours of birth.105,112,132,213 In addition, the mother should be screened for HBsAg as soon as possible to determine the subsequent management of the infant, including the need to administer HBIG.105,112,213 If the mother of a full-term neonate or preterm neonate weighing more than 2 kg at birth is subsequently found to be HBsAg-positive, the infant should receive a dose of HBIG as soon as possible, but within 7 days of birth.105,112,132,133,213 If it is unlikely that the HBsAg status of the mother can be determined within the first 12 hours, the AAP recommends that preterm neonates weighing less than 2 kg receive a dose of HBIG (in addition to a dose of vaccine) within 12 hours of birth since the vaccine may be less immunogenic in these infants.105,213

Postexposure Prophylaxis of HBV Infection

Depending on the exposure circumstances, combined active immunization with hepatitis B vaccine and passive immunization with HBIG may be indicated for postexposure prophylaxis of HBV infection.269,281 When hepatitis B vaccine is indicated for postexposure prophylaxis in certain susceptible exposed individuals, including health-care personnel, sexual assault victims, or contacts of individuals with acute HBV infection (see Uses: Postexposure Prophylaxis), the usual 3-dose vaccine series should be used.130 If the hepatitis B vaccine series was initiated prior to the exposure, the remaining required doses should be administered as originally scheduled.130,269

Occupational Exposure in Susceptible Health-care Personnel

For postexposure prophylaxis of HBV infection in susceptible health-care workers following occupational exposures to blood and other body fluids that might contain HBV,269 combined active immunization with hepatitis B vaccine and passive immunization with HBIG may be indicated.269,281 (See Table 1 under Uses.)

If hepatitis B vaccine is indicated following occupational exposure to HBV in susceptible health-care personnel, the first dose should be administered as soon as possible (preferably within 24 hours) and the second and third doses administered 1 and 6 months, respectively, after the first dose.269,281 If the hepatitis B vaccine series was initiated prior to the exposure, the remaining required doses should be given as originally scheduled.269,281

Unvaccinated or Incompletely Vaccinated Sexual Assault Victims

For postexposure prophylaxis of HBV infection in susceptible victims of sexual assault, the hepatitis B vaccine series should be initiated or completed.130,281 The CDC recommends that the first dose of hepatitis B vaccine should be given at the time of the initial examination within 14 days of the assault (preferably within 24 hours) and the second and third doses given at 1-2 and 4-6 months, respectively, after the initial dose.130 If the perpetrator is HBsAg-positive, the sexual assault victim also should receive a dose of HBIG within 14 days of the assault (preferably within 24 hours).130,281

Unvaccinated or Incompletely Vaccinated Contacts of Individuals with Acute Hepatitis B Virus Infection

For postexposure prophylaxis in unvaccinated or incompletely vaccinated infants younger than 12 months of age exposed to acute HBV infection, active immunization with hepatitis B vaccine is indicated and passive immunization with HBIG also may be indicated.105 If the mother or other primary caregiver has acute HBV infection, a dose of HBIG should be given and primary immunization with hepatitis B vaccine should be initiated or completed.105 However, HBIG is not necessary if the infant already received 2 or more doses of hepatitis B vaccine.105

Previously unvaccinated sexual partners of individuals with acute HBV infection should receive postexposure prophylaxis with a dose of hepatitis B vaccine and a dose of HBIG as soon as possible, preferably within less than 24 hours.130,281 The hepatitis B vaccine series should then be completed.130 If the hepatitis B vaccine series was initiated prior to exposure, the remaining required doses should be given as originally scheduled.130

Individuals Wounded in Mass Casualty Settings

When HBV vaccine is indicated in a mass casualty setting for individuals who are unvaccinated or have an uncertain vaccination history (see Individuals Wounded in Mass Casualty Settings under Uses: Postexposure Prophylaxis), a dose of hepatitis B vaccine should be given as soon as possible (preferably within 24 hours) and not later than 7 days after the event.290 The age-appropriate hepatitis B vaccine series should then be completed at the time of discharge or during follow-up health-care visits.290

Revaccination or Booster Doses

The duration of protection and the need for booster doses after primary immunization with hepatitis B vaccine has not been fully determined.101,120,132,133,213,252,254,282

Antibodies induced by hepatitis B vaccine decline steadily with time125,213,282 and between 30-50% of vaccinees who develop an adequate antibody response to a 3-dose primary series will lose detectable antibody within 7 years, but protection against viremic infection and clinical disease appears to persist in adults and children despite declining antibodies.101,149,150,151,152 (See Pharmacology: Duration of Immunity.) Therefore, ACIP states that booster doses are not routinely recommended in immunocompetent individuals who were vaccinated as infants, children, adolescents, or adults and routine serologic testing to assess antibody levels in these individuals are only necessary in certain circumstances.213,281

The ACIP and AAP state that routine annual serologic testing to monitor anti-HBs levels and determine the need for booster doses is indicated in hemodialysis patients since the immunologic response in these individuals is usually less and of shorter duration than that in healthy individuals, and protection may persist only as long as the anti-HBs level is at least 10 mIU/mL.101,105,132,133,213,281 The ACIP and AAP state that hemodialysis patients should receive a booster dose of vaccine when anti-HBs levels decline to less than 10 mIU/mL.105,213,281

For other immunocompromised individuals (e.g., HIV-infected individuals, hematopoietic stem-cell transplant recipients, individuals receiving chemotherapy or immunosuppressive therapy), the need for booster doses has not been determined.213,281 The ACIP and other experts recommend that annual anti-HBs testing be done in such individuals and that booster doses of the vaccine be considered when anti-HBs levels decline to less than 10 mIU/mL.213,281,278,279

Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens

Hib-HepB (Comvax®)

The commercially available fixed-combination vaccine containing Hib and hepatitis B antigens (Hib-HepB; Comvax^®) is used only for primary immunization in infants 6 weeks to 15 months of age.251

Comvax^® is administered in 0.5-mL doses.251

For primary immunization in infants born to HBsAg- negative women, Comvax^® is given in a series of 3 doses, ideally at 2, 4, and 12-15 months of age.251 If the recommended schedule cannot be followed exactly, the interval between the first 2 doses should be at least 6 weeks and the interval between the second and third dose should be as close as possible to 8-11 months.251

Infants who received a dose of monovalent hepatitis B vaccine at or shortly after birth may receive primary immunization with Comvax^® doses given at 2, 4, and 12-15 months of age.251 There are no data to support the use of a 3-dose series of Comvax^® in infants who previously received more than one dose of monovalent hepatitis B vaccine.251 However, Comvax^® may be administered to children otherwise scheduled to receive a dose of hepatitis B vaccine and a dose of Hib conjugate vaccine (PedvaxHIB^®).251

When primary immunization is initiated in older infants (in the age range of 15 months of age or younger), the immunization schedule for Comvax^® should be considered on an individual basis since the number of doses of PedvaxHIB^® required for primary immunization depends on the age of the child.251 The manufacturer's recommendations should be consulted if use of Comvax^® is being considered for infants who have not been immunized in early infancy according to the recommended primary immunization schedule.251

DTaP-HepB-IPV (Pediarix®)

The fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®) is used only in infants and children 6 weeks of age through 6 years of age.104

Pediarix^® is administered in 0.5-mL doses.104

For primary immunization, Pediarix^® is given in a series of 3 doses at 6- to 8-week intervals (preferably 8 weeks).104 The initial dose usually is given at 2 months of age, but may be given as early as 6 weeks of age.104

