Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices

Epidemiology

In 2015, a total of 3,370 cases of acute HBV infection were reported to CDC. The actual number of acute cases is believed to be 6.5 times the number of reported cases in any year. It is estimated that 21,900 new cases of HBV occurred in 2015 after under-ascertainment and under-reporting were considered (4). The rate of reported acute HBV infections declined 88.5% since recommendations for HepB vaccination were first issued, from 9.6 cases per 100,000 population in 1982 to 1.1 cases per 100,000 population in 2015 (15), although the rate of acute HBV infections remained fairly stable during 2010–2015 (4) (Figure 1). The 2015 incidence is greatest for persons aged 30–39 years (2.6 per 100,000 population). In 2015, persons aged ≤19 years had the lowest incidence (0.02 cases per 100,000 population), likely a result of routine infant vaccination. Although the incidence of acute HBV infection is greater for males than for females, the gap has narrowed; in 2015, the rate for males was approximately 1.6 times higher than that for females (1.3 cases and 0.8 cases per 100,000 population, respectively) (4). During 2009–2013, the combined incidence of acute HBV infection in three states (Kentucky, Tennessee, and West Virginia) increased 114% and was associated with increasing injection-drug use (16).

FIGURE 1

Incidence of hepatitis B virus infection — National Notifiable Diseases Surveillance System, United States, 1980–2015

On the basis of national health survey data, it is estimated that approximately 850,000 persons are living with HBV infection (prevalence) in the United States (17,18). Studies based on data from countries of persons migrating to the United States and census data indicate that the total prevalence of chronic hepatitis B might be as high as 2.2 million persons (19), suggesting that the national health survey-based estimate might be conservative. Foreign-born persons account for approximately 95% of newly reported chronic infections in the United States (20); the prevalence of chronic HBV infection is approximately 3.5% among foreign-born persons (19), and the majority of chronic HBV infections in the United States are among Asians/Pacific Islanders.

Strategy to Eliminate HBV

In 1991, the United States adopted a strategy for universal HepB vaccination of infants (21). A comprehensive strategy to eliminate HBV transmission evolved over the ensuing 3 decades and encompasses 1) routine testing of all pregnant women for HBsAg and prophylaxis for infants born to HBsAg-positive mothers, 2) universal vaccination of infants beginning at birth, 3) routine vaccination of previously unvaccinated children and adolescents, and 4) vaccination of adults at risk for HBV infection (7–11,21–26). Preventing perinatal transmission relies upon testing all pregnant women for HBsAg and administering timely prophylaxis (HepB vaccine and hepatitis B immune globulin [HBIG]) to infants born to infected mothers. Universal HepB vaccination of all infants beginning at birth provides a critical safeguard and prevents infection among infants born to HBsAg-positive mothers not identified prenatally (e.g., in situations where the mother was not tested or when testing, interpretation, or transcription errors occurred). Vaccination of children and adolescents not previously vaccinated and vaccination of adults at risk for HBV infection (e.g., by sexual or percutaneous exposure and international travelers to certain countries) is recommended to prevent HBV transmission outside of the perinatal setting (Box 2).

HBV prevention strategies have been implemented successfully in the United States, but challenges remain. Approximately 88% of commercially insured women and 84% of Medicaid-enrolled women are tested for HBsAg during pregnancy (27). In one study of a large health system in northern California, 93% of HBsAg-positive pregnant women were tested for HBV DNA (28). Most (94.9%) infants born to infected women receive recommended prophylaxis within 12 hours of birth (29). Universal HepB vaccine birth dose coverage, defined as 1 dose of vaccine administered by 3 days of life, is 71.1% (30), an increase from 50.1% during 2003–2005 prior to revised ACIP recommendations for the birth dose before hospital discharge (31), but below the Healthy People 2020 target of 85% (32). HepB vaccine coverage (≥3 doses) among children aged 19–35 months and 13–17 years is 90.5% (30) and 91.4% (33), respectively. Vaccine coverage (≥3 doses) is lower among adults: 27.4% among adults who report chronic liver conditions; 31.6% among adults who traveled outside the United States to countries other than Europe, Japan, Australia, New Zealand, or Canada since 1995; and 24.4% among adults with diabetes aged 19–59 years and 12.6% of adults with diabetes aged ≥60 years (34). Among health care personnel (HCP), ≥3-dose coverage was 64.7%, an increase from 51% in 1992 shortly after implementation of the Needlestick Safety and Prevention Act (35), but well below the Healthy People 2020 target of 90% (32,34).

