Universal Hepatitis B Immunization

Universal Hepatitis B Immunization Committee on Infectious Diseases HEPATITIS B DISEASE AND EPIDEMIOLOGY In the United States 200 000 to 300 000 acute infections with hepatitis B virus (HBV) occur each year.1 2 More than one million persons in the United States have chronic HBV infection, and approximately 4000 to 5000 persons die each year from HBV-induced chronic liver disease and hepatocellular carcinoma. Although HBV infections occur during childhood and adolescence, the full impact of these infections is not recognized until many years later when chronic liver disease and hepatocellular carcinoma may develop. The incidence of HBV infection increases rapidly during adolescence, with higher rates among blacks than among whites (Fig 1). Although rates vary by region, sex, and race, between 3.3% and 25% of all persons have had HBV infection by 25 to 34 years of age. The likelihood of becoming chromcally infected with HBV varies inversely with the age at which infection occurs. HBV transmitted from hepatitis B surface antigen (HBsAg)-positive mothers to their newborns results in HBV carriage for up to 90% of infants. Between 25% and 50% of children infected before 5 years of age become carriers, whereas only 6% to 10% of acutely infected adults become carriers. It is estimated that more than 25% of carrier infants will die from primary hepatocellular carcinoma or cirrhosis of the liver, with most of these deaths occuring during adult life. HBV infection occurs more commonly in certain populations, including Pacific Islanders, Alaskan Natives, immigrants from countries in which infection is highly endemic, persons who require multiple transfusions of blood or blood products, and persons with high-risk lifestyles, including intravenous drug abuse and contact with multiple sexual partners. However, approximately 30% to 40% of acute HBV infections in the United States occur in persons with no identifiable risk factors. HBV is transmitted through exposure to blood and blood products, through sexual contact, and from mothers to infants primarily at the time of birth. It also can be acquired by close contact within families, from person to person through contact between open skin lesions, and possibly by exposure of mucous membranes to other infected body fluids, such as saliva. The Recommendations in this publication do not indicate an exdusive course of treatment or serve as a standard of medical care.. Variations, taking into account individual circumstances, may be appropriate. PEDIATRICS (ISSN 0031 4005). Copyright c 1992 by the American Academy of Pediatrics. VACCINES AND PREVIOUS RECOMMENDATIONS The first HBV vaccine in the United States was licensed in 1982. Although both plasma-derived and recombinant vaccines are licensed in the United States, only recombinant vaccines are produced currently. Both plasma-derived and recombinant vaccines induce more than 90% protection against HBV infection and are highly immunogenic in infants when given in a variety of immunization schedubes.48 More than 95% of infants have developed a satisfactory serologic response (antibody to HBsAg (anti-hb5)) concentration of 10 miu/ml) after administration of three doses of vaccine. Intervals of 4 or more months between the second and third doses resulted in higher geometric mean titers than intervals of 1 or 2 months. These vaccines have been shown to be highly effective in preventing HBV infection in infants whose mothers are chronic HBV carriers.8 9 The recommended doses and volumes of HBV vaccines differ by manufacturer, age of the individual to be immunized, maternal HBsAg serologic status, and presence of underlying disease (Table 1). The two vaccines currently being marketed appear equally immunogenic and may be used interchangeably in their respective, recommended doses. Adverse effects are minimal, consisting primarily of soreness at the injection site. Hypersensitivity to yeast or preservative in the recombinant vaccines has been reported rarely, and no serious adverse effects in children have been linked definitely to HBV vaccines.10 Previously, both the American Academy of Pediatrics (AAP) and the US Public Health Service Immunization Practices Advisory Committee (ACIP) recommended a two-part strategy for control