Pediarix^® may be used to complete the diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP) vaccine series in infants and children younger than 7 years of age who are scheduled to receive the other components of the vaccine.104

Pediarix^® may be used to complete the hepatitis B vaccine series or the IPV vaccine series in infants and children younger than 7 years of age who are scheduled to receive the other components of the vaccine.104

The manufacturer states that Pediarix^® is indicated only in infants born to HBsAg- negative women.104 The ACIP states that Pediarix^® also may be used to complete the hepatitis B vaccination series in infants born to HBsAg- positive women†.213

To complete the DTaP and poliovirus primary vaccine series in children who received a 3-dose primary series of Pediarix^®, a dose of Infanrix^® (DTaP) should be given at 15-18 months of age and a dose of monovalent IPV (IPOL^®) should be given at 4-6 years of age.104

HepA-HepB (Twinrix®)

The fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) is used only for primary immunization in adults 18 years of age or older.262 Twinrix^® is not indicated in infants, children, or adolescents younger than 18 years of age.262

Twinrix^® is given in 1-ml doses.262

For primary immunization, adults 18 years of age or older should receive a series of 3 doses of Twinrix^® given at 0, 1, and 6 months.262,280 Alternatively, if an accelerated dosing schedule is needed, a series of 3 doses may be given on days 0, 7, and 21-30 and a booster dose given at 12 months.262,280

Hepatitis B Vaccine

Hepatitis B vaccine (recombinant) generally is well tolerated.115,116,117,121,132,133,234 Adverse reactions to the vaccine are infrequent, mild, and transient.101,132,133,234 The most common adverse effects are local effects at the site of injection.101,132,133,234

Local Effects

Adverse local effects, including soreness,115,119,121,126,132,133 pain,117,132,133,234 induration,133 tenderness,132 pruritus,117,132,133 erythema,119,132,133 ecchymosis,132,133 swelling,117,132,133 warmth,132 burning,117 and nodule formation,132 have been reported in 10-29% of individuals who received monovalent hepatitis B vaccine.115,119,121,126,132,133,234

Systemic Effects

Mild systemic adverse effects have been reported in about 15% of patients who received monovalent hepatitis B vaccine.132 The most frequently reported systemic effects are fatigue,115,121,126,132,133 weakness,132 headache,115,121,126,132,133 fever (i.e., 37.8°C or higher),115,116,119,121,132,133,234 vertigo/dizziness,132,133 and malaise;126,132,133 these effects have been reported in at least 1% of patients who received the vaccine.132,133 Nausea,132,133 diarrhea,121,132,133 pharyngitis,132 and symptoms of upper respiratory illnesses115,132,133 have also been reported in at least 1% of individuals who received hepatitis B vaccine.132,133

Sweating, achiness, sensation of warmth, lightheadedness, chills, flushing, somnolence,133 disturbed sleep (e.g., insomnia), irritability,133 agitation,133 arthralgia (including monoarticular), myalgia, and pain/stiffness in the back, neck, arm, and/or shoulder have been reported in less than 1% of individuals who received hepatitis B vaccine.132,133 Other adverse effects that have been reported with a frequency of less than 1% include vomiting,132,133 GI disturbances,115,121 constipation,133 abdominal pains/cramps,132,133 dyspepsia,132 anorexia/diminished appetite,132,133 pruritus,132,133 rash,116,132,133 lupus-like syndrome,132 vasculitis,132 polyarteritis nodosa,132 alopecia,132 arthritis,132 pain in the extremities,132 petechiae,133 eczema,132 erythema,132,133 urticaria,132 rhinitis,132 influenza-like symptoms,132,133 cough,132 lymphadenopathy,132,133 nosebleed,115 earache,132 dysuria,132 tachycardia/palpitations,133 and hypotension.132,133

Peripheral neuropathy (including Bell's palsy and hypoesthesia), muscle weakness, paresthesia, Guillain-Barré syndrome, transverse myelitis, migraine, syncope, paresis, tinnitus, conjunctivitis, keratitis, visual disturbances, optic neuritis, and multiple sclerosis have been reported in individuals who received hepatitis B vaccine; however, a definite causal relationship was not established.132,133,187 Although a possible association between Guillain-Barré syndrome and administration of the first dose of plasma-derived vaccine (no longer commercially available in the US) was observed during postmarketing surveillance, a causal relationship was not definitely established.101,134,234 In addition, use of the recombinant vaccine in an estimated 2.5 million adults between 1986-1990 has revealed no evidence of an association between receipt of this vaccine and Guillain-Barré syndrome.234 Other infrequent adverse effects reported with the recombinant vaccine include thrombocytopenia,133 liver function test abnormalities,133 eczema,133 purpura,133 increased erythrocyte sedimentation rate,132 and herpes zoster.133

Anaphylaxis and symptoms of immediate hypersensitivity, including rash, pruritus, urticaria, edema, angioedema, dyspnea, chest discomfort, bronchospasm (including asthma-like symptoms), palpitation, or symptoms consistent with a hypotensive episode, have been reported within the first few hours after administration of hepatitis B vaccine.132 Based on data from the Vaccine Adverse Events Reporting System (VAERS), the incidence rate for anaphylaxis with hepatitis B vaccine appears to be low (i.e., approximately one case per 600,000 doses distributed), and only 2 of the cases were in children.234 In British Columbia, only one case of anaphylaxis was reported among 100,763 children 10-11 years of age who received the recombinant vaccine, and no cases were reported among 166,757 children in New Zealand who received the plasma-derived vaccine (no longer commercially available in the US).234 Although none of these cases was fatal, the vaccine can cause life-threatening hypersensitivity reactions.234,235 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

An apparent serum-sickness reaction with delayed onset has been reported days to weeks after administration hepatitis B vaccine; this reaction consists of arthralgia and/or arthritis (usually transient), fever, and dermatologic reactions such as urticaria, erythema multiforme (including Stevens-Johnson syndrome), ecchymoses, and erythema nodosum.132,133 There is no evidence to date that use of the vaccine causes adverse effects related to changes in titers of antibodies to yeast-derived antigens.115,117 However, up to 5% of the protein contained in hepatitis B vaccine is yeast-derived, and further clinical experience is needed to confirm that sensitization to yeast proteins does not occur following administration of the vaccine.101,119,132,133

DTaP-HepB-IPV (Pediarix®)

The most common adverse effects reported to date with the fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®) are local reactions at the injection site (pain, erythema, swelling), loss of appetite, drowsiness, fever, and fussiness.104

In a US clinical study in infants who received a 3-dose primary series (at 2, 4, and 6 months of age) of either the fixed-combination vaccine (DTaP-HepB-IPV; Pediarix^®) or control vaccines (IPV, DTaP [Infanrix^®], and hepatitis B vaccine [Engerix-B^®] administered concomitantly at separate sites), adverse effects occurring within 4 days of vaccination were solicited from parents and included local injection site reactions (pain, redness, swelling) and systemic effects (fever, drowsiness, irritability/fussiness, loss of appetite).104 All infants also received Haemophilus influenzae type b (Hib) vaccine and pneumococcal 7-valent conjugate vaccine concomitantly at separate sites.104 There was a higher incidence of redness and swelling with the fixed-combination vaccine compared with concomitant administration of all the individual components of the vaccine at separate sites.104 There also was a higher incidence of fever (38°C or higher) after each of the 3 doses of the fixed-combination vaccine compared with when the vaccines were given separately.104

Hib-HepB (Comvax®)