New strategies for further reducing HBV transmission in this report include testing HBsAg-positive pregnant women for HBV DNA to identify infants at greatest risk for infection and guide the use of maternal antiviral therapy (36,37). Published evidence indicates that maternal antiviral therapy during pregnancy further reduces perinatal HBV transmission; hence, AASLD suggests antiviral therapy when maternal HBV DNA is >200,000 IU/mL (5,38,39).

Virus Description and Transmission

HBV is a 40–42-nm enveloped virus classified in the Hepadnaviridae family. HBV contains a circular, partially double-stranded DNA genome that is 3.2 kb in length. After a susceptible person is exposed, the virus enters the liver via the bloodstream. The liver is the primary site of HBV replication (40–43).

HBV has been classified by two separate systems: serologic subtype and genotype. Nine serologic subtypes initially were described based on the heterogeneity of HBsAg: adrq+, adrq–, ayr, ayw1, ayw2, ayw3, ayw4, adw2, and adw4 (44,45). Ten HBV genotypes, designated A–J, have been described. HBV serotypes and genotypes vary geographically. Infection or immunization with one genotype generally confers immunity to all genotypes (7,44,46,47).

HBV is highly infectious, can be transmitted in the absence of visible blood (22), and remains infectious on environmental surfaces for at least 7 days (2,3). All HBsAg-positive persons are infectious, but those with elevated HBV DNA or those with hepatitis B e antigen (HBeAg), a protein from the hepatitis B virus that circulates in the blood and is a marker of infectivity, are most infectious. Persons with occult HBV infection (i.e., those who test negative for HBsAg but have detectable HBV DNA) also might transmit infection (48).

HBV is transmitted through percutaneous, mucosal, or nonintact skin exposure to infectious blood or body fluids. HBV is concentrated most highly in blood, and percutaneous exposure is an efficient mode of transmission. Semen and vaginal secretions are infectious, and HBV also can be detected in saliva, tears, and bile. Cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid are also considered potentially infectious. Urine, feces, vomitus, nasopharyngeal washings, sputum, and sweat are not efficient vehicles of transmission unless they contain blood because they contain low quantities of infectious HBV. HBsAg found in breast milk is also unlikely to lead to transmission, and hence HBV infection is not a contraindication to breastfeeding (2,7,22).

Among adults, HBV is transmitted primarily by percutaneous exposure to blood (e.g., by injection-drug use) and sexual contact. HBV is transmitted efficiently by sexual contact both among heterosexuals and among men who have sex with men (MSM). Risk factors for sexual transmission among heterosexuals include having unprotected sex with an infected partner, having unprotected sex with more than one partner, and a history of another sexually transmitted infection (STI). Risk factors associated with sexual transmission among MSM include having multiple sex partners, history of another STI, and anal intercourse. Transmission can occur from interpersonal contact (e.g., sharing a toothbrush or razor, contact with exudates from dermatologic lesions, or contact with HBsAg-contaminated surfaces) and in settings such as schools, child care centers, and facilities for developmentally disabled persons. Transmission of HBV from transfusion of blood or blood products is rare because of donor screening and viral inactivation procedures. Other possible sources of infection include contaminated medical or dental instruments, unsafe injections, needle-stick injuries, organ transplantation, and dialysis (49).

Clinical Features and Natural History

Clinical manifestations of HBV infection range from asymptomatic infection to fulminant hepatitis. The average incubation period is 60 days (range: 40–90 days) from exposure to onset of abnormal serum ALT levels and 90 days (range: 60–150 days) from exposure to onset of jaundice (8,42,43). Infants, children aged <5 years, and immunosuppressed adults with newly acquired HBV infection typically are asymptomatic, whereas symptomatic illness is noted in 30%–50% of older children, adolescents, and adults (7,8,44,50). When present, signs and symptoms include nausea, vomiting, abdominal pain, fever, dark urine, changes in stool color, hepatomegaly, splenomegaly, and jaundice. Malaise and anorexia might precede jaundice by 1–2 weeks. Fulminant HBV infection is uncommon (<1%) but often results in death or liver failure necessitating liver transplantation. Extrahepatic manifestations of disease (e.g., skin rash, arthralgias, and arthritis) also might occur (51). The fatality rate among persons with reported cases of acute HBV infection is <1.5%, with the highest rates in adults aged ≥55 years. Because a substantial number of infections are asymptomatic and therefore are not reported, the overall fatality rate among all persons with HBV infection is likely lower (8).