of HBV infection, which consisted of selective vaccination of high-risk populations and serologic screening of all pregnant women for HBsAg. #{176} 1 Unfortunately, Selective vaccination strategies have had little impact on the control of HBV infections or their sequelae (Fig 2).12 Individuals in high-risk groups are not identified readily, and they often underuse preventive health care semces 2 3 Universal screening of pregnant women for HBsAg with active and passive immurnzation of their infants will prevent only about 6000 of the more than 200 000 HBV infections that occur in the United States each year. A change in strategy for vaccine use in this country is required to control HBV infections. UNIVERSAL IMMUNIZATION The Academy s Committee on Infectious Diseases considered several possible strategies to improve the PEDIATRICS Vol. 89 No. 4 April 1992 795

Positive 40 (S) 30 20 Black 10 White 0 #{189}. 3#{149} 6-9- 12-15- 18-2 5 8 1114 17 24 Age in years Fig 1. Age-specific prevalence of hepatitis B virus markers for white and black subjects. Data are from the National Center for Health Statistics.3 TABLE 1. Recommended Doses of Licensed He patitis B Vaccines Vaccinet Recombivax HB Engerix-B (MSD) (SKI) iig (ml) g (ml) Infants of hepatitis B surface antigen (HBsAg)- 2.5 (0.25) 10 (0.5) negative mothers and children <1 1 y Infants of HBsAg-positive mothers (HBIG (0.5 5 (0.5) 10 (0.5) ml) should also be given) Children and adolescents 11 to 19 y 5 (0.5) 20 (1.0) Adults20y 10 (1.0) 20 (1.0) Dialysis patients and other immunosuppressed 40 (1.0)11 40 (2.0) persons S Heptavax B (MSD), a plasma-derived vaccine, is also licensed, but no longer produced in the US. t Vaccines should be stored at 2#{176}C to 8#{176}C. Freezing destroys effectiveness. Merck, Sharp & Dohme. The Food and Drug Administration has approved this vaccine for use in an optional schedule: four doses at 0, 1, 2, and 12 months (see 1991 Report of the Committee on Infectious Diseases #{176}P244). I Smith Kline Biologicals. I Special formulation for dialysis patients. 5* Four-dose schedule recommended at 0, 1, 2, and 12 months. Adapted from the 1991 Report of the Committee on Infectious Diseases.10244 50 40 020 70 10 0 hepatitis B vaccine 78715081 5088889 90 Year of Report Fig 2. Estimated incidence of acute hepatitis B, United States, 1978 through 1990. Source: Centers for Disease Control, 1991. 796 HEPATITIS B IMMUNIZATION control of HBV infections including immunizing in infancy, at adolescence, or a combination approach. Infant immunization offers the most feasible approach to protecting all persons and eventual elimination of disease, but the complete effect of this strategy will not be noted for 25 or more years. Universal immunization of adolescents alone has the advantage of a more immediate effect, but this strategy is problematic. Adolescents at the highest risk would most likely be the least compliant, and asking adolescents to participate in a three-dose immunization series over a 6-month period is likely to result in high drop out rates. Therefore, the Academy recommends a combination strategy, including universal immunization of all infants. Immunization of all infants has been shown to be cost-saving in controlling HBV infections (Centers for Disease Control, 1991).12 A major factor in the cost-effectiveness is the bower dose of vaccine given infants (Table 1). In Alaska the universal HBV

immunization program has resulted in interruption of HBV transmission among Native American children. 4 Universal infant immunization has been impbemented in several of the Pacific Islands under the jurisdiction of the United States, and Hawaii recently has initiated universal immunization of infants for HBV. At least 20 other countries now recommend HBV vaccine for all infants.15 Routine serologic screening of all pregnant women for HBsAg continues to be recommended. Screening should be performed during a prenatal visit for each pregnancy. The dose and schedule of the vaccine to be given to the infant, as well as the use of hepatitis B immune globulin (HBIG), are based on the HBsAg status of the mother (Table 1). Routine Immunization of Infants Born to HBsAg-Negative Mothers The Academy recommends administering the first dose of HBV vaccine to newborns before hospital