In clinical studies in healthy infants 6 weeks to 15 months of age, the fixed-combination vaccine containing Hib and hepatitis B antigens (Hib-HepB; Comvax^®) generally was well tolerated and adverse effects were similar in type and frequency to those reported in infants who received monovalent Hib vaccine (PedvaxHIB^®) and monovalent hepatitis B vaccine (Recombivax HB^®) concomitantly at separate sites.251

In infants who received Hib-HepB (Comvax^®), local effects at the injection site occurring within 5 days after a vaccine dose included pain/soreness in 23.9-34.5%, erythema in 22.4-27.2%, and swelling/induration in 27.2-30.4%.251

In infants who received Hib-HepB (Comvax^®), systemic effects occurring within 5 days after a dose included irritability in 32.2-57%, somnolence in 21.1-49.5%, crying (unusual, high-pitched) in 2.9-10.6%, and fever (38.3-39°C) in 10.5-14.2%.251

HepA-HepB (Twinrix®)

The fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) generally is well tolerated in adults and adverse effects reported with the vaccine have been mild and transient (usually persisting for no longer than 48 hours).262 Adverse effects reported with the fixed-combination vaccine were similar to those reported when monovalent hepatitis A virus vaccine inactivated (Havrix^®) and monovalent hepatitis B vaccine (Engerix-B^®) were administered simultaneously at different sites.262 No increase in the frequency of adverse effects has been reported with successive doses of the fixed-combination vaccine.262 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).262

Adverse local reactions reported in adults receiving HepA-HepB (Twinrix^®) include soreness (35-41%), erythema (8-11%), and swelling (4-6%).262

Adverse systemic reactions reported in adults receiving HepA-HepB (Twinrix^®) include upper respiratory tract infections, sweating, weakness, flushing, influenza-like symptoms, headache, fatigue, diarrhea, nausea, fever, vomiting, syncope, abdominal pain, anorexia, arthralgia, myalgia, back pain, migraine, paresthesia, vertigo, somnolence, insomnia, irritability, agitation, and dizziness.262

Precautions and Contraindications

Monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) is contraindicated in individuals hypersensitive to any ingredient in the vaccine, including yeast.132,133 Hepatitis B vaccine also is contraindicated in individuals with a history of previous hypersensitivity to any hepatitis B vaccine.133

The fixed-combination vaccine containing Hib and hepatitis B antigens (Hib-HepB; Comvax^®) is contraindicated in individuals hypersensitive to any vaccine component, including yeast.251

The fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®) is contraindicated in individuals with a history of hypersensitivity to any ingredient in the vaccine (e.g., yeast, neomycin, polymyxin B) or a history of serious allergic reaction (e.g., anaphylaxis) temporally associated with a previous dose of the vaccine or any vaccine component.104 In addition, the vaccine is contraindicated (because of the pertussis antigen) in individuals with encephalopathy (e.g., coma, decreased consciousness, prolonged seizures) within 7 days of a previous dose of vaccine containing pertussis antigens that could not be attributed to another identifiable cause and in individuals with progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy.104

The fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) is contraindicated in individuals hypersensitive to any ingredient in the vaccine, including the hepatitis A virus vaccine inactivated component (Havrix^®), the hepatitis B vaccine component (Engerix-B^®), yeast, or neomycin.262 The vaccine also is contraindicated in individuals with previous hypersensitivity reactions to Twinrix^® or monovalent hepatitis A or hepatitis B vaccines.262

Sensitivity Reactions

Prior to administration of hepatitis B vaccine or fixed-combination vaccines containing hepatitis B vaccine, all known precautions should be taken to prevent adverse reactions, including a review of the patient's history with respect to possible sensitivity to the vaccine or to similar vaccines.104,132,133,262

Anaphylaxis and symptoms of immediate hypersensitivity have been reported with hepatitis B vaccine.132 (See Systemic Effects under Cautions: Hepatitis B Vaccine.)

Epinephrine and other appropriate agents should be available for immediate treatment of an anaphylactoid reaction if it occurs.132,133,262 Individuals with symptoms of hypersensitivity after a previous dose should not receive additional vaccine doses.132,133,234

Yeast Allergy

The manufacturing process for hepatitis B vaccine involves baker's yeast ( Saccharomyces cerevisiae )104,132,133,251,262 and monovalent hepatitis B vaccine and fixed-combination vaccines containing hepatitis B vaccine contain up to 5% yeast protein.104,132,133,262

The manufacturers state that monovalent and fixed-combination vaccines containing hepatitis B vaccine should not be used in individuals with yeast allergy.104,132,133,251,262 There is a theoretical risk of an allergic reaction in individuals allergic to yeast, but there is no evidence to date that such reactions have occurred when hepatitis B vaccine was used in such individuals.101,119,132,133,213,281

Allergy to Neomycin or Other Anti-infectives

The fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®) contains trace amounts of neomycin sulfate (not exceeding 0.05 ng) and polymyxin B (not exceeding 0.01 ng).104 The fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) contains trace amounts of neomycin sulfate (not exceeding 20 ng).262 The manufacturers state that Pediarix^® and Twinrix^® are contraindicated in individuals hypersensitive to these anti-infectives.104,262

Neomycin allergy usually results in delayed-type (cell-mediated) hypersensitivity reactions manifested as contact dermatitis.105,131 The ACIP and 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 a delayed-type hypersensitivity reaction to neomycin if benefits of vaccination outweigh risks.105,131

Latex Allergy

Some packaging components (e.g., needle cover, syringe plunger) of the single-dose prefilled syringes of Engerix-B^® or single-dose prefilled syringes of DTaP-HepB-IPV (Pediarix^®) contain dry natural latex.104,133 The stopper on vials of Comvax^® contains natural rubber latex.251

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;275,276,277 rarely, hypersensitivity reactions to natural latex proteins have been fatal.275,276,277

The ACIP states that vaccines supplied in vials or syringes containing dry natural rubber or natural rubber latex may be administered to individuals with latex allergies other than anaphylactic allergies (e.g., history of contact allergy to latex gloves), but should not be used in those with a history of severe (anaphylactic) allergy to latex, unless the benefits of vaccination outweigh the risk of a potential allergic reaction.131

Individuals with Altered Immunocompetence

The recommendations regarding use of hepatitis B vaccine in individuals with altered immunocompetence generally are the same as those for individuals who are not immunocompromised.220 Hepatitis B vaccine may be used in immunocompromised individuals, including those who have human immunodeficiency virus (HIV) infection or immunocompromised because of congenital immunodeficiency, leukemia, lymphoma, generalized malignancy, or therapy with alkylating agents, antimetabolites, radiation, or corticosteroids.213,220,278,279 The vaccine also may be used in solid organ or hematopoietic stem cell transplant recipients, patients with asplenia, renal failure, diabetes, alcoholism, or alcoholic cirrhosis.213,220 The possibility that the immune response to the vaccine may be reduced in these individuals should be considered.101,127,128,133,212,213,220,278,279

Recommendations regarding the use of hepatitis B vaccine in HIV-infected individuals are the same as those for individuals who are not HIV-infected.278,279,280 Some HIV-infected individuals may not have a satisfactory response to hepatitis B vaccine and anti-HBs may persist for shorter periods of time in HIV-infected individuals.101,127,128,129,212,220,278,279 Immunogenicity of higher than usual vaccine doses or additional vaccine doses in HIV-infected individuals have not been fully evaluated; therefore, firm recommendations cannot be made regarding use of such doses in these individuals.101,147,148,153,160,220,278,279 (See Individuals with Altered Immunocompetence under Uses: Primary Immunization.)