Chronic infection occurs among 80%–90% of persons infected during infancy, 30% of persons infected before age 6 years, and <1%–12% of persons infected as an older child or adult (7,52–54). Approximately 95% of primary infections in immunocompetent adults are self-limited, with elimination of the virus from blood and generally immunity to reinfection. Chronic infection develops more frequently in immunosuppressed persons (e.g., hemodialysis patients and persons with human immunodeficiency virus [HIV] infection) (54,55) and persons with diabetes (54). Chronic HBV infection can result in cirrhosis of the liver, liver cancer, liver failure, and death. Approximately 25% of persons who become chronically infected during childhood and 15% of those who become chronically infected after childhood will die prematurely from cirrhosis or liver cancer (8,56–58).

There are four phases of chronic HBV infection: immune tolerant, immune active, immune inactive, and reactivation. Chronically infected persons do not necessarily pass through these phases in a linear fashion. Persons in the immune tolerant phase have no or minimal hepatic inflammation or fibrosis; most chronically infected children will remain in the immune tolerant phase until late childhood or adolescence. The immune active phase is characterized by an active immune response resulting in hepatic inflammation, with or without fibrosis. Persons who remain in the immune active phase for prolonged periods of time are at high risk for developing cirrhosis and hepatocellular carcinoma. Persons in the immune inactive phase have improvement of hepatic inflammation and fibrosis. Risk for progression to hepatocellular carcinoma is lower among persons in the immune inactive phase compared with the active phase. Persons in the reactivation phase have active liver inflammation with or without fibrosis (44,59–61). HBV reactivation might occur with immunosuppressive therapy or treatment for HCV (62).

No specific treatment exists for acute HBV infection; supportive care is the mainstay of therapy. Guidelines for management of chronic HBV infection in children and adults, including disease monitoring and antiviral therapy, are available (5). Antiviral therapy generally should be initiated in patients with chronic HBV infection who are likely to respond to treatment and who are at high risk for liver-related morbidity (5). Maternal antiviral therapy to reduce perinatal transmission is suggested for HBsAg-positive pregnant women whose HBV DNA level is >200,000 IU/mL (5).

In areas in which HBV is highly endemic, HBV frequently is transmitted perinatally from HBV-infected pregnant women to their newborns. The majority of cases of perinatal HBV transmission occur during delivery, with rare instances of in utero transmission (63). HBV transmission might occur in germ cell lines, as the virus has been detected in sperm, oocytes, and embryos. Available data do not support the need for a cesarean delivery among HBV-infected pregnant women with low HBV DNA (63). Prior to the widespread availability of postexposure prophylaxis, the proportion of infants born to HBsAg-positive women acquiring HBV infection was approximately 30% for those born to HBeAg-negative mothers and 85% for those born to HBeAg-positive mothers. With postexposure prophylaxis, comprised of HepB vaccine and HBIG at birth, followed by completion of the HepB vaccine series, 0.7%–1.1% of infants develop infection (28,29,64); infants born to mothers with high viral loads are at greatest risk for infection despite receipt of HepB vaccine and HBIG (29). Unvaccinated infants and children are also at risk for horizontal transmission from infected household and other contacts.

Interpretation of Serologic Markers

Serologic markers for HBV infection include HBsAg, antibody to HBsAg (anti-HBs), immunoglobulin class M (IgM) antibodies to hepatitis B core antigen (IgM anti-HBc), and immunoglobulin class G (IgG) anti-HBc (IgG anti-HBc) (49,65,66). At least one serologic marker is present during the different phases of infection. HBV DNA is a measure of viral load and reflects viral replication (49) (Table 1). Hepatitis B e antigen (HBeAg) can be detected in persons with acute or chronic HBV infection; the presence of HBeAg correlates with viral replication and high infectivity; antibody to HBeAg (anti-HBe) correlates with the loss of replicating virus, although reversion to HBeAg positivity can occur (7).

A confirmed positive HBsAg result indicates current HBV infection, either acute or chronic. All HBsAg-positive persons are infectious. If HBsAg persists for >6 months, spontaneous clearance is unlikely, and the infection is deemed chronic. HBV DNA can be detected prior to the detection of HBsAg in an infected person. Occult infection occurs when HBsAg is undetectable despite the presence of HBV DNA (66–68). Transient HBsAg positivity can occur up to 18 days following vaccination (up to 52 days among hemodialysis patients) and is clinically insignificant (69).

In acute HBV infection, anti-HBc (initially both IgM and IgG) appears 1–2 weeks after the appearance of HBsAg (49) (Figure 2). IgM anti-HBc often becomes undetectable within 6 months, and IgG anti-HBc predominates and remains detectable for a lengthy period of time, often life-long (65,66). The presence of IgM anti-HBc is indicative of acute infection, while IgG anti-HBc indicates past infection (65,66). In persons who recover from HBV infection, HBsAg is eliminated from the blood and anti-HBs develops, typically within 3–4 months. The presence of anti-HBs is generally indicative of immunity to HBV infection (8). Anti-HBs also can be detected for 4–6 months following HBIG administration (10). Persons who recover from natural HBV infection are typically positive for both anti-HBs and anti-HBc, whereas persons who respond to HepB vaccine are positive only for anti-HBs. Approximately 0.5%–2% of persons with chronic infection spontaneously clear HBsAg yearly; anti-HBs will develop in the majority of these persons (8).

