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Experience with hepatitis A and B vaccines
The American Journal of Medicine (2005) Vol 118 (10A), 7S–15S
Experience with hepatitis A and B vaccines Jeffrey P. Davis, MD Bureau of Communicable Diseases and Preparedness, Wisconsin Division of Public Health, Madison, Wisconsin, USA. KEYWORDS: Combination vaccine; Efficacy; Hepatitis A; Hepatitis B; Immunogenicity; Vaccine
The lengthy history of efforts to understand the pathogenesis and means of preventing and controlling both hepatitis A and B is noteworthy for many exceptional scientific achievements. Among these are the development of vaccines to prevent the spread of infection through induction of active immunity to hepatitis A virus (HAV) and hepatitis B virus (HBV). The first plasma-derived hepatitis B vaccine was licensed in the United States in 1981 and was replaced by recombinant hepatitis B vaccines in 1986 and 1989. Vaccines to prevent HAV infection were licensed in the United States in 1995 and 1996. Subsequently, combination vaccines that included both hepatitis A and B vaccine components, or the hepatitis B component in combination with other commonly administered vaccines, were licensed in the United States. Despite significant reductions in hepatitis-related morbidity and mortality that have resulted from widespread use of these vaccines, vaccine-preventable morbidity and mortality still occur. The purposes of this article are to review clinical trial and other experience with hepatitis A and B vaccines in healthy individuals as well as in those with chronic liver disease, infected with the human immunodeficiency virus, or requiring hemodialysis; describe the impact that these vaccines and national recommendations for vaccination have had on reducing the incidence of HAV and HBV infection; and recommend expansion of these recommendations to include universal vaccination of adults as a means of further reducing the burden of viral hepatitis. © 2005 Elsevier Inc. All rights reserved.
The lengthy history of efforts to describe, delineate, control, and prevent hepatitis A and B is rich and noteworthy for many exceptional scientific achievements. Efforts to prevent and control hepatitis A and B have posed enormous challenges to the public health and healthcare delivery systems. Important strides were made when the epidemiologic features of infectious hepatitis (hepatitis A) and homologous serum hepatitis (hepatitis B) were delineated in the 1940s and when evidence of hepatitis B virus (HBV) and, subsequently, hepatitis A virus (HAV) infections became specifically detectable in the 1970s by means of serologic tests.1–3 Nonetheless, in the 1970s, hepatitis A and B were high-incidence conditions, associated with labor-intensive Address correspondence to Jeffrey P. Davis, MD, Bureau of Communicable Diseases and Preparedness, Wisconsin Division of Public Health, 1 West Wilson Street, Room 318, Madison, Wisconsin 53702. E-mail address: [email protected]
0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.07.011
control measures involving active case finding, follow-up, public health education, application of hygienic measures, and time-sensitive administration of immune globulin (hepatitis A) or hepatitis B immune globulin to provide shortterm passive immunity for preventing infection in contacts and others at risk. Great advances in the control of HAV and HBV infections occurred following the availability of vaccines to induce active immunity, with use of the vaccines based on understanding of risk factors for transmission of these infections. A vaccine produced using plasma-derived hepatitis B virus surface antigen (HBsAg) was licensed in the United States in 1981.4 The current hepatitis B vaccines manufactured using recombinant DNA technology were licensed in the United States in 1986 and 1989. Vaccines to prevent HAV infection were licensed in the United States in 1995 and 1996.3 Despite the significant reduction in HAV- and
8S HBV-related morbidity that occurred as a result of widespread use of these vaccines, significant vaccine-preventable morbidity still occurs. This article provides a brief review and discussion of experiences with hepatitis A and B vaccines and discusses the ways in which recommended use of these vaccines has had a substantial impact on reducing the incidence of HAV- and HBV-related infection and disease.
Hepatitis A and B vaccines currently available in the United States Several safe and effective hepatitis A and B vaccines are available worldwide. Vaccines currently licensed and available in the United States, and the vaccine companies that make them, include the single-antigen hepatitis A vaccines (Havrix, GlaxoSmithKline, Research Triangle Park, NC; Vaqta, Merck and Co., Inc., Whitehouse Station, NJ); the single-antigen hepatitis B vaccines (Engerix-B, GlaxoSmithKline; Recombivax HB, Merck and Co., Inc.); and a combination vaccine that includes both hepatitis A and B vaccine components (Twinrix; GlaxoSmithKline). Other combination vaccines that have a hepatitis B vaccine component include Pediarix (diphtheria and tetanus toxoids, acellular pertussis adsorbed, recombinant hepatitis B, and inactivated poliovirus: GlaxoSmithKline), and Comvax (Haemophilus influenzae type b conjugate [Hib] and recombinant hepatitis B: Merck and Co., Inc.).
Hepatitis A vaccines HAV, a picornavirus, exists as a single serotype worldwide. Protective antibodies that develop in response to HAV infection confer lifelong immunity.5 Hepatitis A vaccines are derived from a cell-culture-adapted virus grown in human fibroblasts that is then purified, inactivated with formalin, and adsorbed to an aluminum hydroxide adjuvant.3 Havrix is prepared with 2-phenoxyethanol as a preservative, and Vaqta is formulated without a preservative. Formulations are available for administration to children and adolescents and to adults (Table 1).3,6,7
The American Journal of Medicine, Vol 118 (10A), October 2005 are considered equivalent to preservative-free products; this vaccine may contain trace amounts (⬍0.3 g) of mercury after postproduction thimerosal removal, but these amounts have no biological effect.8,9 There are 4 known subtypes of HBsAg, but the vaccines protect against HBV strains because of determinants unrelated to subtype.2,10 Protection from hepatitis B vaccine is derived, in part, from immunologic memory established following vaccination. While levels of vaccine-induced antibodies gradually decline, immune memory in healthy individuals following receipt of a full series of hepatitis B vaccinations persists for ⬎15 years; consequently, booster doses of hepatitis B vaccine are not routinely recommended.4 Formulations are available for administration to children, adolescents, adults, and patients requiring dialysis (Table 2).4,11,12
Combination hepatitis A and B vaccine Twinrix is approved for use in the United States in persons ⱖ18 years of age who need protection against both HAV and HBV.3 It contains hepatitis A antigen (720 enzyme-linked immunosorbent assay [ELISA] units) and HBsAg (20 g) and is administered on a 0-, 1-, and 6- to 12-month schedule. Its hepatitis A vaccine component is equivalent to the pediatric dose of Havrix and its hepatitis B vaccine component is equivalent to the adult dose of Engerix-B.