The anti-HBs response generally is lower and persists for shorter periods in hemodialysis patients than in healthy adults.101,132,133 Only 50-86% of hemodialysis patients reportedly develop protective levels of anti-HBs after receiving a 3-dose vaccine series consisting of 40-mcg doses of hepatitis B vaccine (i.e., 10 mIU/mL or greater measured 1-2 months after completion of the hepatitis B vaccine series).132,133 Therefore, larger vaccine doses (e.g., 2-4 times the usual adult dose) are required to induce protective antibody levels in a large proportion of patients undergoing hemodialysis.101,132,133,136,137,138,139,140,141,142,143,144,145,146 (See Dosage and Administration: Dosage.)

Concomitant Illness

The decision whether to administer or delay administration of 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.131,132,133,217 The ACIP states that a minor acute illness, such as mild diarrhea or mild upper respiratory tract infection (with or without fever), generally does not preclude vaccination, but vaccination should be deferred in individuals with moderate or severe acute illness (with or without fever).131,217 Some manufacturers state that the vaccine may be given to individuals with acute infection or febrile illness if withholding the vaccine poses a greater risk to the patient.132

The manufacturer of hepatitis B vaccine (Recombivax HB^®) recommends that the vaccine be used with caution and appropriate care in individuals with severely compromised cardiopulmonary status or in others in whom a febrile or systemic reaction could pose a significant risk.132

Exacerbation of multiple sclerosis has been reported following administration of hepatitis B vaccine or other vaccines; however, a causal relationship has not been established.133,282 One manufacturer states that the benefits of hepatitis B vaccination should be weighed against the risk of exacerbation of multiple sclerosis.133

Individuals with Bleeding Disorders

Hepatitis B vaccine and fixed-combination vaccines containing hepatitis B vaccine should be administered IM with caution to individuals with thrombocytopenia or a bleeding disorder (e.g., hemophilia) or in those receiving anticoagulant therapy, since bleeding may occur following IM administration in these individuals.100,131,132,133,262

The manufacturers of monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) state that the vaccine can be administered by subcutaneous rather than IM injection in individuals at risk of hemorrhage (e.g., hemophilia patients).132,133 However, subcutaneous administration of hepatitis B vaccine has been associated with reduced antibody response.133 In addition, an increased incidence of local reactions, including subcutaneous nodules, has been reported following subcutaneous administration of other aluminum-adsorbed vaccines; therefore, hepatitis B vaccine should be administered by subcutaneous injection only in individuals at risk for hemorrhage following IM administration.132,133

The ACIP states that vaccines 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.100,131 In these cases, a fine needle (23 gauge) should be used to administer the vaccine and firm pressure should be applied to the injection site (without rubbing) for at least 2 minutes.100,131,213 If IM administration is used in individuals with a bleeding disorder who are receiving antihemophilic factor or other similar therapy, the IM dose can be scheduled shortly after a dose of such therapy to minimize the risk of bleeding.100,131,213 The individual and/or their family should be instructed concerning the risk of hematoma from the injection.100,131

Use of Combination Vaccines

When the fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®), the fixed-combination vaccine containing Hib and hepatitis antigens (Hib-HepB; Comvax^®), or the fixed-combination vaccine containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) is used, the adverse effects, precautions, and contraindications associated with each antigen should be considered.104,251,262

For more complete information regarding the adverse effects, precautions, and contraindications associated with use of vaccines that contain diphtheria, tetanus, and pertussis antigens, see Cautions in Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed/Tetanus Toxoid and Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed 80:08.

For more complete information regarding the adverse effects, precautions, and contraindications associated with use of vaccines that contain Hib antigens, see Cautions in Haemophilus b Vaccine 80:12.

For more complete information regarding the adverse effects, precautions, and contraindications associated with use of vaccines that contain poliovirus antigens, see Cautions in Poliovirus Vaccine Inactivated 80:12.

For more complete information regarding the adverse effects, precautions, and contraindications associated with use of vaccines that contain hepatitis A antigens, see Cautions in Hepatitis A Virus Vaccine Inactivated 80:12.

Limitations of Vaccine Effectiveness

Hepatitis B vaccine may not protect all vaccine recipients against HBV infection,132,133 especially individuals who have not achieved protective titers of anti-HBs (i.e., 10 mIU/mL or greater measured 1-2 months after completion of the hepatitis B vaccine series).132,133

Unrecognized HBV infection may be present in some individuals at the time of vaccination since the infection has an incubation period of 6 weeks to 6 months and hepatitis B vaccine may not prevent infection in such individuals.130,132,133,282

Monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) provides protection only against HBV.132,133 The fixed-combination vaccine containing hepatitis A virus vaccine and hepatitis B vaccine (Twinrix^®) provides protection only against hepatitis A virus (HAV) and HBV.262 Monovalent hepatitis B vaccine and fixed-combination vaccines containing hepatitis B vaccine generally will also prevent hepatitis D virus (HDV) infection since HDV occurs only as a coinfection or superinfection in patients with HBV infection.105,133 These vaccines do not provide protection against other hepatitis viruses (e.g., hepatitis C virus [HCV], hepatitis E virus [HEV]).132,133,262

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and a reduced immune response in vaccinees.286 Hepatitis B vaccine should not be administered if it has been mishandled or has not been stored at the recommended temperature.286 (See Chemistry and Stability: Stability.)

All vaccines should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.286 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.131,286

Pediatric Precautions

Monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) is highly immunogenic in infants and children.132,133 In neonates, passively acquired maternal anti-HBs antibodies do not appear to interfere with the active immune response to hepatitis B vaccine.132,133 However, there is some evidence that the seroconversion rate is lower in low-birthweight infants when the initial dose of hepatitis B vaccine is administered shortly after birth than when it is administered when the infant is older or weighs more than 2 kg.105,131,221

Safety and efficacy of Recombivax^® HB Dialysis Formulation have not been established in children.132

Safety and efficacy of Hib-HepB (Comvax^®) have not been established in infants younger than 6 weeks of age or in infants or children older than 15 months of age.251

Safety and efficacy of DTaP-HepB-IPV (Pediarix^®) have not been established in infants younger than 6 weeks of age or in children 7 years of age or older.104

Safety and efficacy of HepA-HepB (Twinrix^®) have not been established in children younger than 18 years of age.262

Geriatric Precautions

Clinical studies of monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) did not include sufficient numbers of individuals 65 years of age or older to determine whether these individuals respond differently than younger individuals.132,133 Other reported clinical experience indicates that hepatitis B vaccine may be less immunogenic in individuals 65 years of age or older than in younger individuals.132,133 No overall differences in safety have been reported between geriatric individuals and younger adults.132,133

Clinical studies of 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.262

Hib-HepB (Comvax^®) and DTaP-HepB-IPV (Pediarix^®) are not indicated for use in adults, including geriatric adults.104,251

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of hepatitis B vaccine132,133 or fixed-combination vaccines containing hepatitis B vaccine.251,262

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with hepatitis B vaccine.132,133 It is not known whether the vaccine can cause fetal harm when administered to a pregnant woman.132,133 Hepatitis B vaccine should be used during pregnancy only when clearly needed.132,133

Because of the potential risks from exposure to HBV infection in a pregnant woman and the potential for development of chronic infection in the neonate, pregnancy is not considered a contraindication to use of hepatitis B vaccine when clearly needed.101,105,125,213,280,290 Since hepatitis B vaccine contains only noninfectious hepatitis B surface antigen (HBsAg) particles, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that the theoretical risk to the fetus from the vaccine should be negligible.213