FIGURE 2

Acute hepatitis B virus infection with recovery

Abbreviations: anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to hepatitis B e antigen; anti-HBs = antibody to hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; IgM = immunoglobulin class M.

In certain persons, anti-HBc is the only serologic marker detected. Isolated anti-HBc-positivity can be detected following HBV infection in persons who have recovered but whose anti-HBs levels have waned; in populations with a high prevalence of HBV infection, isolated anti-HBc likely indicates previous infection with loss of anti-HBs. Some chronically infected persons with isolated anti-HBc-positivity have circulating HBsAg that is not detectable by a laboratory assay. HBV DNA has been detected in <10% of persons with isolated anti-HBc (70,71), although the presence of detectable HBV DNA might fluctuate (72). These persons are unlikely to transmit infection except under circumstances in which they are the source of a large exposure, such as a blood transfusion (8,73). Persons who are HBsAg-negative and anti-HBc-positive can experience reactivation of infection during chemotherapy or immunosuppressive therapy, with reappearance of HBsAg (49). Infection with a mutant HBV strain can result in positive laboratory tests for HBsAg, total anti-HBc, anti-HBs, and HBV DNA, with a negative IgM anti-HBc.

Perinatal HBV infection in a child aged ≤24 months is typically asymptomatic although fulminant hepatitis can occur; a positive HBsAg test, positive HBeAg test, or detectable HBV DNA may be considered laboratory evidence of perinatal HBV in an infant born to an HBV-infected mother if timing criteria are met (74). Infants who are born to HBsAg-positive mothers and who do not become infected might have detectable anti-HBc for up to 24 months after birth from passively acquired maternal antibody (7).

Adults at Risk for HBV Infection

In 2015, CDC received 3,370 surveillance case-reports of acute HBV infection. Of 2,207 case-reports with risk information, 1,151 (52.2%) indicated no risk for HBV during the 6 weeks to 6 months prior to illness onset, and the remainder indicated at least one risk factor. Injection-drug use and multiple sex partners were the most common reported sources of HBV transmission (4).

Injection-drug use. Injection-drug use was reported by 30.3% of 1,657 new reported HBV cases that included information about injection-drug use (4). Since 2009, there has been an increase in acute HBV infection among non-Hispanic whites aged 30–39 years residing in nonurban areas reporting injection-drug use as a risk factor (16). Chronic HBV infection has been identified in 3.5%-20.0% (midpoint estimate: 11.8%) of persons who inject drugs (PWID) in a variety of settings (75) and 22.6% of PWID have evidence of past infection (75). The proportion of HBV cases reporting injection-drug use in three states (Kentucky, Tennessee, and West Virginia) increased significantly, from 53% during 2006–2009 to 75% during 2010–2013 (p<0.001, chi-square) (16).

Sexual (heterosexual and MSM) exposure. Among persons with case-reports of HBV infection with information about sexual exposure, 26.4% reported having two or more sexual partners, 3.3% reported sexual contact with an HBV-infected person, and 11.8% of males reported having had sex with another male (4). As many as 10%–40% of adults seeking treatment in STI clinics have evidence of current or past HBV infection. Among adults with acute HBV infection, 39% were screened or sought care for an STI prior to becoming infected with HBV (76).

Household contacts. An estimated 45% of persons living in households with others with chronic HBV infection have serologic evidence of past HBV infection, and 16% have evidence of current infection (CDC, unpublished data, 2017. Prior to universal infant vaccination, the risk for infection was greatest among unvaccinated children living with a person with chronic HBV infection in a household or in an extended family setting (67,77,78).

Developmentally disabled persons in long-term-care facilities. Developmentally disabled persons in residential and nonresidential facilities historically have had a chronic HBV infection prevalence as high as 20%. The prevalence of infection has declined substantially since the implementation of routine HepB vaccination in these settings (79–82).

Correctional facilities. The prevalence of chronic HBV infection has been higher among prison inmates (1.0%–3.7%) than among the general population (83,84), reflecting an overrepresentation of persons entering correctional facilities with risks for HBV infection (e.g., injection-drug use and histories of multiple sex partners).