Other combination vaccines with a hepatitis B component Pediarix is licensed for use in children aged 6 weeks to 6 years and is administered in 3 doses, at 2, 4, and 6 months of age, including those infants who received a birth dose of hepatitis B vaccine13; it is not approved for booster doses.4 The hepatitis B component in Pediarix is Engerix-B. Comvax can be used when either hepatitis B or Hib conjugate vaccine is indicated, but it cannot be used in infants aged ⬍6 weeks.4 The hepatitis B component and dosage in Comvax is the same as in Recombivax HB. Both Pediarix and Comvax can be used in infants whose mothers are HBsAgpositive or whose HBsAg status is unknown.4
Hepatitis B vaccines HBV, a member of the hepadnaviridae family, has numerous antigenic components. The antigen used in currently available hepatitis B vaccines is recombinant HBsAg that is produced by inserting a plasmid containing the gene for HBsAg into yeast (Saccharomyces cerevisiae) cells.4 Following harvesting and purification of the HBsAg, it is adsorbed to aluminum hydroxide. The final product contains ⬎95% HBsAg protein and ⬍5% yeast-derived protein; no yeast DNA is detectable in the vaccine. Recombivax HB formulations are preservative free. Engerix-B formulations
Immunogenicity and efficacy Healthy individuals Hepatitis A vaccines are safe, highly and rapidly immunogenic, and provide durable protection against infection in persons who receive the recommended doses.14 –19 Of note, after a single dose of vaccine, antibody titers are higher than those produced by known protective levels of immune glob-
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Experience with Hepatitis A and B Vaccines Table 1
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Recommended doses of hepatitis A vaccines
Vaccine
Age (y)
Havrix6†
2–18 ⬎18 1–18 ⬎18
Vaqta7‡
Dose
Volume (mL)
2-Dose Schedule (mo)*
720 ELU 1440 ELU 25 U 50 U
0.5 1.0 0.5 1.0
0, 0, 0, 0,
6–12 6–12 6–18 6–18
ELU ⫽ ELISA (enzyme-linked immunosorbent assay) units; U ⫽ antigen units. *0 months represents timing of the initial dose; subsequent numbers represent months after the initial dose. † GlaxoSmithKline, Research Triangle Park, NC. ‡ Merck & Co., Inc., Whitehouse Station, NJ. Adapted from Epidemiology and Prevention of Vaccine-Preventable Diseases.3
Table 2
Recommended doses of hepatitis B vaccines
Vaccine
Age (y) or Group
Dose (g)
Volume (mL)
Dosing Schedule (mo)*
⬍11‡ 11–19 ⱖ20 Dialysis§ ⬍11‡ 11–19 ⱖ20 Predialysis/dialysis¶
10 10 20 40 5 5 10 40
0.5 0.5 1.0 2.0 0.5 0.5 1.0 1.0
0, 0, 0, 0, 0, 0, 0, 0,
11†
Engerix-B
Recombivax HB12㛳
1, 1, 1, 1, 1, 1, 1, 1,
6 6 6 2, 6 6 6 6 6
*0 months represents timing of the initial dose; subsequent numbers represent months after the initial dose. † GlaxoSmithKline, Research Triangle Park, NC. ‡ Infants whose mothers are hepatitis B surface antigen (HBsAg)–positive should also receive hepatitis B immune globulin at birth. § Two 1.0-mL doses given at 1 site. 㛳 Merck & Co., Inc., Whitehouse Station, NJ. ¶ Special formulation for patients on dialysis. Adapted from Epidemiology and Prevention of Vaccine-Preventable Diseases.4
ulin, defined as 10 to 20 mIU/mL (10 to 20 IU/L), but lower than those produced following natural infection.16,19 –21 Within 1 month of receiving the first dose, ⬎97% of children and adolescents and ⬎95% of adults develop protective levels of antibody.22–26 Within 1 month of receiving the second dose, virtually 100% of recipients have protective levels of antibody.23,24,27–29 Both hepatitis A vaccines are highly efficacious in protecting against clinical hepatitis A. In studies conducted in settings with high rates of hepatitis A, the efficacy of 2 doses of Havrix administered 1 month apart during a double-blind, placebo-controlled, randomized clinical trial involving 38,157 children (1 to 16 years old) in Thailand was 94%,17 and the efficacy of Vaqta administered during a trial involving 1,037 children (2 to 16 years old) in upstate New York was 100%.14,30 Although longer-term measures of vaccine efficacy are needed, mathematical models suggest that protective levels of antibody will persist for 24 to 47 years following receipt of a second dose administered 6 to 12 months after the initial dose.31
Hepatitis B vaccine protection, defined as titers of antibodies to hepatitis B surface antigen (anti-HBs) of ⱖ10 mIU/mL (ⱖ10 IU/L), increases with increasing number of doses received. Among infants, reported ranges in antibody response are 16% to 40% following dose 1, 80% to 95% following dose 2, and 98% to 100% following dose 3.4 Preterm infants weighing ⬍2 kg have been shown to have lower seroconversion rates than do full-term infants.4,32 Among teens and adults, reported ranges in antibody response are 20% to 30% following dose 1, 75% to 80% following dose 2, and 90% to 95% following dose 3.4 Factors that may lower vaccine response rates include age ⬎40 years, male gender, smoking, obesity, and immune deficiency. In general, vaccine efficacy is typically 95%, with a reported range in efficacy of 80% to 100% among those who receive the complete vaccination series.2 Immunologic memory is established following hepatitis B vaccination (anamnestic anti-HBs response) and influences longterm efficacy of the vaccine; chronic infection is rarely
10S documented among individuals who demonstrate a response to the vaccine.2 Among healthy individuals, the immunogenicity of the combination hepatitis A and B vaccine for each component is at least as good as that noted for the single-antigen vaccines administered separately (Table 3).33 Geometric mean titers for both the hepatitis A and B components are higher than with separate injections,33 and antibody persistence for ⱖ4 years following vaccination with the combination vaccine has been observed.34
The American Journal of Medicine, Vol 118 (10A), October 2005 vaccine administered on a 0-, 1-, and 6-month schedule was reduced at month 7 (77% seroconversion; GMT ⫽ 636 mIU/mL [636 IU/L]) compared with the immunogenicity in 20 HIV-negative MSM (100% seroconversion; GMT ⫽ 1,687 mIU/mL).45 Studies conducted among HIV-positive patients during the late 1980s and 1990s demonstrated response rates of 33% to 56% to both recombinant and plasma-derived hepatitis B vaccines, and the response was related to the CD4 cell count. Among HIV-positive patients who demonstrated a response, protective antibody titers were noted to be lower than those in HIV-negative control subjects (Table 4).44,46 – 49
Individuals with chronic liver disease Among persons with chronic liver disease (CLD), the risk of HAV infection in susceptible individuals is not increased, but the risk of fulminant hepatitis A is.3 Seroconversion rates 1 month after receiving dose 2 of single-antigen hepatitis A vaccine (on a 0- and 6-month schedule) are similar among healthy adults (98.2% of 167) and adults with chronic HBV infection (97.7% of 44), chronic HCV infection (94.3% of 87), or other causes of CLD (95.2% of 63).35 The response at month 7 to hepatitis A vaccine among recipients with decompensated liver disease (n ⫽ 35; seroconversion ⫽ 65.7%; geometric mean titer [GMT] ⫽ 103 mIU/mL [103 IU/L]), however, is significantly lower than the response among recipients with compensated liver disease (n ⫽ 49; seroconversion ⫽ 98%; GMT ⫽ 328 mIU/ mL; P ⫽ 0.001).36 Studies on the immunogenicity and efficacy of hepatitis B vaccine in patients with CLD are limited to patients with alcoholic liver disease or chronic hepatitis C. In patients with mild alcoholic liver disease or mild or moderate chronic hepatitis C, the anti-HBs seroconversion rate following 3 doses of hepatitis B vaccine is similar to that in healthy individuals, reaching as high as 100% in some studies.37–39 In patients with documented alcoholic cirrhosis, however, seroconversion rates are lower, ranging from 12% to 75%.37,40,41 The seroconversion rate in individuals waiting for liver transplantation or in immunosuppressed liver transplant recipients is much lower; response rates have been observed in the range of 7% to 55%.37,42 Additional information on the immunogenicity and efficacy of hepatitis A and B vaccines in individuals with CLD and the possible need for higher vaccine doses or booster vaccinations in this population can be found elsewhere in this supplement.43
Patients with human immunodeficiency virus infection The immunogenicity of hepatitis A and B vaccines is impaired in patients with human immunodeficiency virus (HIV) infection.44 Among 14 HIV-positive men who have sex with men (MSM), the immunogenicity of hepatitis A
Patients receiving hemodialysis Hepatitis A vaccines confer similar protection in both patients requiring hemodialysis and healthy individuals. In 1 study, 42 (98%) of 43 patients receiving hemodialysis developed antibodies following a 3-dose series of hepatitis A vaccine.50 Patients undergoing hemodialysis generally have a lower rate of seroprotection following hepatitis B vaccination than do healthy vaccinees, and the hepatitis B vaccine dosage for these individuals is greater than in healthy adults (Table 2).4 Seroprotection has been documented in 64% of patients undergoing hemodialysis following a 3-dose series and in 86% of these patients following a 4-dose series.51 The need for booster doses of hepatitis B vaccine in patients requiring hemodialysis should be assessed annually by testing vaccinees for anti-HBs levels; booster doses should be provided to vaccinees whose antibody levels are ⬍10 mIU/mL.4