discharge, the second dose at 1 to 2 months of age, and the third dose at 6 to 18 months of age (Table 2). The dose recommended for newborns of HBsAgnegative mothers is different for the two vaccines (Table 1). An alternative schedule of the three doses administered at 2, 4, and 6 to 18 months during regularly scheduled visits and concurrently with other routine vaccines, may be used for HBsAg-negative infants not vaccinated at birth. These recommendations are based on the need for flexible scheduling of HBV vaccination in the first 18 months of life to integrate this vaccine into routine preventive health care. Since HBV vaccine is highly immunogenic in a variety of schedules, extra visits should not be required to incorporate it into a child s routine health care. A schedule of immunization at birth, 1 month, and 6 to 18 months may avoid the need to administer three injections of different vaccines at the same visit. Administration of the first dose in the hospital also reduces the need for extra office visits and helps to emphasize to parents and hospital-based personnel the importance of immunizations and preventive services. For premature and other infants with illnesses in the first few days of life, HBV vaccine may be delayed until hospital discharge, provided the mother is not HBsAg-positive. Immunization of Infants Born to HBsAg-Positive Mothers Infants born to HBsAg-positive women should receive HBIG at or shortly after birth and should be immunized at birth (within 7 days, preferably with 12 hours). The second and third doses of vaccine should be administered at 1 and 6 months of age, according to current recommendations (Table 2). The dose of Recombivax HB vaccine (Merck, Sharp & Dohme) for infants of carrier mothers is twice (0.5 ml) that given to infants of HBsAg-negative mothers. The dose of Engerix B vaccine (Smith Kline Biobogicals) is the same (0.5 ml) for infants of both HBsAgpositive and HBsAg-negative mothers (Table 1). For infants born to HBsAg-positive women, immunization starting at birth is highly effective in preventin& HBV transmission from mother to infant.9 16 7 In infants who have received three doses of HBV vaccine with administration of the first dose by 7 days of age, the risk of chronic HBsAg carriage was reduced by 65% to 90%. The additional administration of HBIG at or shortly after birth has further reduced the risk by 5% to 20%, according to some studies. 6 7 Infants of HBsAg-positive mothers should be tested for HBsAg and anti-hbs at 9 months of age or later (at beast 1 month after the third dose of vaccine). A fourth dose of HBV vaccine should be administered to infants who are HBsAg-negative and have titers of anti-hbs < 10 miu/ml. These children should be retested 1 month later for anti-hbs (see The Report of the Committee on Infectious Diseases10 P251). Additional doses (up to two more) may be considered for those who fail to respond. Immunization of Infants Whose Mothers Have Unknown HBsAg Status An infant whose mother s HBsAg status is unknown and cannot be determined before delivery should be immunized at birth with the dose of vaccine recommended for infants of HBsAg-positive mothers (Table 1). The additional administration of HBIG should depend on the results of the serologic screening of the mother. The mother should be screened for HBsAg as soon as possible, since the efficacy of HBIG has been proven only when given within 12 hours of birth. If the mother is HBsAg-positive, HBIG should be administered immediately to the infant, provided that the infant is bess than 1 week old. Efficacy of HBIG given 12 to 48 hours after birth and 7 days of age is not known. The HBsAg status of the mother also determines the subsequent vaccine dose and schedule, as previously described. TABLE 2. Recommended Routine Hepatitis B Immunization Schedules Maternal Hepatitis B Surface Antigen Status Dose Negative 1 2 3 Positive it 2 3 Age 0-2 d 1-2mo 6-l8mo 0 d imo #{243}mo S Alternative schedule: dose one at 1 to 2 months of age, dose two at 4 months, and dose three at 6 to 18 months. t Hepatitis B immune globulin should also be administered. Downloaded from www.aappublications.org/news ADMINISTRATION OF HEPATITIS B VACCINE Concurrent Administration With Other Vaccines Hepatitis B virus vaccine can be given simultaneously with diphtheria-tetanus toxoids-pertussis (DTP), Haemophilus influenzae type b, polio, and/or measles-mumps-rubella vaccines without interference.6 8 Hepatitis B virus vaccine should not be mixed in the same syringe with any other vaccine or medication because compatibility between products has not been demonstrated. Combined products are likely to become available in the future (see Future Developments ). by guest on June 27, 2018 AMERICAN ACADEMY OF PEDIATRICS 797