Persons at risk for occupational exposure to HBV. Before HepB vaccination was widely implemented, HBV infection was recognized as a common occupational risk among HCP (85,86). Routine HepB vaccination of HCP and the use of standard precautions have resulted in a 98% decline in HBV infections from 1983 through 2010 among HCP (10). The Occupational Safety and Health Administration mandates that employers offer HepB vaccination to all employees who have occupational risk and that postexposure prophylaxis be available following an exposure (10,87).

Hemodialysis patients. Since the initiation of HepB vaccination and additional infection control precautions for hepatitis B in dialysis centers, the incidence of HBV infection among hemodialysis patients has declined approximately 95% (88,89). Since 1995, the annual incidence has been stable and HBsAg seroprevalence has remained at 1% (90). Receipt of dialysis was reported in <1% of acute HBV surveillance cases with information reported to CDC (4).

Persons with HCV infection. The number of reported HCV cases in four Appalachian states (Kentucky, Tennessee, Virginia, and West Virginia) increased 364% during 2006–2012 among persons aged ≤30 years, with injection-drug use as the most common reported risk factor (91). The increase in HCV infections occurred concomitantly with an increase in HBV infections among young adults in rural communities in Appalachian states.

Persons with chronic liver disease. Persons with chronic liver disease (e.g., cirrhosis, fatty liver disease, alcoholic liver disease, and autoimmune hepatitis) are not at increased risk for HBV infection unless they have percutaneous or mucosal exposure to blood or body fluids. However, concurrent chronic HBV infection might increase the risk for progressive chronic liver disease in these persons (92).

Travelers to countries where HBV is endemic. Short-term travelers to countries in which HBV infection is of high or intermediate endemicity (Box 3) typically are at risk for infection only through exposure to blood in medical or disaster-relief activities, receipt of medical care that involves parenteral exposures, sexual activity, or drug use. Monthly incidence of 25–420 per 100,000 travelers has been reported among long-term travelers to countries where the disease is endemic (93).

Persons with HIV. Approximately 10% of HIV-positive persons are coinfected with HBV (94–97). Chronic HBV infection has been identified in 6%–14% of HIV-positive persons, including in 9%–17% of MSM and in 7%–10% of PWID (98). Coinfected persons have increased rates of cirrhosis and liver-related mortality (99).

Persons with diabetes. Compared with adults without diabetes, adults with diabetes have a 60% higher prevalence of past or present HBV infection and twice the odds of acquiring acute HBV. Repeated outbreaks of HBV infection associated with assisted blood glucose monitoring underscore the continued risk for this population (100–102). Data also suggest the possibility of a higher case-fatality proportion among persons with diabetes acutely infected with HBV compared with those without diabetes (9).

Hepatitis B Vaccines and Hepatitis B Immune Globulins

HepB vaccination is the mainstay of HBV prevention efforts; HBIG is generally used as an adjunct to HepB vaccine in infants born to HBsAg-positive mothers and in certain other postexposure prophylaxis situations. The first HepB vaccines consisted of plasma-derived HBsAg. Recombinant HepB vaccines containing yeast-derived HBsAg purified by biochemical and biophysical separation techniques replaced the plasma-derived vaccines in the United States by the late 1980s (64,103,104). HepB vaccines recommended for use in the United States are formulated to contain 10–40 µg of HBsAg protein/mL and do not contain thimerosal as a preservative (105). HBIG can augment protection until a response to vaccination is attained. For those who do not respond to HepB vaccination, HBIG administered alone is the primary means of protection after an HBV exposure. HBIG provides passively acquired anti-HBs and temporary protection (i.e., 3–6 months). Passively acquired anti-HBs can be detected for 4–6 months after administration of HBIG (10).

HepB vaccines are available as a single-antigen formulation and in combination with other vaccines. The two single-antigen vaccines recommended for use in the United States, Engerix-B (GlaxoSmithKline Biologicals, Rixensart, Belgium) and Recombivax HB (Merck & Co., Inc., Whitehouse Station, New Jersey), are used for the vaccination of persons starting at birth. Of the two combination vaccines, Pediarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is used for the vaccination of persons aged 6 weeks–6 years and contains recombinant HBsAg, diphtheria and tetanus toxoids and acellular pertussis adsorbed, and inactivated poliovirus and Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is used for the vaccination of persons aged ≥18 years and contains recombinant HBsAg and inactivated hepatitis A virus (Table 2). Comvax (Merck & Co., Inc., Whitehouse Station, New Jersey), which was used previously for the vaccination of persons aged 6 weeks–15 months and contained recombinant HBsAg and Haemophilus b conjugate vaccine, has not been available for purchase directly from Merck since January 1, 2015. Discontinuation of Comvax was not related to any product safety or manufacturing issues. Aluminum salts generally are used as adjuvants to enhance the immune response of vaccinated persons.