Impact of hepatitis A and B vaccines on incidence of infection Hepatitis A vaccination Following the licensure of hepatitis A vaccines in the United States in 1995 and 1996, the initial Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) recommendations for hepatitis A vaccination published in 1996 were risk based and included use in persons traveling to or working in countries highly or moderately endemic for hepatitis A, in MSM, in persons who use illegal injection drugs, in persons who have clotting-factor disorders, in persons with occupational risk, and in persons with CLD.52 Broader, population-based recommendations followed in 1999 and included routine vaccination of children aged ⱖ2 years in communities with high endemic rates of hepatitis A and with hepatitis A outbreaks, such as the Native American and Alaskan native populations, and in states (11 states primarily in the western United States),
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Experience with Hepatitis A and B Vaccines
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Table 3 Immunogenicity of combination hepatitis A and B vaccines compared with monovalent vaccines
Vaccine
N
Combination A/B
264
Monovalent vaccines
269
Time Point (mo)
Seroconversion for Hepatitis A (%)*
Seroprotection for Hepatitis B (%)†
1 2 7 1 2 7
91.6 97.7 99.6 98.1 98.9 99.3
17.9 61.2 95.1 7.5 50.4 92.2
(To convert conventional units to SI units, change units to “international units per liter [IU/L].”) *Geometric mean titer of antibodies to hepatitis A virus ⱖ33 mIU/mL. † Geometric mean titer of antibodies to hepatitis B surface antigen ⱖ10 mIU/mL. Adapted with permission from Vaccine.33
Table 4 Response to hepatitis B vaccine administered on a 0-, 1-, 6-month schedule in human immunodeficiency virus (HIV)-positive and HIV-negative men who have sex with men (MSM) Number of Patients with Response to Hepatitis B Vaccine/Number Tested (% with response) Study 49
Wong et al. Loke et al.48 Collier et al.47 Carne et al.46 Combined range (%)
HIV-Positive MSM
HIV-Negative MSM
6/14 (42.9) 9/27 (33.3) 9/16 (56.3) 9/17 (52.9) (33.3–56.3)
105/120 (87.5) 69/77 (89.6) 62/68 (91.2) 17/18 (94.4) (87.5–94.4)
Adapted with permission from Clin Infect Dis.44
counties, or communities where the average annual reported hepatitis A incidence during 1987–1997 was ⱖ20 cases per 100,000 population.5 In addition, routine vaccination was to be considered for all children aged ⱖ2 years in states, counties, or communities where the average annual reported hepatitis A incidence during 1987–1997 was ⱖ10 cases but ⬍20 cases per 100,000 population. The reported incidence of hepatitis A decreased from 12 cases per 100,000 in 1995 to 3.1 cases per 100,000 in 2002 (Figure 1).53 Reduction in mean incidence was greatest in the 11 states where routine statewide vaccination of all children aged ⱖ2 years was recommended by the ACIP in 1999 (67% reduction from 7.2 cases [mean] per 100,000 population in 1999 to 2.4 cases [mean] per 100,000 in 2002) and was proportionally similar in the 6 states where routine vaccination of all children aged ⱖ2 years was to be considered (69% reduction from 6.4 cases [mean] per 100,000 population in 1999 to 2.0 cases [mean] per 100,000 in 2002).53 In the remaining 33 states with no routine age-based recommendation for hepatitis A vaccination, reductions in incidence were much smaller (35% reduction from 3.4
cases [mean] per 100,000 population in 1999 to 2.2 cases [mean] per 100,000 in 2002).53 The greatest reduction in reported incidence of acute hepatitis A cases between 1996 and 2002 occurred in 5- to 14-year-old children. Children aged ⬍5 years and adults aged ⱖ40 years have the lowest reported rates of acute hepatitis A infection, and persons aged 15 to 39 years have the highest rate of infection. The low and stable rate of acute infection in persons aged ⱖ40 years is thought to be a result of high rates of immunity from previous infection in this population.53 Although sexual and household contact remain the leading modes of transmission of hepatitis A, the incidences among international travelers and MSM have increased dramatically since 1995,53 despite recommendations to vaccinate persons in these groups at high risk. Among international travelers, the reported incidence of hepatitis A increased from 2.8 cases per 100,000 in 1995 to 9.4 cases per 100,000 in 2002; among MSM, the rate increased from 2.3 cases to 8.4 cases per 100,000 during this same period.53 Incidences have decreased in illegal injection drug users and in those with day-care contact. In communities with sustained transmission of HAV, substantial decreases in community hepatitis A rates—as a
12S result of targeted vaccination efforts with a single dose of hepatitis A vaccine— have been noted.14,54 –56 Additional information on the efficacy of single doses of hepatitis A vaccine in preventing infection can be found elsewhere in this supplement.57
The American Journal of Medicine, Vol 118 (10A), October 2005 modes of transmission of hepatitis B. Much like the incidence of acute hepatitis A, the incidence of acute hepatitis B is increasing among MSM, despite recommendations to vaccinate persons in this group at high risk.
Benefits of combination vaccines Hepatitis B vaccination Following initial licensure of the plasma-derived formulation of hepatitis B vaccine in 1981, the initial ACIP recommendations for hepatitis B vaccination published in 1982,58 1985,59 and 198760 were risk based and included use in travelers to hepatitis B– endemic countries, MSM, users of illegal injection drugs, and those with clotting-factor disorders or occupational risk of exposure. Because of a variety of events, particularly the emergence of the acquired immunodeficiency syndrome reported among recipients of blood and certain blood products, the initial uptake of the safe and effective plasma-derived hepatitis B vaccine was less than anticipated.4 Thus, despite the availability of safe and effective vaccines and national guidelines for vaccination, the reported incidence of acute hepatitis B continued to increase until 1985, when a decline in morbidity among MSM and healthcare workers ensued, followed by declines in morbidity among injecting drug users.53 The ACIP recommendations that contributed to subsequent substantial reductions in incidence of acute hepatitis B included the 1988 recommendation to screen pregnant women for HBsAg and protect neonates born to HBV-infected mothers,61 the 1991 recommendation for routine vaccination of all infants with hepatitis B vaccine,10 and the 1996 recommendation— endorsed by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American Medical Association—for routine immunization of adolescents aged 11 and 12 years with hepatitis B vaccine.62 In 1999, the ACIP expanded its recommendation of universal vaccination of adolescents to include all those aged ⬍19 years63; however, no additional age-based recommendations exist. Thus, the plethora of risk-based recommendations for vaccination in persons aged ⱖ19 years adds complexity to screening individuals for hepatitis B risk factors and reduces the likelihood that these persons will be appropriately vaccinated.64 The cumulative effect in the United States of the use of hepatitis B vaccines stimulated by these policies has been striking reductions in the reported incidence of acute hepatitis B from 9.2 cases per 100,000 in 1981 to 2.8 cases per 100,000 in 2002, a rate that has been stable since 1999 (Figure 2).53 Although the greatest reduction in incidence of acute hepatitis B cases occurred in 15- to 39-year-olds, this age group still has the highest incidence of acute infection. As with hepatitis A, the lowest reported rates of acute HBV infection occur in children aged ⬍5 years and adults aged ⱖ40 years. Sexual encounters (i.e., multiple sexual partners) and illegal injection drug use are the leading
Combination vaccines that contain hepatitis A and/or hepatitis B components (Twinrix, Pediarix, Comvax) provide an option for the administration of fewer injections while safety and immunogenicity remain similar to that associated with separately administered vaccines.33 Licensed combination vaccines are at least as immunogenic as separate injections of component vaccines. The ACIP, AAP, and AAFP recommend that licensed combination vaccines be used whenever any component of the combination vaccine is indicated and its other components are not contraindicated.65
Summary Several well-substantiated observations are fundamental to the experiences with hepatitis A and B vaccines. First, hepatitis A and B vaccines confer high rates of immunity in healthy children, adolescents, and adults; seroconversion rates for hepatitis A and B vaccines in patients with CLD and HIV infection may be lower. Patients receiving hemodialysis may have lower rates of seroprotection after hepatitis B vaccination, but they show a good response to hepatitis A vaccine. Vaccination early in the course of illness in these patients at high risk maximizes protection. Second, combined hepatitis A and B vaccine offers safety and immunogenicity equivalent to that of separate vaccines with fewer injections and is preferable to separate vaccines when both vaccine components are indicated. Recommended use of hepatitis A and B vaccines has had a substantial impact on reducing the respective incidences of HAV and HBV infection and their related morbidity and mortality. Of particular note, age-based recommendations for vaccination of individuals against hepatitis A and B have proven to be highly effective. Expansion of such recommendations to include universal vaccination of adults should be considered to provide maximal protection among the general population of the United States. It is important to achieve early vaccination of individuals at high risk for acquiring hepatitis A or B. Because the time of exposure to these viruses is unpredictable, earlier vaccination maximizes the likelihood of successful immunization. Furthermore, immunity induced by each of these vaccines can last for many years, if not a lifetime, and vaccination of individuals at high risk as soon as they are identifiable will reduce missed opportunities to vaccinate, particularly in those individuals likely to be difficult to access later in life.