Site of Administration Hepatitis B virus vaccine can be given intramuscularly safely and effectively in the anterolateral thigh or in the upper arm at all ages, including at birth (Coberly J, Halsey N. Personal communication, 1991). HBV vaccine and other vaccines should not be administered in the buttocks, because this practice has resulted in inadequate serologic response rates in adults and could cause damage to the sciatic nerve. 9 Intradermal immunization is not recommended for infants or children since intradermal injections are difficult in infants and have no advantage over intramuscular administration (Coberby J, Halsey N. Personal communication, 1991). When simultaneous administration of HBV vaccine and other vaccines, such as DTP and H influenzae type b vaccines, is indicated, two injections, one or more inches apart, may be administered in the same anterolateral thigh or deltoid. DURATION OF IMMUNITY The full duration of protection induced by three doses of HBV vaccine administered in infancy has not been determined. However, adult recipients of plasma-derived HBV vaccine have been protected from acute and chronic illness for as long as 9 years.5 Although 20% to 60% of vaccinated adults had anti- HBs titers decline to less than 10 miu/ml 5 to 9 years after immunization, immunologic memory was retamed, and anamnestic antibody responses occurred after exposure to HBV. Studies of infants whose mothers are chronic HBsAg carriers have shown that the vaccine has provided the infants with continued high levels of protection from chronic HBV infection for at least 5 years. Routine administration of booster doses for infants born to HBsAg-negative mothers and routine testing for antibodies to HBsAg, therefore, are not indicated at this time. IMMUNIZATION OF ADOLESCENTS AND OLDER CHILDREN Older children and adolescents at increased risk of exposure to HBV infection (see Table 3) should be immunized. Major risk factors for acquisition of HBV infection in adolescents include multiple sexual partners (defined as more than one in 6 months) and intravenous drug abuse. In addition, immunization should be emphasized for adolescents living in areas where increased rates of parenterab drug abuse, teenage pregnancy, and/or sexually transmitted diseases occur. The AAP recommends that universal immunization of all adolescents should be implemented when resources permit. The current policy of selective immunization of teenagers at high risk for acquisition of HBV infection requires prospective assessment of behavioral risk factors, which is often difficult and inadequate. Although the costs would be higher than for infant immunization due to the larger dose of vaccine administered, the additional strategy of universal adolescent immunization will result in a more rapid reduction of HBV transmission and infection, 798 HEPATITIS B IMMUNIZATION TABLE 3. High-Risk Groups Who Should Receive Hepatitis B Immunization Regardless of Age*. Hemophiliac patients and other recipients of certain blood products Downloaded from www.aappublications.org/news. Intravenous drug abusers. Heterosexual persons who have had more than one sex partner in the previous 6 months and/or those with a recent episode of a sexually transmitted disease. Sexually active homosexual and bisexual males. Household and sexual contacts of hepatitis B virus (HBV) cartiers. Members of households with adoptees from HBV-endemic, high-risk countries who are hepatitis B surface antigen-positive. Children and other household contacts in populations of high HBV endemnicity. Staff and residents of institutions for the developmentally disabled. Staff of nonresidential day care and school programs for developmentally disabled if attended by known HBV carrier; other attendees in certain circumstances. Hemodialysis patients. Health