Two HBIG products are licensed for use in the United States: HepaGam B (Cangene Corporation, Winnipeg, Canada) and Nabi-HB (Biotest Pharmaceuticals Corporation, Boca Raton, Florida). HBIG is prepared from the plasma of donors with high concentrations of anti-HBs. Source plasma tests negative for evidence of HIV, HBV, and HCV. Investigational nucleic acid testing for hepatitis A virus and parvovirus B19 also is performed on pooled samples of source plasma. The manufacturing process contains two steps to inactivate viruses in the final product: the solvent and detergent step inactivates enveloped viruses, and the virus filtration step removes viruses based on their size. HBIG products licensed for use in the United States contain no preservative and are intended for single use only (106).

Vaccine-Induced Seroprotection

The presence of anti-HBs typically indicates immunity against HBV infection. Immunocompetent children and adults who have vaccine-induced anti-HBs levels of ≥10 mIU/mL 1–2 months after having received a complete HepB vaccine series are considered seroprotected and deemed vaccine responders (107). Vaccine-induced seroprotection is considered a surrogate of clinical protection. Anti-HBs levels wane over time following vaccination related in part to the age at vaccination. Approximately 16% of persons vaccinated at age <1 year have antibody levels of ≥10 mIU/mL 18 years following vaccination, compared with 74% for those vaccinated at age ≥1 year (10). However, persons initially responding to the full 3-dose HepB vaccine series and who are later found to have anti-HBs <10 mIU/mL remain protected. Most persons (88%) who receive a challenge dose of HepB vaccine 30 years after HepB vaccination as children or adults develop an antibody response of ≥10 mIU/mL indicating persistent immunity to HBV infection (108). Data from this and other studies suggests protection against acute symptomatic and chronic HBV infection persists for 30 years or more among immunocompetent persons who originally responded to HepB vaccine (108–110).

The 3-dose HepB vaccine series produces a protective antibody response (anti-HBs ≥10 mIU/mL) in approximately 95% of healthy infants overall (response is lower for infants with lower birth weights) (64) and >90% of healthy adults aged <40 years (111,112). Among healthy infants, 25% and 63% achieve anti-HBs levels ≥10 mIU/mL after the first and second dose, respectively. Among healthy adults aged <40 years, 30%–55% and 75% achieve anti-HBs levels ≥10 mIU/mL after the first and second dose, respectively (7,8,64). Vaccine response is decreased among infants weighing <2000 grams and older adults. Other factors (e.g., smoking, obesity, aging, chronic medical conditions, drug use, diabetes, male sex, genetic factors, and immune suppression) contribute to a decreased response to vaccine (113–116). Although immunogenicity is lower among immunocompromised persons, those who achieve and maintain seroprotective antibody levels before exposure to HBV have a high level of protection (8).

Birth dose. A birth dose of HepB vaccine serves as postexposure prophylaxis to prevent perinatal HBV infection among infants born to HBV-infected mothers. Although infants requiring postexposure prophylaxis should be identified by maternal HBsAg testing, administration of a birth dose to all infants (even without HBIG) serves as a safeguard to prevent perinatal transmission among infants born to HBsAg-positive mothers not identified prenatally because of lack of maternal HBsAg testing or failures in reporting test results. HepB vaccine or HBIG given alone are 75% and 71% effective in preventing perinatal HBV transmission, respectively; their combined efficacy is 94% (29,52,117). The birth dose also provides protection to infants at risk from household exposure after the perinatal period (29,64).

Vaccination produces seroprotection in 98% of healthy term infants. Vaccine response is lower among infants with birth weights <2000 grams (64). A study among low birth weight infants demonstrated that more infants achieved seroprotective anti-HBs levels when vaccine was initiated at 1 month of age versus within the first 3 days of life (96% vs. 68%, p<0.02) (118). Vaccine response among infants does not vary appreciably by maternal HBsAg status or HBIG administration (64).

Adolescents. Approximately 95% of adolescents achieve seroprotection following HepB vaccination with a complete series (7). The adult (10 µg) dose of Recombivax HB administered using a 2-dose compressed schedule at 0 and 4 months or 0 and 6 months for persons aged 11–15 years produces seroprotection proportions nearly equivalent to those obtained with the standard regimen of 5 µg administered on a 3-dose schedule at 0, 1, and 6 months (99.2% vs. 98.3%) (119,120). Data on long-term antibody persistence or protection among adolescents for 2-dose schedules are lacking.

Adults. Vaccination with a complete series results in seroprotection in >90% of healthy adults aged <40 years. Response decreases with age, and seroprotection is achieved in 75% of persons aged 60 years (8).