HepA-HepB (Twinrix^®) should be used during pregnancy only when clearly needed.262 Clinicians are encouraged to register pregnant women who receive Twinrix^® with the manufacturer's vaccination pregnancy registry at 888-452-9622.262

Hib-HepB (Comvax^®) and DTaP-HepB-IPV (Pediarix^®) are not indicated for use in women of childbearing age.104,251

Fertility

It is not known whether hepatitis B vaccine or fixed-combination vaccines containing hepatitis B vaccine affect fertility.104,132,133,251,262

Lactation

It is not known whether the antigens contained in hepatitis B vaccine are distributed into milk.132,133 The manufacturers state that hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) and HepA-HepB (Twinrix^®) should be used with caution in nursing women.132,133,262

Although specific data are not available, the ACIP, CDC, and AAP state that breast-feeding is not a contraindication to administration of hepatitis B vaccine and lactating women should receive the vaccine as recommended for other adults.105,125,131

Anti-infective Agents

Concurrent use of anti-infective agents generally does not affect the immune response to inactivated vaccines, including hepatitis B vaccine (recombinant).131

Blood Products

Hepatitis B vaccine does not need to be deferred in individuals who have received a blood transfusion or other blood products.290

Immune Globulins

There is no evidence that immune globulin (immune globulin IM [IGIM], immune globulin IV [IGIV]) or specific immune globulin (hepatitis B immune globulin [HBIG], rabies immune globulin [RIG], tetanus immune globulin [TIG], varicella zoster immune globulin [VZIG]) interferes with the immune response to inactivated vaccines.131 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that inactivated vaccines such as hepatitis B vaccine may be given simultaneously with (using different syringes and different injection sites) or at any interval before or after immune globulin preparations.131

Hepatitis B Immune Globulin

Passively acquired antibody to hepatitis B surface antigen (anti-HBs), which is present in HBIG, does not appear to interfere with the active immune response stimulated by hepatitis B vaccine.132,133 Clinical studies in neonates indicate that the immune response to hepatitis B vaccine is not altered by concomitant use of HBIG.132,133

When combined active immunization with hepatitis B vaccine and passive immunization with HBIG is indicated, the first dose of vaccine should be administered simultaneously with HBIG (using different syringes and different injection sites).105,112,132,133,213,269,281 The manufacturer of HepaGam B^® states that HBIG administered simultaneously with or up to 1 month before hepatitis B vaccine does not appear to impair the active immune response to the vaccine.289

Immunosuppressive Agents

Individuals receiving immunosuppressive therapy (e.g., corticotropin, corticosteroids, alkylating agents, antimetabolites, radiation) may have a reduced response to hepatitis B vaccine.101,133,220 The ACIP recommends that vaccines generally be administered 2 weeks prior to initiation of immunosuppressive therapy or deferred until at least 3 months after such therapy is discontinued.131,133,217,220 Individuals receiving immunosuppressive therapy may require larger than usual doses of hepatitis B vaccine in order to develop adequate circulating antibody levels.101 (See Dosage and Administration: Dosage.)

Vaccines

Although specific studies may not be available evaluating concurrent administration of hepatitis B vaccine with each antigen, simultaneous administration with other age-appropriate vaccines, including live virus vaccines, toxoids, or inactivated or recombinant vaccines, during the same health-care visit is not expected to affect immunologic responses or adverse reactions to any of the preparations.105,131

Immunization with hepatitis B vaccine can be integrated with immunization against diphtheria, tetanus, pertussis, Haemophilus influenzae type b (Hib), hepatitis A, human papillomavirus (HPV), influenza, poliovirus, measles, mumps, rubella, rotavirus, meningococcal disease, pneumococcal disease, and varicella.112,105,131 However, unless combination vaccines appropriate for the age and vaccination status of the recipient are used, each parenteral vaccine should be administered using a different syringe and different injection site.131

Inactivated Vaccines and Toxoids

Since hepatitis B vaccine is a noninfectious inactivated preparation, concomitant administration with killed vaccines is not likely to cause interference with the immune response to these vaccines.131 However, hepatitis B vaccine should not be mixed in the same syringe with any other vaccine since compatibility between products has not been demonstrated and injections should preferably be given at different sites.105,214

Diphtheria and Tetanus Toxoids and Pertussis Vaccines

Hepatitis B vaccine may be administered concomitantly (at a different site) with diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP).105,112,131,215,216 Alternatively, hepatitis B vaccine is commercially available in a fixed-combination vaccine containing DTaP, hepatitis B vaccine, and poliovirus vaccine inactivated (IPV) (DTaP-HepB-IPV; Pediarix^®).104 Depending on the age and vaccination status of the child, this combination vaccine can be used instead of separate injections of DTaP and hepatitis B vaccine when indicated and if there are no contraindications to any of the individual components.104,112,213 (See Uses: Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens.) Extemporaneous preparations of hepatitis B vaccine mixed with commercially available monovalent vaccines containing these antigens should not be prepared since compatibility between these preparations has not been demonstrated.214

Concomitant administration of tetanus toxoid and reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap) (Adacel^®) and hepatitis B vaccine (Recombivax HB^®) did not result in reduced antibody responses to either vaccine.287 Therefore, Tdap may be administered simultaneously with (using different syringes and injection sites) or at any time before or after hepatitis B vaccine.105,131

Haemophilus b Vaccines

Monovalent hepatitis B vaccine may be administered concomitantly with monovalent Hib vaccine; however, the vaccines should be administered at different sites using separate syringes.105,112,214,216 Alternatively, hepatitis B vaccine is commercially available in a fixed-combination vaccine that contains Hib vaccine and hepatitis B vaccine (Hib-HepB; Comvax^®) and this combination vaccine can be used whenever a dose of hepatitis B vaccine and a dose of Hib vaccine are both indicated in an infant 6 weeks to 15 months of age.213,251 (See Uses: Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens.) However, extemporaneous vaccine combinations of hepatitis B vaccine and Hib vaccine should not be prepared by admixing commercially available monovalent hepatitis B vaccine and monovalent Hib vaccine.214,216

Hepatitis A Vaccine

Studies have shown that monovalent hepatitis A virus vaccine inactivated and monovalent hepatitis B vaccine can be administered simultaneously at different sites using separate syringes without interfering with the immune response to either vaccine.263,264,265 Alternatively, hepatitis B vaccine and hepatitis A virus vaccine inactivated may be given simultaneously as the commercially available fixed-combination vaccine (HepA-HepB; Twinrix^®).262 (See Uses: Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens.)