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Figure 1 Incidence (reported cases per 100,000 population) of acute hepatitis A in the United States by year, 1980 –2002. ACIP ⫽ Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. (Data from Centers for Disease Control and Prevention.53)
Figure 2 Incidence (reported cases per 100,000 population) of acute hepatitis B in the United States by year, 1980 –2002. HBsAg ⫽ hepatitis B virus surface antigen. (Data from Centers for Disease Control and Prevention.53)
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Vaccine-Preventable Diseases. 8th ed. Washington, DC: Public Health Foundation, 2004:191–212. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1999;48(RR-12):1–37. Havrix prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2005. Vaqta prescribing information. Whitehouse Station, NJ: Merck and Co., Inc.; 2005. Halsey NA. Limiting infant exposure to thimerosal in vaccines and other sources of mercury [editorial]. JAMA. 1999;282:1763–1766. Offit PA. Preventing harm from thimerosal in vaccines [letter]. JAMA. 2000;283:2104 –2105.
14S 10. Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep. 1991;40(RR-13):1–19. 11. Engerix-B prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2004. 12. Recombivax HB prescribing information. Whitehouse Station, NJ: Merck and Co., Inc.; 2004. 13. American Academy of Pediatrics. Hepatitis B. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003: 318 –336. 14. Werzberger A, Mensch B, Kuter B, et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med. 1992;327:453– 457. 15. Nalin DR, Kuter BJ, Brown L, et al. Worldwide experience with the CR326F-derived inactivated hepatitis A virus vaccine in pediatric and adult populations: an overview. J Hepatol. 1993;18(suppl 2):S51–S55. 16. Shouval D, Ashur Y, Adler R, et al. Safety, tolerability, and immunogenicity of an inactivated hepatitis A vaccine: effects of single and booster injections, and comparison to administration of immune globulin. J Hepatol. 1993;18(suppl 2):S32–S37. 17. Innis BL, Snitbhan R, Kunasol P, et al. Protection against hepatitis A by an inactivated vaccine. JAMA. 1994;271:1328 –1334. 18. Vidor E, Fritzell B, Plotkin S. Clinical development of a new inactivated hepatitis A vaccine. Infection. 1996;24:447– 458. 19. Van Damme P, Thoelen S, Cramm M, de Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol. 1994;44:446 – 451. 20. Hoke CH Jr, Binn LN, Egan JE, et al. Hepatitis A in the US Army: epidemiology and vaccine development. Vaccine. 1992;10(suppl 1): S75–S79. 21. Fujiyama S, Odoh K, Kuramoto I, Mizuno K, Tsurusaki R, Sato T. Current seroepidemiological status of hepatitis A with a comparison of antibody titers after infection and vaccination. J Hepatol. 1994;21: 641– 645. 22. Horng YC, Chang MH, Lee CY, Safary A, Andre FE, Chen DS. Safety and immunogenicity of hepatitis A vaccine in healthy children. Pediatr Infect Dis J. 1993;12:359 –362. 23. Clemens R, Safary A, Hepburn A, Roche C, Stanbury WJ, Andre FE. Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis. 1995;171(suppl 1):S44 –S49. 24. Nalin DR. VAQTATM, hepatitis A vaccine, purified inactivated. Drugs Future. 1995;20:24 –29. 25. McMahon BJ, Williams J, Bulkow L, et al. Immunogenicity of an inactivated hepatitis A vaccine in Alaska native children and native and non-native adults. J Infect Dis. 1995;171:676 – 679. 26. Balcarek KB, Bagley MR, Pass RF, Schiff ER, Krause DS. Safety and immunogenicity of an inactivated hepatitis A vaccine in preschool children. J Infect Dis. 1995;171(suppl 1):S70 –S72. 27. Lee SD, Lo KJ, Chan CY, Yu MY, Wang YJ, Safary A. Immunogenicity of inactivated hepatitis A vaccine in children. Gastroenterology. 1993;104:1129 –1132. 28. Nalin D, Brown L, Kuter B, et al. Inactivated hepatitis A vaccine in childhood: implications for disease control. Vaccine. 1993;11(suppl 1):S15–S17. 29. Block SL, Hedrick JA, Tyler RD, et al. Safety, tolerability and immunogenicity of a formalin-inactivated hepatitis A vaccine (VAQTA) in rural Kentucky children. Pediatr Infect Dis J. 1993;12:976 –980. 30. Werzberger A, Kuter B, Shouval D, et al. Anatomy of a trial: a historical view of the Monroe inactivated hepatitis A protective efficacy trial. J Hepatol. 1993;18(suppl 2):S46 –S50. 31. Wiedermann G, Kundi M, Ambrosch F, Safary A, D’Hondt E, Delem A. Inactivated hepatitis A vaccine: long-term antibody persistence. Vaccine. 1997;15:612– 615.