Diabetes. A review of studies assessing HepB vaccine response among persons with diabetes mellitus demonstrated seroprotection in 93.9% for children with diabetes mellitus compared with 100% for children without diabetes mellitus (112,121).

Among adults, 88.2% of those with diabetes mellitus, compared with 93.6% of those without diabetes mellitus, achieved seroprotection (112). Among hemodialysis/chronic kidney disease patients, the median proportion protected was 60.1% for those with diabetes mellitus, compared with 75.1% for those without diabetes mellitus (112).

Immunocompromising conditions. The humoral response to HepB vaccine is reduced in children and adults who are immunocompromised (e.g., hematopoietic stem cell transplant recipients, patients undergoing chemotherapy, and HIV-infected persons) (122,123). Modified dosing regimens, including a doubling of the standard antigen dose or administration of additional doses, might increase response rates. However, data on response to these alternative vaccination schedules are limited (6).

Vaccine Safety

In prelicensure trials, adverse events following HepB vaccination were most commonly injection site reactions and mild systemic reactions (106). Commonly reported mild adverse events from postmarketing data include pain (3%–29%), erythema (3%), swelling (3%), fever (1%–6%), and headache (3%) (124). The estimated incidence of anaphylaxis among HepB vaccine recipients is 1.1 per million vaccine doses (125). In 2011, the Institute of Medicine concluded that the evidence convincingly supports a causal relationship between HepB vaccine and anaphylaxis in yeast-sensitive persons, and that the evidence is inadequate to accept or reject a causal relation between HepB vaccine and several neurologic, chronic, and autoimmune diseases (126).

During early postlicensure surveillance, several adverse events following HepB vaccination have been described in the scientific literature, including Guillain-Barré Syndrome (GBS), chronic fatigue syndrome, optic neuritis, multiple sclerosis, and diabetes mellitus; however, multiple studies have demonstrated no association between receipt of HepB vaccine and these conditions (126–129). In addition, no evidence of a causal association between rheumatoid arthritis (130), Bell’s palsy (131), autoimmune thyroid disease (132), hemolytic anemia in children (133), anaphylaxis (134), optic neuritis (135), Guillain-Barré Syndrome (136), sudden-onset sensorineural hearing loss (137), or other chronic illnesses and receipt of HepB vaccine has been demonstrated through analysis of VSD data.

During 2005–2015, a total of 20,231 reports of adverse events following HepB vaccination among all ages were submitted to VAERS. The majority of primary U.S. reports (15,787 of 20,231, 78%) were following HepB vaccine administered with other vaccines on the same visit. Among these, the percentage classified as serious (i.e., if one or more of the following is reported: death, life-threatening illness, hospitalization or prolongation of existing hospitalization, or permanent disability)^† was 16.7%, including 402 deaths, of which 388 were among infants aged 6 weeks–23 months (138). The most frequently reported adverse events for vaccines given in combination were fever (23%), injection site erythema (11%), and vomiting (10%) (138). Among the 4,444 single-antigen HepB reports, 6.5% were classified as serious, including 43 deaths, of which 27 were among infants aged ≤4 weeks. The most frequently reported adverse events for single-antigen HepB vaccine were nausea/dizziness (8%) and fever/headache (7%).

Vaccination Schedules

Vaccine schedules are determined on the basis of immunogenicity data, and, for infants and children, the need to integrate HepB vaccine into a harmonized immunization schedule (Tables 3 and 4). Primary vaccination generally consists of three intramuscular doses administered on a 0-, 1-, and 6-month schedule (Table 4). Recombivax HB may be administered in a 2-dose schedule at 0 and 4–6 months for persons aged 11–15 years using the adult formulation. Pediarix is administered at ages 2, 4, and 6 months; it is not used for the birth dose. Twinrix may be administered before travel or any other potential exposure on an accelerated schedule at 0, 7, and 21–30 days, followed by a dose at 12 months. HepB vaccination of adult hemodialysis patients consists of high-dose (40 µg) Recombivax HB administered on a 0-, 1-, and 6-month schedule or high-dose (40 µg) Engerix-B administered on a 0-, 1-, 2-, and 6-month schedule (106).

Alternative vaccination schedules (e.g., 0, 1, and 4 months or 0, 2, and 4 months) have been demonstrated to elicit dose-specific and final rates of seroprotection similar to those obtained on a 0-, 1-, and 6-month schedule. Increasing the interval between the first 2 doses has little effect on immunogenicity or the final antibody concentration (139–141). The third dose confers the maximum level of seroprotection and provides long-term protection (142). Longer intervals between the last 2 doses (e.g., 11 months) result in higher final antibody levels (142) but might increase the risk for acquisition of HBV infection among persons who have a delayed response to vaccination. Higher geometric mean titers are associated with longer persistence of measurable anti-HBs.