Human Papillomavirus Virus Vaccine

Concomitant administration of the complete primary immunization series (3 doses each) of quadrivalent HPV vaccine (HPV4) and hepatitis B vaccine (at different injection sites) during the same health-care visit in women 16-23 years of age did not decrease the antibody response to either vaccine and did not increase the incidence of clinically important adverse effects compared with administration during separate visits.283,284 Therefore, HPV vaccine and hepatitis B vaccine may be administered concomitantly using different syringes and different injection sites.284

Influenza Virus Vaccine

Hepatitis B vaccine may be administered concurrently with influenza virus vaccine inactivated (TIV) at a different site using a separate syringe.105

Pneumococcal Vaccines

Hepatitis B vaccine should not interfere with the response to pneumococcal 23-valent polysaccharide vaccine (PPSV23).259,260

Hepatitis B vaccine may be administered concurrently with pneumococcal 7-valent conjugate vaccine (PCV13) at a different site using a separate syringe.259,260

Live Vaccines

Although specific studies evaluating simultaneous administration of hepatitis B vaccine and measles, mumps, and rubella virus vaccine live (MMR) or varicella virus vaccine live are not available, these vaccines may be administered concomitantly.105,125,131,215,216 However, hepatitis B vaccine should not be mixed in the same syringe with any other vaccine since compatibility between products has not been demonstrated and injections should preferably be given at different sites.105,214 If hepatitis B vaccine is administered simultaneously with another vaccine and if injections are administered into the same anterolateral thigh or deltoid, the injections must be given one or more inches apart.214

Hepatitis B vaccine can be given concurrently with yellow fever vaccine using different syringes and different injection sites without affecting safety or immunogenicity.131,217

Pharmacology

Hepatitis B vaccine (recombinant) stimulates active immunity to hepatitis B virus (HBV) infection.282 Hepatitis B surface antigen (HBsAg), which is present in hepatitis B vaccine, promotes the production of antibody to HBsAg (anti-HBs); anti-HBs neutralizes HBV so that its infective or pathogenic properties are inhibited.282

Protection against HBV infection is virtually complete in immunocompetent individuals who develop adequate antibody levels after immunization with hepatitis B vaccine.101,213,281,282 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) defines a protective level of anti-HBs as 10 mIU/mL or greater measured 1-2 months after completion of the hepatitis B vaccine series.101,213,281 While only anti-HBs levels expressed in mIU/mL and determined against the World Health Organization (WHO) anti-HBs reference preparation have been standardized, the ACIP in 1987 suggested that the minimum anti-HBs level of 10 mIU/mL is approximately equivalent to 10 sample ratio units (SRU) determined by radioimmunoassay (RIA) or a positive enzyme immunoassay (EIA) because of similarities in the degree of immunogenicity represented by such determinations.218,282 The SRU value of 10 was based on results of routine screening and hepatitis B vaccine efficacy studies conducted in the early 1980s and the EIA indicator was based on the manufacturers' recommended positive threshold for such immunoassays.218 More recently, the Centers for Disease Control and Prevention (CDC) compared the predictive level of these latter tests relative to the WHO standard measure in several hundred public safety workers vaccinated 1-6 months prior to testing.218 Results of this comparison indicated the predictive value of currently available RIA and EIA tests in indicating an anti-HBs titer of at least 10 mIU/mL as being 99.2 and 97.6%, respectively.218 Thus, while these tests are highly predictive, a small number of individuals tested since March 1986 and reported as having a protective antibody level based only (i.e., who did not also have a WHO-standardized quantitative determination of anti-HBs) on an RIA determination of at least 10 SRU and/or positivity by RIA may not actually have developed an adequate response to the vaccine (i.e., falsely positive immunity determinations secondary to oversensitivity of these assays).218 Therefore, the CDC states that any such individual who subsequently is exposed to an HBsAg-positive source without having had a quantitative determination of anti-HBs (based on a value of at least 10 mIU/mL) should be considered as having an unknown response to the vaccine when making decisions regarding the possible need for postexposure prophylaxis.218

Administration of hepatitis B vaccine during the incubation period of infection (i.e., after exposure to HBV but prior to onset of clinical symptoms) may only modify or ameliorate, rather than prevent, infection.132,133

The active immune response produced by hepatitis B vaccine does not appear to be suppressed by hepatitis B immune globulin (HBIG) when HBIG is administered concomitantly at a separate site.132,133 (See Drug Interactions.)

Hepatitis B Virus and Infection

HBV is a DNA virus from the family Hepadnaviridae282 consisting of antigenically distinct surface and core components.281,282 The presence of HBsAg in serum indicates the presence of active HBV infection (either acute or chronic).282,291 HBsAg may also be found in other body fluids and tissues.282 (See Uses: Risks of Exposure and Infection.) The HBV viral core consists of DNA, DNA polymerase, hepatitis B core antigen (HBcAg), and hepatitis B e antigen (HBeAg).281,282 All HBsAg-positive individuals are infectious and those that are positive for HBeAg will also have high HBV titers and are considered highly infectious.105,213,281,282 The presence of HBeAg and HBV DNA in serum generally indicates high levels of viral replication and suggests that the serum is highly infectious.105,213,281,282,291

The incubation period from exposure to HBV to onset of symptoms of HBV infection is 6 weeks to 6 months (average: 90-150 days).130,213,282,291 Serologic markers of HBV infection (i.e., HBsAg, HBeAg, antibody to hepatitis B core antigen [anti-HBc], antibody to hepatitis B e antigen [anti-HBe], anti-HBs) are used to define clinical status of those exposed to HBV infection or virus.105,213,281,282,291 HBsAg appears in the serum about 30 days (range 6-60 days) after exposure and indicates an ongoing HBV infection.213,281,282,291 HBsAg persists during an acute infection and usually disappears as the acute infection resolves; however, the presence of HBsAg in the serum for 6 months or longer generally indicates chronic infection.105,213,281,282,291 Anti-HBs develops during convalescence after an acute HBV infection (usually within 3-4 months).105,213,281,282 The presence of anti-HBs indicates recovery from and immunity to further HBV infection.105,213,281,282

Acute HBV infection may be self-limited resulting in production of antibody to HBsAg (anti-HBs) and immunity against reinfection; however, it may also progress to chronic HBV infection (especially in infants or young children, immunocompromised individuals, patients with diabetes) or to fatal, fulminant hepatitis.105,213,281,282 The case fatality rate is 0.5-1.5% among those with acute HBV infection213,281,290 and the highest fatality rates are in adults older than 60 years of age.213,281 Chronic HBV infection develops in 90% or more of infants infected perinatally, 25-50% of children infected at 1-5 years of age, and less than 5% of those infected at 5 years of age or older.105,213,281,282,290,291 Chronic infection is associated with persistent HBV replication in the liver and may result in liver cirrhosis, liver cancer, liver failure, and death.105,213,281,282,290 Data from 2006 indicate that approximately 800,000-1.4 million people in the US have chronic HBV infection.291 HBV is transmitted by percutaneous or mucosal exposure to HBsAg-positive blood, serum, plasma, semen, or saliva105,269,213,281,282,291 and can be transmitted perinatally from mother to infant at birth, usually from blood exposures during labor and delivery.105,213,282,291

Response to Hepatitis B Vaccine (Recombinant)

Neonates and Infants 18 Months of Age or Younger

Studies evaluating immunogenicity of hepatitis B vaccine administered to neonates in various dosage schedules beginning at birth or 2 months of age indicate that protective levels of anti-HBs generally are attained in more than 95% of infants following 3 doses of vaccine.132,133,227,228,229 However, geometric mean titers (GMTs) of antibody achieved generally are lower when accelerated dosing schedules are used.133,227,228,229 The effect of higher antibody levels on long-term disease protection currently is not known, but achievement of high titers ensures longer persistence of antibody.230,231,232

In a study using Engerix-B^® in healthy neonates born to healthy HBsAg- negative women, administration of 10-mcg doses at birth and 1 and 2 months of age or at birth and 1 and 6 months of age induced protective levels of anti-HBs in about 96% of infants at 6-7 months; GMTs of antibody in seroconverters at 7 months were 420 mIU/mL in those who received the accelerated schedule and 3142 mIU/mL in those who received the other schedule.228 In a study using Recombivax HB^® in healthy infants born to HBsAg- negative women, GMTs of antibody (1 month after the third dose) were 1358 mIU/mL in those who received 2.5-mcg doses at 2, 4, and 12 months of age and 3424 mIU/mL in those who received 2.5-mcg doses at 2, 4, and 15 months of age.227