The American Journal of Medicine, Vol 118 (10A), October 2005 32. Patel D, Butler J, Feldman S, Graves GR, Rhodes PG. Immunogenicity of hepatitis B vaccine in healthy very low birth weight infants. J Pediatr. 1997;130:641– 643. 33. Joines RW, Blatter M, Abraham B, et al. A prospective, randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix®) with corresponding monovalent vaccines (Havrix® and Engerix-B®) in adults. Vaccine. 2001;19:4710 – 4719. 34. Van Damme P, Leroux-Roels G, Law B, et al. Long-term persistence of antibodies induced by vaccination and safety follow-up, with the first combined vaccine against hepatitis A and B in children and adults. J Med Virol. 2001;65:6 –13. 35. Keeffe EB, Iwarson S, McMahon BJ, et al. Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease. Hepatology. 1998;27:881– 886. 36. Arguedas MR, Johnson A, Eloubeidi MA, Fallon MB. Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients. Hepatology. 2001;34:28 –31. 37. Keeffe EB. Vaccination against hepatitis A and B in chronic liver disease. Viral Hepat Rev. 1999;5:77– 88. 38. Keeffe EB, Krause DS. Hepatitis B vaccination of patients with chronic liver disease [letter]. Liver Transpl Surg. 1998;4:437– 439. 39. Lee SD, Chan CY, Yu MI, Lu RH, Chang FY, Lo KJ. Hepatitis B vaccination in patients with chronic hepatitis C. J Med Virol. 1999; 59:463– 468. 40. De Maria N, Idilman R, Colantoni A, Van Thiel DH. Increased effective immunogenicity to high-dose and short-interval hepatitis B virus vaccination in individuals with chronic hepatitis without cirrhosis. J Viral Hepat. 2001;8:372–376. 41. Idilman R, De Maria N, Colantoni A, Nadir A, Van Thiel DH. The effect of high dose and short interval HBV vaccination in individuals with chronic hepatitis C. Am J Gastroenterol. 2002;97:435– 439. 42. Dominguez M, Barcena R, Garcia M, Lopez-Sanroman A, Nuno J. Vaccination against hepatitis B virus in cirrhotic patients on liver transplant waiting list. Liver Transplantation. 2000;6:440 – 442. 43. Keeffe EB. Acute hepatitis A and B in patients with chronic liver disease: prevention through vaccination. Am J Med. 2005;118(suppl 10A):21S–27S. 44. Kahn J. Preventing hepatitis A and hepatitis B virus infections among men who have sex with men. Clin Infect Dis. 2002;35:1382–1387. 45. Hess G, Clemens R, Bienzle U, Schönfeld C, Schunck B, Bock HL. Immunogenicity and safety of an inactivated hepatitis A vaccine in anti-HIV positive and negative homosexual men. J Med Virol. 1995; 46:40 – 42. 46. Carne CA, Weller IVD, Waite J, et al. Impaired responsiveness of homosexual men with HIV antibodies to plasma derived hepatitis B vaccine. Br Med J (Clin Res Ed). 1987;294:866 – 868. 47. Collier AC, Corey L, Murphy VL, Handsfield HH. Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination. Ann Intern Med. 1988;109:101–105. 48. Loke RHT, Murray-Lyon IM, Coleman JC, Evans BA, Zuckerman AJ. Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: an indicator of poor prognosis. J Med Virol. 1990;31:109 –111. 49. Wong EKL, Bodsworth NJ, Slade MA, Mulhall BP, Donovan B. Response to hepatitis B vaccination in a primary care setting: influence of HIV infection, CD4⫹ lymphocyte count and vaccination schedule. Int J STD AIDS. 1996;7:490 – 494. 50. Fleischmann EH, Kruppenbacher J, Bock HL, Weber M. Active immunization against hepatitis A in dialysis patients. Nephrol Dial Transplant. 2002;17:1825–1828. 51. Centers for Disease Control and Prevention. Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep. 2001;50(RR-5):1– 43. 52. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1996;45(RR-15):1–30.
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53. Centers for Disease Control and Prevention. Hepatitis Surveillance Report No. 59. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2004. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/hep_ surveillance_59.pdf. Accessed June 8, 2005. 54. McMahon BJ, Beller M, Williams J, Schloss M, Tanttila H, Bulkow L. A program to control an outbreak of hepatitis A in Alaska by using an inactivated hepatitis A vaccine. Arch Pediatr Adolesc Med. 1996;150: 733–739. 55. Averhoff F, Shapiro C, Hyams I, et al. Use of inactivated hepatitis A vaccine to interrupt a communitywide hepatitis A outbreak. Presented at: 36th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15–18, 1996; New Orleans, Louisiana. Abstract H073. 56. Craig AS, Sockwell DC, Schaffner W, et al. Use of hepatitis A vaccine in a community-wide outbreak of hepatitis A. Clin Infect Dis. 1998; 27:531–535. 57. Connor BA. Hepatitis A vaccine in the last-minute traveler. Am J Med. 2005;118(suppl 10A):58S– 62S. 58. Centers for Disease Control and Prevention. Recommendation of the Immunization Practices Advisory Committee (ACIP): inactivated hepatitis B virus vaccine. MMWR Morb Mortal Wkly Rep. 1982;31:317– 322,327–328.
15S 59. Centers for Disease Control and Prevention. Recommendations for protection against viral hepatitis. MMWR Morb Mortal Wkly Rep. 1985;34:313–324,329 –335. 60. Centers for Disease Control and Prevention. Update on hepatitis B prevention. MMWR Morb Mortal Wkly Rep. 1987;36:353–360,366. 61. Centers for Disease Control and Prevention. Prevention of perinatal transmission of hepatitis B virus: prenatal screening of all pregnant women for hepatitis B surface antigen. MMWR Morb Mortal Wkly Rep. 1988;37:341–346,351. 62. Centers for Disease Control and Prevention. Immunization of adolescents: recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association. MMWR Recomm Rep. 1996;45(RR-13):1–16. 63. Centers for Disease Control and Prevention. Update: recommendations to prevent hepatitis B virus transmission—United States. MMWR Morb Mortal Wkly Rep. 1999;48:33–34. 64. Poland GA. Evaluating existing recommendations for hepatitis A and B vaccination. Am J Med. 2005;118(suppl 10A):16S–20S. 65. Centers for Disease Control and Prevention. Combination vaccines for childhood immunization. MMWR Recomm Rep. 1999;48(RR5):1–14.
Experience with hepatitis A and B vaccines Jeffrey P. Davis, MD Bureau of Communicable Diseases and Preparedness, Wisconsin Division of Public Health, Madison, Wisconsin, USA. KEYWORDS: Combination vaccine; Efficacy; Hepatitis A; Hepatitis B; Immunogenicity; Vaccine
The lengthy history of efforts to understand the pathogenesis and means of preventing and controlling both hepatitis A and B is noteworthy for many exceptional scientific achievements. Among these are the development of vaccines to prevent the spread of infection through induction of active immunity to hepatitis A virus (HAV) and hepatitis B virus (HBV). The first plasma-derived hepatitis B vaccine was licensed in the United States in 1981 and was replaced by recombinant hepatitis B vaccines in 1986 and 1989. Vaccines to prevent HAV infection were licensed in the United States in 1995 and 1996. Subsequently, combination vaccines that included both hepatitis A and B vaccine components, or the hepatitis B component in combination with other commonly administered vaccines, were licensed in the United States. Despite significant reductions in hepatitis-related morbidity and mortality that have resulted from widespread use of these vaccines, vaccine-preventable morbidity and mortality still occur. The purposes of this article are to review clinical trial and other experience with hepatitis A and B vaccines in healthy individuals as well as in those with chronic liver disease, infected with the human immunodeficiency virus, or requiring hemodialysis; describe the impact that these vaccines and national recommendations for vaccination have had on reducing the incidence of HAV and HBV infection; and recommend expansion of these recommendations to include universal vaccination of adults as a means of further reducing the burden of viral hepatitis. © 2005 Elsevier Inc. All rights reserved.