care workers and others with occupational risk. International travelers who will live for more than 6 months in areas of high HBV endemnicity and who otherwise will be at risk. Inmates of long-term correctional facilities * Adapted from the 1991 Report of the Committee on Infectious Disease #{176} (see pp 246-249 for further details and explanation). particularly among adolescents, the age group of children currently most at risk for acquiring HBV infection. Universal infant immunization will have an immediate impact on reducing vertical transmission of HBV infection from mothers to infants and will diminish or eliminate horizontal transmission between preschool-age children within 5 years. Transmission among teenagers, however, would remain unaffected for the next one to two decades. Other groups who should receive HBV vaccine are listed in Table 3. Children who are not in these groups will be immunized at adolescence. Although it may be ideal to immunize such children at this time, this recommendation is not being made currently because of limited resources. The usual schedule of immunization for older children, adolescents, and adults is 0, 1, and 6 months. The dose, according to vaccine and age, is listed in Table 1. FUTURE DEVELOPMENTS Manufacturers are developing products combining HBV vaccine with DTP and/or H influenzae type b vaccines. If and when these products become available, integration of HBV vaccine into the routine immunization schedule for infants of HBsAg-negative mothers at 2, 4, and 6 months of age will be simplifled. The need for booster doses of HBV vaccine in older children and adolescents and for those immunized in infancy will be assessed as individuals are followed for 10 or more years after primary immunization. Routine serologic testing for HBV immunity is not indicated for these persons. by guest on June 27, 2018

SUMMARY OF RECOMMENDATIONS The highest priority should be for immunization of high-risk children and all infants, followed by immunization of adolescents living in high-risk areas, and then all adolescents. A summary of recommendations is as follows: 1. Routine serologic screening of all pregnant women for HB5Ag should continue. 2. All infants should be immunized with HBV vaccine. The appropriate doses and schedules are detailed in Tables 1 and 2. A. For infants born to HBsAg-negative mpthers:. The recommended schedule is adniinistration of the first dose to newborns before discharge from the hospital; the second dose should be administered at 1 to 2 months of age, followed by the third dose at 6 to 18 months of age (Table 3).. Infants who did not receive a dose of vaccine at birth should receive three doses by 18 months of age. The minimal interval between the first two doses is 1 month and between the second and third doses is 2 months, but 4 months or more may be preferable.. The alternative schedule of immunization at 2, 4, and 6 to 18 months of age, although not preferred, is acceptable, provided the infant s mother is HBsAg-negative. B. Infants born to HBsAg-positive women must be immunized at or shortly after birth with the appropriate dose of vaccine (Table 1) and should receive one dose of HBIG as soon as possible after birth. The second dose of vaccine should be administered at 1 month and the third dose at 6 months. These infants should be followed up and their serologic status checked at 9 months of age, as recommended in the 1991 Report ofthe Committee on Infectious Diseases. #{176} 249 C. If the mother s HBsAg status is unknown at the time of delivery, the infant should be immunized at birth with the dose of vaccine recommended for infants born to HBsAg-positive mothers. The mother should be screened for HB5Ag as soon as possible to determine the subsequent management of the infant, including the need to administer HBIG. 3. Older children, adolescents, and adults at increased risk of HBV infection (Table 3) should be immunized with HBV vaccine (Table 1). 4. Routine immunization of all adolescents against HBV should be encouraged and implemented when feasible. 