Adults and Adolescents

In several studies, at least 90% of healthy young adults and teenagers developed protective levels of anti-HBs after a series of three 10-mcg doses of hepatitis B vaccine given IM into the deltoid.117,121,124,132,133 The seroconversion rate following administration of hepatitis B vaccine may be lower in men than in women117,207,209 and appears to vary with age.124,132,133,207,209 The seroconversion rate following administration of 3 doses of hepatitis B vaccine in infants and children 19 years of age or younger is 96-100%, but is 94-99% in adults 20-39 years of age and 88-91% in adults 40 years of age or older.132,133 After 40 years of age, the proportion of adults who have a protective antibody response after a 3-dose vaccination regimen declines below 90%, and by 60 years of age, protective antibody levels occur in only 75% of those vaccinated.281

Results of an open, randomized, multicenter study in adolescents 11-15 years of age indicate that the immunogenicity of a 2-dose regimen of 10-mcg doses of Recombivax HB^® (second dose given 4-6 months after the first dose) is similar to that of a 3-dose regimen of 5-mcg doses of Recombivax HB^® (second and third doses given 1 and 6 months, respectively, after the first dose) and that both regimens are equally well tolerated.132,257 At one month after the last dose, 99% of those who received the 2-dose regimen and 98% of those who received the 3-dose regimen had protective levels of antibody.132 Short-term follow-up data indicate that the rate of decline in antibody levels for the 2-dose regimen is similar to that of the 3-dose regimen; however, data are not available to assess long-term protection (beyond 2 years) or immunologic memory following vaccination with the 2-dose regimen and it is not known whether booster doses of vaccine will be required.257

Individuals with Altered Immunocompetence

The anti-HBs response in hemodialysis patients and immunocompromised patients generally is less than that in immunocompetent individuals, and adequate levels generally persist for shorter periods.101,132,133,136,137,138,139,140,141,142,143,144,145,146,281

Only 50-86% of hemodialysis patients reportedly develop protective levels of anti-HBs after receiving three 40-mcg doses of hepatitis B vaccine.132,133 Larger vaccine doses (e.g., 2-4 times the usual adult dose) or an increased number of doses (4 doses) are required to induce protective antibody levels in a large proportion of patients undergoing hemodialysis.101,136,137,138,139,140,141,142,143,144,145,146,282

Larger vaccine doses (e.g., 2-4 times the usual adult dose) or an increased number of doses (4 doses) in the hepatitis B vaccine series may be necessary to induce protective antibody levels in other immunocompromised individuals, including those receiving immunosuppressive therapy or with human immunodeficiency virus (HIV) infection.101,133,136,137,138,139,140,141,142,143,144,145,146,281 HIV-infected children (especially older children or those with CD4⁺ T-cell counts less than 200/mm³) may have lower antibody responses to hepatitis B vaccine than those who do not have HIV infection.279 The seroconversion rate in HIV-infected adults is 18-72% following vaccination with hepatitis B vaccine and is lower than that reported in healthy adults.278 In addition, mean antibody titers are lower and decline faster in HIV-infected individuals than in those who are not infected with HIV.101,127,128,129,212,220,278 (See HIV-infected Individuals under Primary Immunization: Individuals with Altered Immunocompetence, in Uses.)

Immunogenicity of hepatitis B vaccine may be reduced in parenteral drug abusers, possibly secondary to altered immunity in these individuals.208

Individuals with Hepatitis C Virus Infection

The immunologic response to hepatitis B vaccine may be decreased in patients with hepatitis C virus (HCV) infection and may be adversely affected by HCV viral load.267,268 In one study that used an accelerated 3-dose vaccination schedule of hepatitis B vaccine (doses given at 0, 1, and 2 months), a protective antibody response was attained in 63.6% of adults with chronic HCV infection compared with 93.9% of healthy adults.268 Among the HCV patients, nonresponders had higher viral loads of HCV than those who responded to the vaccine.268 There was no evidence that vaccination with hepatitis B vaccine affected the HCV viral load during or after vaccination.268 In another study that used the usual 3-dose vaccination schedule (Engerix B^® doses of 20 mcg given at 0, 1, and 6 months), a protective antibody response was attained in 72.9% of adults with chronic HCV infection (without cirrhosis) compared with 90.9% of healthy adults.267 In addition, although the clinical importance is unclear, only 34.1% of the HCV patients still had seroprotective titers of anti-HBs 1 year after completion of the vaccine regimen compared with 90% of the healthy controls.267

Response to Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens

Hib-HepB (Comvax®)

Results of a randomized, open-label study in 882 infants approximately 2 months of age who had not previously received any doses of haemophilus b (Hib) vaccine or hepatitis B vaccine indicate that a 3-dose regimen of the fixed-combination vaccine containing Hib and hepatitis B antigens (Hib-HepB; Comvax^®) results in an immunologic response rate similar to that attained when monovalent Hib vaccine (PedvaxHIB^®) and monovalent hepatitis B vaccine (Recombivax HB^®) are given concurrently at different sites.251 In this study, vaccine doses were given at approximately 2, 4, and 12-15 months of age.251 The PRP antibody response (anti-PRP) after the second dose of Comvax^® (72.4% had levels exceeding 1 mcg/mL with a GMT of 2.5 mcg/mL) was comparable to that in infants who received the monovalent Hib vaccine (76.2% with a GMT of 2.8 mcg/mL).251 Therefore, efficacy of Comvax^® in preventing invasive Hib disease is expected to be similar to that reported with monovalent PedvaxHIB^®.251 The anti-HBs response after the third dose of Comvax^® (98.4% had levels 10 mIU/mL or greater with a GMT of 4467.5) was slightly lower than that in infants who received the monovalent hepatitis B vaccine (100% with a GMT of 6943.9).251 Although this difference in GMT may result in differences in the duration of anti-HBs response after a number of years, this probably is not clinically important because of immunologic memory.251 In addition, the anti-HBs response to Comvax^® is considered protective.251 Therefore, because the HBsAg component of Comvax^® induces an antibody response comparable to that obtained with Recombivax HB^®, efficacy of the fixed-combination vaccine in providing protection against HBV infection is expected to be similar.251

HepA-HepB (Twinrix®)

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 containing hepatitis A and hepatitis B antigens (HepA-HepB; Twinrix^®) is similar to that of a 2-dose series (at 0 and 6 months) of the monovalent hepatitis A virus vaccine inactivated (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.262

In adults who received a 3-dose series of the fixed-combination vaccine, 99.9% developed anti-hepatitis A virus (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.262 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 virus vaccine inactivated and monovalent hepatitis B vaccine concurrently.262 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).262 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.262

When an accelerated dosage regimen of 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 virus vaccine inactivated (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).262 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).262 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.262

DTaP-HepB-IPV (Pediarix®)

Following a 3-dose series of the fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens (DTaP-HepB-IPV; Pediarix^®), the immunologic response generally is similar to that reported following 3 primary doses of separately administered Infanrix^®, Engerix-B^®, and inactivated poliovirus vaccine (IPV).104

Duration of Immunity

The duration of protection from HBV infection following administration of hepatitis B vaccine and the need for additional booster doses of the vaccine have not yet been fully defined.101,120,132,133,213,252,254,282 In one study in adults, anti-HBs levels 1.5 years after administration of a series of 3 doses of hepatitis B vaccine reportedly had decreased to less than the minimum protective level in 24% of those who received 20-mcg doses and 48% of those who received 10-mcg doses of the vaccine.119