The lengthy history of efforts to describe, delineate, control, and prevent hepatitis A and B is rich and noteworthy for many exceptional scientific achievements. Efforts to prevent and control hepatitis A and B have posed enormous challenges to the public health and healthcare delivery systems. Important strides were made when the epidemiologic features of infectious hepatitis (hepatitis A) and homologous serum hepatitis (hepatitis B) were delineated in the 1940s and when evidence of hepatitis B virus (HBV) and, subsequently, hepatitis A virus (HAV) infections became specifically detectable in the 1970s by means of serologic tests.1–3 Nonetheless, in the 1970s, hepatitis A and B were high-incidence conditions, associated with labor-intensive Address correspondence to Jeffrey P. Davis, MD, Bureau of Communicable Diseases and Preparedness, Wisconsin Division of Public Health, 1 West Wilson Street, Room 318, Madison, Wisconsin 53702. E-mail address: [email protected]
0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.07.011
control measures involving active case finding, follow-up, public health education, application of hygienic measures, and time-sensitive administration of immune globulin (hepatitis A) or hepatitis B immune globulin to provide shortterm passive immunity for preventing infection in contacts and others at risk. Great advances in the control of HAV and HBV infections occurred following the availability of vaccines to induce active immunity, with use of the vaccines based on understanding of risk factors for transmission of these infections. A vaccine produced using plasma-derived hepatitis B virus surface antigen (HBsAg) was licensed in the United States in 1981.4 The current hepatitis B vaccines manufactured using recombinant DNA technology were licensed in the United States in 1986 and 1989. Vaccines to prevent HAV infection were licensed in the United States in 1995 and 1996.3 Despite the significant reduction in HAV- and
8S HBV-related morbidity that occurred as a result of widespread use of these vaccines, significant vaccine-preventable morbidity still occurs. This article provides a brief review and discussion of experiences with hepatitis A and B vaccines and discusses the ways in which recommended use of these vaccines has had a substantial impact on reducing the incidence of HAV- and HBV-related infection and disease.
Hepatitis A and B vaccines currently available in the United States Several safe and effective hepatitis A and B vaccines are available worldwide. Vaccines currently licensed and available in the United States, and the vaccine companies that make them, include the single-antigen hepatitis A vaccines (Havrix, GlaxoSmithKline, Research Triangle Park, NC; Vaqta, Merck and Co., Inc., Whitehouse Station, NJ); the single-antigen hepatitis B vaccines (Engerix-B, GlaxoSmithKline; Recombivax HB, Merck and Co., Inc.); and a combination vaccine that includes both hepatitis A and B vaccine components (Twinrix; GlaxoSmithKline). Other combination vaccines that have a hepatitis B vaccine component include Pediarix (diphtheria and tetanus toxoids, acellular pertussis adsorbed, recombinant hepatitis B, and inactivated poliovirus: GlaxoSmithKline), and Comvax (Haemophilus influenzae type b conjugate [Hib] and recombinant hepatitis B: Merck and Co., Inc.).
Hepatitis A vaccines HAV, a picornavirus, exists as a single serotype worldwide. Protective antibodies that develop in response to HAV infection confer lifelong immunity.5 Hepatitis A vaccines are derived from a cell-culture-adapted virus grown in human fibroblasts that is then purified, inactivated with formalin, and adsorbed to an aluminum hydroxide adjuvant.3 Havrix is prepared with 2-phenoxyethanol as a preservative, and Vaqta is formulated without a preservative. Formulations are available for administration to children and adolescents and to adults (Table 1).3,6,7
The American Journal of Medicine, Vol 118 (10A), October 2005 are considered equivalent to preservative-free products; this vaccine may contain trace amounts (⬍0.3 g) of mercury after postproduction thimerosal removal, but these amounts have no biological effect.8,9 There are 4 known subtypes of HBsAg, but the vaccines protect against HBV strains because of determinants unrelated to subtype.2,10 Protection from hepatitis B vaccine is derived, in part, from immunologic memory established following vaccination. While levels of vaccine-induced antibodies gradually decline, immune memory in healthy individuals following receipt of a full series of hepatitis B vaccinations persists for ⬎15 years; consequently, booster doses of hepatitis B vaccine are not routinely recommended.4 Formulations are available for administration to children, adolescents, adults, and patients requiring dialysis (Table 2).4,11,12
Combination hepatitis A and B vaccine Twinrix is approved for use in the United States in persons ⱖ18 years of age who need protection against both HAV and HBV.3 It contains hepatitis A antigen (720 enzyme-linked immunosorbent assay [ELISA] units) and HBsAg (20 g) and is administered on a 0-, 1-, and 6- to 12-month schedule. Its hepatitis A vaccine component is equivalent to the pediatric dose of Havrix and its hepatitis B vaccine component is equivalent to the adult dose of Engerix-B.
Other combination vaccines with a hepatitis B component Pediarix is licensed for use in children aged 6 weeks to 6 years and is administered in 3 doses, at 2, 4, and 6 months of age, including those infants who received a birth dose of hepatitis B vaccine13; it is not approved for booster doses.4 The hepatitis B component in Pediarix is Engerix-B. Comvax can be used when either hepatitis B or Hib conjugate vaccine is indicated, but it cannot be used in infants aged ⬍6 weeks.4 The hepatitis B component and dosage in Comvax is the same as in Recombivax HB. Both Pediarix and Comvax can be used in infants whose mothers are HBsAgpositive or whose HBsAg status is unknown.4
Hepatitis B vaccines HBV, a member of the hepadnaviridae family, has numerous antigenic components. The antigen used in currently available hepatitis B vaccines is recombinant HBsAg that is produced by inserting a plasmid containing the gene for HBsAg into yeast (Saccharomyces cerevisiae) cells.4 Following harvesting and purification of the HBsAg, it is adsorbed to aluminum hydroxide. The final product contains ⬎95% HBsAg protein and ⬍5% yeast-derived protein; no yeast DNA is detectable in the vaccine. Recombivax HB formulations are preservative free. Engerix-B formulations
Immunogenicity and efficacy Healthy individuals Hepatitis A vaccines are safe, highly and rapidly immunogenic, and provide durable protection against infection in persons who receive the recommended doses.14 –19 Of note, after a single dose of vaccine, antibody titers are higher than those produced by known protective levels of immune glob-
Davis
Experience with Hepatitis A and B Vaccines Table 1
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Recommended doses of hepatitis A vaccines
Vaccine
Age (y)
Havrix6†
2–18 ⬎18 1–18 ⬎18
Vaqta7‡
Dose
Volume (mL)
2-Dose Schedule (mo)*
720 ELU 1440 ELU 25 U 50 U
0.5 1.0 0.5 1.0
0, 0, 0, 0,
6–12 6–12 6–18 6–18
ELU ⫽ ELISA (enzyme-linked immunosorbent assay) units; U ⫽ antigen units. *0 months represents timing of the initial dose; subsequent numbers represent months after the initial dose. † GlaxoSmithKline, Research Triangle Park, NC. ‡ Merck & Co., Inc., Whitehouse Station, NJ. Adapted from Epidemiology and Prevention of Vaccine-Preventable Diseases.3
Table 2
Recommended doses of hepatitis B vaccines
Vaccine
Age (y) or Group
Dose (g)
Volume (mL)
Dosing Schedule (mo)*
⬍11‡ 11–19 ⱖ20 Dialysis§ ⬍11‡ 11–19 ⱖ20 Predialysis/dialysis¶
10 10 20 40 5 5 10 40
0.5 0.5 1.0 2.0 0.5 0.5 1.0 1.0
0, 0, 0, 0, 0, 0, 0, 0,
11†
Engerix-B
Recombivax HB12㛳
1, 1, 1, 1, 1, 1, 1, 1,
6 6 6 2, 6 6 6 6 6
*0 months represents timing of the initial dose; subsequent numbers represent months after the initial dose. † GlaxoSmithKline, Research Triangle Park, NC. ‡ Infants whose mothers are hepatitis B surface antigen (HBsAg)–positive should also receive hepatitis B immune globulin at birth. § Two 1.0-mL doses given at 1 site. 㛳 Merck & Co., Inc., Whitehouse Station, NJ. ¶ Special formulation for patients on dialysis. Adapted from Epidemiology and Prevention of Vaccine-Preventable Diseases.4