Response to Revaccination

A challenge dose of HepB vaccine may be used to determine the presence of vaccine-induced immunologic memory through generation of an anamnestic response. The term “booster dose” has been used to refer to a dose of HepB vaccine administered after a primary vaccination series to provide rapid protective immunity against significant infection (i.e., infection resulting in serologic test results positive for HBV and/or clinically significant disease). Among persons who were vaccinated prior to age 1 year and found to have anti-HBs levels <10 mIU/mL 6–18 years later, a single challenge dose of HepB vaccine resulted in anti-HBs levels ≥10 mIU/mL in 60%–97% of those tested. Similar results were found among persons initially vaccinated at age ≥1 year (10). Immunocompetent persons with a response ≥10 mIU/mL following a challenge dose are considered protected, regardless of subsequent declines in anti-HBs (10,109).

One study found that of infants born to HBsAg-positive women who were not infected at birth and who did not respond to a primary vaccine series, all developed seroprotective levels of anti-HBs after receipt of 3 additional doses (143). No data exist that suggest that children who have no detectable antibody after 6 doses of vaccine benefit from additional doses.

Maternal Antiviral Therapy for Preventing Perinatal HBV Transmission

Antiviral therapy (i.e., lamivudine, telbivudine, and tenofovir) has been studied as an intervention to reduce perinatal HBV transmission among pregnant women with high HBV DNA levels (e.g., average HBV DNA levels of 7.6 log10 IU/mL) (144). Maternal antiviral therapy started at 28–32 weeks’ gestation, as an adjunct to HepB vaccine and HBIG administered to the infant shortly after delivery, has been associated with significantly reduced rates of perinatal HBV transmission (5). The use of lamivudine and telbivudine is limited by viral resistance and mutations. Tenofovir is not associated with resistance and is the preferred agent (5). Available data support the safety of tenofovir during pregnancy, although its use might be associated with reduced bone mineral content in infants with in utero exposure (5,39,63,144–146). AASLD suggests antiviral therapy to reduce perinatal HBV transmission when maternal HBV DNA is >200,000 IU/mL. Maternal therapy is generally discontinued at birth to 3 months postpartum (5).

Cost-Effectiveness Considerations

HBV prevention strategies targeting perinatal transmission are considered very cost-effective (i.e., an incremental cost-effectiveness ratio <$25,000). The current strategy of administering HepB vaccine and HBIG within 12 hours of birth for infants born to HBsAg-positive mothers and universal infant vaccination prior to hospital discharge has an incremental cost-effectiveness ratio of $6,957 per quality-adjusted life year (QALY) saved when compared with a strategy of universal infant HepB vaccination prior to hospital discharge alone (147). CDC’s U.S. Perinatal Hepatitis B Prevention Program (https://www.cdc.gov/hepatitis/partners/perihepbcoord.htm), which provides case management services to infants born to HBsAg-positive women, also has been demonstrated to decrease infections, increase QALYs saved, and be a cost-effective use of resources (148). A strategy of testing HBsAg-positive pregnant women for HBV DNA, followed by maternal antiviral prophylaxis for women with high HBV DNA, would cost an additional $3 million but would save 2,080 QALYs and prevent 324 chronic HBV infections, and therefore would be considered cost-effective, with an incremental cost-effectiveness ratio of $1,583 per QALY saved (36).

Cost-effectiveness also has been assessed for HBV prevention strategies outside of the perinatal setting. Vaccinating adults aged 20–59 years with diabetes mellitus costs $75,094 per QALY saved; cost-effectiveness ratios increase with age at vaccination (149). Among previously vaccinated current HCP (including those in training), pre-exposure anti-HBs testing followed by revaccination and retesting (if necessary, based on anti-HBs levels), compared with no intervention, was not considered cost-effective with an incremental cost per QALY saved of $3–$4 million at year one and approximately $800,000 over 10 years (150).

Prevention of Perinatal HBV Transmission

Persons Recommended for HepB Vaccination

Implementation Strategies

Postexposure Prophylaxis

This section provides recommendations for management of persons who are exposed to HBV through a distinct, identifiable exposure to blood or body fluids that contain blood, in occupational and nonoccupational settings.

• Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water. Using antiseptics (e.g., 2%–4% chlorhexidine) for wound care or expressing fluid by squeezing the wound further have not been shown to reduce the risk for HBV transmission; however, the use of antiseptics is not contraindicated. The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended.

Immunization Management Issues