There is some evidence from long-term follow-up of vaccine recipients that immunologic memory may persist for at least 10-20 years in individuals who respond to hepatitis B vaccine, and that maintenance of detectable anti-HBs levels may not be necessary to protect these individuals against clinically important breakthrough infections.105,125,213,252,253,282 Because immunologic memory may confer protection, it has been suggested that booster doses of vaccine may not be necessary in immunocompetent individuals even if antibody titers decline after vaccination.253,254,282 Subsequent exposure to HBV results in an anamnestic anti-HBs response that prevents clinically important HBV infection.213,282

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 (Twinrix^®) containing hepatitis A virus vaccine inactivated (Havrix^®) and hepatitis B vaccine (Engerix-B^®), anti-HAV and anti-HBsAg levels were maintained for at least 4 years.262

Chemistry and Stability

Chemistry

Hepatitis B Vaccine (Recombinant)

Monovalent hepatitis B vaccine is commercially available in the US as Recombivax HB^® and Engerix-B^®.132,133 Both Recombivax HB^® and Engerix-B^® contain hepatitis B surface antigen (HBsAg) prepared using yeast cells ( Saccharomyces cerevisiae ) and recombinant DNA technology.132,133 These vaccines are available in several formulations containing different concentrations of HBsAg.132,133

Each 1-mL dose of Engerix-B^® Adult contains 20 mcg of HBsAg adsorbed onto 0.5 mg of aluminum (as aluminum hydroxide) and each 0.5-mL dose of Engerix-B^® Pediatric/Adolescent contains 10 mcg of HBsAg adsorbed onto 0.25 mg of aluminum (as aluminum hydroxide).133 Engerix-B^® Adult and Engerix-B^® Pediatric/Adolescent are formulated without preservatives.133 Before shaking, Engerix-B^® may occur as a fine white deposit with a clear colorless supernatant; after shaking, the vaccine occurs as a slightly turbid white suspension.133

Each 1-mL dose of Recombivax HB^® Adult Formulation contains 10 mcg of HBsAg; each 0.5-mL dose of Recombivax HB^® Pediatric/Adolescent Formulation contains 5 mcg of HBsAg; and each 1-mL dose of Recombivax HB^® Dialysis Formulation contains 40 mcg of HBsAg.132 In each formulation, the antigen is adsorbed onto approximately 0.5 mg of aluminum (as amorphous aluminum hydroxyphosphate sulfate) per mL of vaccine.132 Recombivax HB^® preparations do not contain thimerosal or any other preservative.132 After shaking, Recombivax HB^® occurs as a slightly opaque white suspension.132

Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens

DTaP-HepB-IPV (Pediarix®)

DTaP-HepB-IPV (Pediarix^®) is a fixed-combination vaccine containing diphtheria, tetanus, pertussis, hepatitis B, and poliovirus antigens.104

The hepatitis B antigen contained in Pediarix^® is identical to that contained in Engerix-B^® monovalent hepatitis B vaccine.104 The diphtheria, tetanus, and pertussis antigens are identical to those contained in Infanrix^® (DTaP) vaccine.104 For information on these DTaP antigens, see Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed/Tetanus Toxoid and Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed 80:08. The poliovirus antigens contained in Pediarix^® are similar to those contained in the commercially available monovalent IPV vaccine.104 For information on the poliovirus antigens, see Poliovirus Vaccine Inactivated 80:12.

After vigorous shaking, Pediarix^® appears as a homogeneous, turbid, white suspension.104 Each 0.5-mL dose of Pediarix^® is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 58 mcg of pertussis antigens, 10 mcg of HBsAg, 40 D-antigen units (DU) of Type 1 poliovirus, 8 DU of Type 2 poliovirus, and 32 DU of Type 3 poliovirus.104 Each 0.5 mL of Pediarix^® contains 4.5 mg of sodium chloride, not more than 0.85 mg of aluminum adjuvant, not more than 100 mcg of polysorbate 80, and not more than 100 mcg of residual formaldehyde.104 Although neomycin sulfate and polymyxin B are used in the manufacturing process of the poliovirus antigen component, Pediarix^® contains no more than 0.05 and 0.01 ng, respectively, of these anti-infectives per dose.104 No more than 5% yeast protein may be present in Pediarix^® as part of the hepatitis B antigen component.104 Pediarix^® does not contain thimerosal or any other preservatives.104

Hib-HepB (Comvax®)

Hib-HepB (Comvax^®) is a fixed-combination vaccine containing Hib and hepatitis B antigens.251

The antigens used to produce Comvax^® are the same as those used to produce PedvaxHIB^® monovalent Hib vaccine and Recombivax HB^® monovalent hepatitis B vaccine.251 Each antigenic component is prepared separately and then pooled to form the fixed-combination vaccine.251 After thorough agitation, the vaccine appears as a slightly opaque, white suspension.251

Each 0.5-mL dose of Comvax^® contains 7.5 mcg of purified Hib capsular polysaccharide conjugated to approximately 125 mcg of Neisseria meningitidis outer membrane protein complex (OMPC), 5 mcg of HBsAg), approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate), and 35 mcg sodium borate (decahydrate) as a pH stabilizer in 0.9% sodium chloride.251 Comvax^® does not contain thimerosal or any other preservative.251

HepA-HepB (Twinrix®)

HepA-HepB (Twinrix^®) is a fixed-combination vaccine that contains both hepatitis A and hepatitis B antigens.262 Twinrix^® is a sterile suspension containing the antigenic components used to produce Havrix^® monovalent hepatitis A virus vaccine inactivated and Engerix-B^® monovalent hepatitis B vaccine.262 Each antigenic component is adsorbed separately onto aluminum phosphate or aluminum hydroxide and then pooled to form the fixed-combination vaccine.262

Following thorough agitation, Twinrix^® appears as a homogeneous, turbid, white suspension.262 Each 1-mL dose of Twinrix^® contains 720 units of hepatitis A viral antigen and 20 mcg of HBsAg and also contains 0.45 mg of aluminum (as aluminum hydroxide and aluminum phosphate).262 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^®) 20.262 Twinrix^® does not contain thimerosal or any other preservatives.262 The vaccine has a pH of 5.8-6.6.261

Stability

Hepatitis B Vaccine (Recombinant)

Monovalent hepatitis B vaccine (Engerix-B^®, Recombivax HB^®) should be refrigerated at 2-8°C; storage above or below this temperature may reduce potency.132,133,286 Freezing of the vaccine results in a substantial decrease in potency and must be avoided.132,133 If freezing occurs, the vaccine should be discarded.133

Combination Vaccines Containing Hepatitis B Vaccine and Other Antigens

DTaP-HepB-Hib (Pediarix®)

DTaP-HepB-Hib (Pediarix^®) should be refrigerated at 2-8°C and should not be frozen.104 If freezing occurs, the vaccine should be discarded.104 Improper storage may result in formation of a gel-like substance and the vaccine should be discarded if this occurs.104

Hib-HepB (Comvax®)

Hib-HepB (Comvax^®) should be refrigerated at 2-8°C and should not be frozen.251

HepA-HepB (Twinrix®)

HepA-HepB (Twinrix^®) should be refrigerated at 2-8°C and should not be frozen; if freezing occurs, the vaccine should be discarded.262 When stored as recommended, the vaccine has an expiration date of 3 years after the date of manufacture.261

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.

Only references cited for selected revisions after 1984 are available electronically.

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