ulin, defined as 10 to 20 mIU/mL (10 to 20 IU/L), but lower than those produced following natural infection.16,19 –21 Within 1 month of receiving the first dose, ⬎97% of children and adolescents and ⬎95% of adults develop protective levels of antibody.22–26 Within 1 month of receiving the second dose, virtually 100% of recipients have protective levels of antibody.23,24,27–29 Both hepatitis A vaccines are highly efficacious in protecting against clinical hepatitis A. In studies conducted in settings with high rates of hepatitis A, the efficacy of 2 doses of Havrix administered 1 month apart during a double-blind, placebo-controlled, randomized clinical trial involving 38,157 children (1 to 16 years old) in Thailand was 94%,17 and the efficacy of Vaqta administered during a trial involving 1,037 children (2 to 16 years old) in upstate New York was 100%.14,30 Although longer-term measures of vaccine efficacy are needed, mathematical models suggest that protective levels of antibody will persist for 24 to 47 years following receipt of a second dose administered 6 to 12 months after the initial dose.31
Hepatitis B vaccine protection, defined as titers of antibodies to hepatitis B surface antigen (anti-HBs) of ⱖ10 mIU/mL (ⱖ10 IU/L), increases with increasing number of doses received. Among infants, reported ranges in antibody response are 16% to 40% following dose 1, 80% to 95% following dose 2, and 98% to 100% following dose 3.4 Preterm infants weighing ⬍2 kg have been shown to have lower seroconversion rates than do full-term infants.4,32 Among teens and adults, reported ranges in antibody response are 20% to 30% following dose 1, 75% to 80% following dose 2, and 90% to 95% following dose 3.4 Factors that may lower vaccine response rates include age ⬎40 years, male gender, smoking, obesity, and immune deficiency. In general, vaccine efficacy is typically 95%, with a reported range in efficacy of 80% to 100% among those who receive the complete vaccination series.2 Immunologic memory is established following hepatitis B vaccination (anamnestic anti-HBs response) and influences longterm efficacy of the vaccine; chronic infection is rarely
10S documented among individuals who demonstrate a response to the vaccine.2 Among healthy individuals, the immunogenicity of the combination hepatitis A and B vaccine for each component is at least as good as that noted for the single-antigen vaccines administered separately (Table 3).33 Geometric mean titers for both the hepatitis A and B components are higher than with separate injections,33 and antibody persistence for ⱖ4 years following vaccination with the combination vaccine has been observed.34
The American Journal of Medicine, Vol 118 (10A), October 2005 vaccine administered on a 0-, 1-, and 6-month schedule was reduced at month 7 (77% seroconversion; GMT ⫽ 636 mIU/mL [636 IU/L]) compared with the immunogenicity in 20 HIV-negative MSM (100% seroconversion; GMT ⫽ 1,687 mIU/mL).45 Studies conducted among HIV-positive patients during the late 1980s and 1990s demonstrated response rates of 33% to 56% to both recombinant and plasma-derived hepatitis B vaccines, and the response was related to the CD4 cell count. Among HIV-positive patients who demonstrated a response, protective antibody titers were noted to be lower than those in HIV-negative control subjects (Table 4).44,46 – 49
Individuals with chronic liver disease Among persons with chronic liver disease (CLD), the risk of HAV infection in susceptible individuals is not increased, but the risk of fulminant hepatitis A is.3 Seroconversion rates 1 month after receiving dose 2 of single-antigen hepatitis A vaccine (on a 0- and 6-month schedule) are similar among healthy adults (98.2% of 167) and adults with chronic HBV infection (97.7% of 44), chronic HCV infection (94.3% of 87), or other causes of CLD (95.2% of 63).35 The response at month 7 to hepatitis A vaccine among recipients with decompensated liver disease (n ⫽ 35; seroconversion ⫽ 65.7%; geometric mean titer [GMT] ⫽ 103 mIU/mL [103 IU/L]), however, is significantly lower than the response among recipients with compensated liver disease (n ⫽ 49; seroconversion ⫽ 98%; GMT ⫽ 328 mIU/ mL; P ⫽ 0.001).36 Studies on the immunogenicity and efficacy of hepatitis B vaccine in patients with CLD are limited to patients with alcoholic liver disease or chronic hepatitis C. In patients with mild alcoholic liver disease or mild or moderate chronic hepatitis C, the anti-HBs seroconversion rate following 3 doses of hepatitis B vaccine is similar to that in healthy individuals, reaching as high as 100% in some studies.37–39 In patients with documented alcoholic cirrhosis, however, seroconversion rates are lower, ranging from 12% to 75%.37,40,41 The seroconversion rate in individuals waiting for liver transplantation or in immunosuppressed liver transplant recipients is much lower; response rates have been observed in the range of 7% to 55%.37,42 Additional information on the immunogenicity and efficacy of hepatitis A and B vaccines in individuals with CLD and the possible need for higher vaccine doses or booster vaccinations in this population can be found elsewhere in this supplement.43
Patients with human immunodeficiency virus infection The immunogenicity of hepatitis A and B vaccines is impaired in patients with human immunodeficiency virus (HIV) infection.44 Among 14 HIV-positive men who have sex with men (MSM), the immunogenicity of hepatitis A
Patients receiving hemodialysis Hepatitis A vaccines confer similar protection in both patients requiring hemodialysis and healthy individuals. In 1 study, 42 (98%) of 43 patients receiving hemodialysis developed antibodies following a 3-dose series of hepatitis A vaccine.50 Patients undergoing hemodialysis generally have a lower rate of seroprotection following hepatitis B vaccination than do healthy vaccinees, and the hepatitis B vaccine dosage for these individuals is greater than in healthy adults (Table 2).4 Seroprotection has been documented in 64% of patients undergoing hemodialysis following a 3-dose series and in 86% of these patients following a 4-dose series.51 The need for booster doses of hepatitis B vaccine in patients requiring hemodialysis should be assessed annually by testing vaccinees for anti-HBs levels; booster doses should be provided to vaccinees whose antibody levels are ⬍10 mIU/mL.4
Impact of hepatitis A and B vaccines on incidence of infection Hepatitis A vaccination Following the licensure of hepatitis A vaccines in the United States in 1995 and 1996, the initial Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) recommendations for hepatitis A vaccination published in 1996 were risk based and included use in persons traveling to or working in countries highly or moderately endemic for hepatitis A, in MSM, in persons who use illegal injection drugs, in persons who have clotting-factor disorders, in persons with occupational risk, and in persons with CLD.52 Broader, population-based recommendations followed in 1999 and included routine vaccination of children aged ⱖ2 years in communities with high endemic rates of hepatitis A and with hepatitis A outbreaks, such as the Native American and Alaskan native populations, and in states (11 states primarily in the western United States),
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Experience with Hepatitis A and B Vaccines
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Table 3 Immunogenicity of combination hepatitis A and B vaccines compared with monovalent vaccines
Vaccine
N
Combination A/B
264
Monovalent vaccines
269
Time Point (mo)
Seroconversion for Hepatitis A (%)*
Seroprotection for Hepatitis B (%)†
1 2 7 1 2 7
91.6 97.7 99.6 98.1 98.9 99.3
17.9 61.2 95.1 7.5 50.4 92.2
(To convert conventional units to SI units, change units to “international units per liter [IU/L].”) *Geometric mean titer of antibodies to hepatitis A virus ⱖ33 mIU/mL. † Geometric mean titer of antibodies to hepatitis B surface antigen ⱖ10 mIU/mL. Adapted with permission from Vaccine.33
Table 4 Response to hepatitis B vaccine administered on a 0-, 1-, 6-month schedule in human immunodeficiency virus (HIV)-positive and HIV-negative men who have sex with men (MSM) Number of Patients with Response to Hepatitis B Vaccine/Number Tested (% with response) Study 49
Wong et al. Loke et al.48 Collier et al.47 Carne et al.46 Combined range (%)
HIV-Positive MSM
HIV-Negative MSM
6/14 (42.9) 9/27 (33.3) 9/16 (56.3) 9/17 (52.9) (33.3–56.3)
105/120 (87.5) 69/77 (89.6) 62/68 (91.2) 17/18 (94.4) (87.5–94.4)
Adapted with permission from Clin Infect Dis.44