5. The dose of vaccine depends on the manufacturer, the patient s age, the maternal HBsAg status, and the presence of underlying disease (Table 1). COMMFI-rEE ON INFECTIOUS DISEASES, 1991 TO 1992 Caroline Breese Hall, MD, Chair James G. Easton, MD Dan M. Granoff, MD Donald S. Gromisch, MD Neal A. Halsey, MD Steve Kohl, MD Edgar K. Marcuse, MD Melvin I. Marks, MD George A. Nankervis, MD Larry K. Pickerin& MD Gwendolyn B. Scott, MD Russell W. Steele, MD Ex-Officio Georges Peter, MD Liaison Representatives Kenneth J. Bart, MD, MPH, National Vaccine Program Claire Broome, MD, Centers for DIsease Control M. Carolyn Hardegree, MD, Food and Drug Administration John R. La Montagne, PhD, National Institute of Allergy and Infectious Diseases Noni E. MacDonald, MD, Canadian Paediatric Society Walter A. Orenstein, MD, Centers for Disease Control REFERENCES 1. Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies.jama. 1990;263:1218-1222 2. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis. 1991;1 1:84-92 3. McQuillan GM, Townsend TR, Fields HA, et al. Seroepidemiology of hepatitis B in the United States: i976 to 1980. Am I Med. 1989;87: 5S-1OS 4. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engi I Med. 1980;303:833-841 5. Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engi / Med. 1986;315:209-214 6. Smego R, Halsey N. The case for routine hepatitis B immunization in infancy for populations at increased risk. Pediatr Infect Dis I. 1987;6: ii-i9 7. Stevens CE, Toy PT, Tong MJ, et a!. Pennatal hepatitis B virus transmission in the United States. Prevention by passive-active immunization. JAMA. 1985;253:1740-1745 8. Stevens CE, Toy PT, Tong MJ, et al. Yeast-recombinant hepatitis B vaccine: efficacy with hepatitis B immune globulin in prevention of pennatal hepatitis B virus transmission. JAMA. 1987;257:2612-2616 9. Poovorawan Y, Sanpavat 5, Pongpunlert W, et a!. Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBs antigenpositive mother. JAM.4. 1989;261:3278-3281 10. Committee on Infectious Diseases, American Academy of Pediatrics. The Report ofthe Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1991:238-255 I I. Centers for Disease Control. Protection against viral hepatitis: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 1990;39:5-22 12. Jonas MM, Schiff EF, O Sullivan MJ, et al. Failure of the Centers for Disease Control criteria to identify hepatitis B infection in a large municipal obstetrical population. Ann Intern Med. 1987;107:335-337 13. McQuillan GM, Townsend TR, Johannes CB, et al. Prevention of perinatal transmission of hepatitis B virus: the sensitivity specificity and predictive value of the recommended screening questions to detect high risk women in an obstetric population. Am I Epidemiol. 1987;126: 484-491 Downloaded from www.aappublications.org/news 14. McMahon BJ, Rhoades ER, Heyward WL, et al. A comprehensive programme to reduce the incidence of hepatitis B virus infection and its sequelae in Alaskan natives. Lancet. 1987;2:1134-1136 15. MaynardJE, Kane MA, Hadler SC. Global control of hepatitis B through vaccination: role of hepatitis B vaccine in Expanded Programme on Immunization. Rev Infect Dis. 1989;il:574-578 by guest on June 27, 2018 AMERICAN ACADEMY OF PEDIATRICS 799

16. Ip HMH, Lelie PN, Wong VCW, et al. Prevention of hepatitis B virus carrier state in infants according to maternal serum levels of HBV DNA. Lancet. 1989;1:406-409 17. Xu Z-Y, Liu C-B, Francis DP, et al. Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial. Pcdiatrics. 1985;76:713-718 18. Huang LM, Lee CY, Hsu CY, et al. Effect of monovalent measles and trivalent measles-mumps-rubella vaccines at various ages and concurrent administration with hepatitis B vaccine. Pediatr Infect Dis I. 1990; 9(7):461-465 19. Shaw FE, Guess HA, Roets JM, et al. Effect of anatomic injection site, age and smoking on the immune response to hepatitis B vaccination. Vaccine. 1989;7:425-430 800 HEPATITIS B IMMUNIZATION

Universal Hepatitis B Immunization Pediatrics 1992;89;795 Updated Information & Services Permissions & Licensing Reprints including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/89/4/795 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/permissions.xhtml Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Universal Hepatitis B Immunization Pediatrics 1992;89;795 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/89/4/795 Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1992 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.