counties, or communities where the average annual reported hepatitis A incidence during 1987–1997 was ⱖ20 cases per 100,000 population.5 In addition, routine vaccination was to be considered for all children aged ⱖ2 years in states, counties, or communities where the average annual reported hepatitis A incidence during 1987–1997 was ⱖ10 cases but ⬍20 cases per 100,000 population. The reported incidence of hepatitis A decreased from 12 cases per 100,000 in 1995 to 3.1 cases per 100,000 in 2002 (Figure 1).53 Reduction in mean incidence was greatest in the 11 states where routine statewide vaccination of all children aged ⱖ2 years was recommended by the ACIP in 1999 (67% reduction from 7.2 cases [mean] per 100,000 population in 1999 to 2.4 cases [mean] per 100,000 in 2002) and was proportionally similar in the 6 states where routine vaccination of all children aged ⱖ2 years was to be considered (69% reduction from 6.4 cases [mean] per 100,000 population in 1999 to 2.0 cases [mean] per 100,000 in 2002).53 In the remaining 33 states with no routine age-based recommendation for hepatitis A vaccination, reductions in incidence were much smaller (35% reduction from 3.4
cases [mean] per 100,000 population in 1999 to 2.2 cases [mean] per 100,000 in 2002).53 The greatest reduction in reported incidence of acute hepatitis A cases between 1996 and 2002 occurred in 5- to 14-year-old children. Children aged ⬍5 years and adults aged ⱖ40 years have the lowest reported rates of acute hepatitis A infection, and persons aged 15 to 39 years have the highest rate of infection. The low and stable rate of acute infection in persons aged ⱖ40 years is thought to be a result of high rates of immunity from previous infection in this population.53 Although sexual and household contact remain the leading modes of transmission of hepatitis A, the incidences among international travelers and MSM have increased dramatically since 1995,53 despite recommendations to vaccinate persons in these groups at high risk. Among international travelers, the reported incidence of hepatitis A increased from 2.8 cases per 100,000 in 1995 to 9.4 cases per 100,000 in 2002; among MSM, the rate increased from 2.3 cases to 8.4 cases per 100,000 during this same period.53 Incidences have decreased in illegal injection drug users and in those with day-care contact. In communities with sustained transmission of HAV, substantial decreases in community hepatitis A rates—as a
12S result of targeted vaccination efforts with a single dose of hepatitis A vaccine— have been noted.14,54 –56 Additional information on the efficacy of single doses of hepatitis A vaccine in preventing infection can be found elsewhere in this supplement.57
The American Journal of Medicine, Vol 118 (10A), October 2005 modes of transmission of hepatitis B. Much like the incidence of acute hepatitis A, the incidence of acute hepatitis B is increasing among MSM, despite recommendations to vaccinate persons in this group at high risk.
Benefits of combination vaccines Hepatitis B vaccination Following initial licensure of the plasma-derived formulation of hepatitis B vaccine in 1981, the initial ACIP recommendations for hepatitis B vaccination published in 1982,58 1985,59 and 198760 were risk based and included use in travelers to hepatitis B– endemic countries, MSM, users of illegal injection drugs, and those with clotting-factor disorders or occupational risk of exposure. Because of a variety of events, particularly the emergence of the acquired immunodeficiency syndrome reported among recipients of blood and certain blood products, the initial uptake of the safe and effective plasma-derived hepatitis B vaccine was less than anticipated.4 Thus, despite the availability of safe and effective vaccines and national guidelines for vaccination, the reported incidence of acute hepatitis B continued to increase until 1985, when a decline in morbidity among MSM and healthcare workers ensued, followed by declines in morbidity among injecting drug users.53 The ACIP recommendations that contributed to subsequent substantial reductions in incidence of acute hepatitis B included the 1988 recommendation to screen pregnant women for HBsAg and protect neonates born to HBV-infected mothers,61 the 1991 recommendation for routine vaccination of all infants with hepatitis B vaccine,10 and the 1996 recommendation— endorsed by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American Medical Association—for routine immunization of adolescents aged 11 and 12 years with hepatitis B vaccine.62 In 1999, the ACIP expanded its recommendation of universal vaccination of adolescents to include all those aged ⬍19 years63; however, no additional age-based recommendations exist. Thus, the plethora of risk-based recommendations for vaccination in persons aged ⱖ19 years adds complexity to screening individuals for hepatitis B risk factors and reduces the likelihood that these persons will be appropriately vaccinated.64 The cumulative effect in the United States of the use of hepatitis B vaccines stimulated by these policies has been striking reductions in the reported incidence of acute hepatitis B from 9.2 cases per 100,000 in 1981 to 2.8 cases per 100,000 in 2002, a rate that has been stable since 1999 (Figure 2).53 Although the greatest reduction in incidence of acute hepatitis B cases occurred in 15- to 39-year-olds, this age group still has the highest incidence of acute infection. As with hepatitis A, the lowest reported rates of acute HBV infection occur in children aged ⬍5 years and adults aged ⱖ40 years. Sexual encounters (i.e., multiple sexual partners) and illegal injection drug use are the leading
Combination vaccines that contain hepatitis A and/or hepatitis B components (Twinrix, Pediarix, Comvax) provide an option for the administration of fewer injections while safety and immunogenicity remain similar to that associated with separately administered vaccines.33 Licensed combination vaccines are at least as immunogenic as separate injections of component vaccines. The ACIP, AAP, and AAFP recommend that licensed combination vaccines be used whenever any component of the combination vaccine is indicated and its other components are not contraindicated.65
Summary Several well-substantiated observations are fundamental to the experiences with hepatitis A and B vaccines. First, hepatitis A and B vaccines confer high rates of immunity in healthy children, adolescents, and adults; seroconversion rates for hepatitis A and B vaccines in patients with CLD and HIV infection may be lower. Patients receiving hemodialysis may have lower rates of seroprotection after hepatitis B vaccination, but they show a good response to hepatitis A vaccine. Vaccination early in the course of illness in these patients at high risk maximizes protection. Second, combined hepatitis A and B vaccine offers safety and immunogenicity equivalent to that of separate vaccines with fewer injections and is preferable to separate vaccines when both vaccine components are indicated. Recommended use of hepatitis A and B vaccines has had a substantial impact on reducing the respective incidences of HAV and HBV infection and their related morbidity and mortality. Of particular note, age-based recommendations for vaccination of individuals against hepatitis A and B have proven to be highly effective. Expansion of such recommendations to include universal vaccination of adults should be considered to provide maximal protection among the general population of the United States. It is important to achieve early vaccination of individuals at high risk for acquiring hepatitis A or B. Because the time of exposure to these viruses is unpredictable, earlier vaccination maximizes the likelihood of successful immunization. Furthermore, immunity induced by each of these vaccines can last for many years, if not a lifetime, and vaccination of individuals at high risk as soon as they are identifiable will reduce missed opportunities to vaccinate, particularly in those individuals likely to be difficult to access later in life.
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Figure 1 Incidence (reported cases per 100,000 population) of acute hepatitis A in the United States by year, 1980 –2002. ACIP ⫽ Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. (Data from Centers for Disease Control and Prevention.53)
Figure 2 Incidence (reported cases per 100,000 population) of acute hepatitis B in the United States by year, 1980 –2002. HBsAg ⫽ hepatitis B virus surface antigen. (Data from Centers for Disease Control and Prevention.53)
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