1. Hepatitis B Vaccines Susan Goldstein, M.D. Division of Viral Hepatitis Centers for Disease Control and Prevention

2. 2 Hepatitis B Vaccines  Available since 1981  Composed of HBsAg adsorbed to aluminum hydroxide  Elicits development of neutralizing antibodies to HBsAg (anti-HBs) which confer protection from infection  Plasma-derived and recombinant formulations

3. 3 Plasma-Derived Hepatitis B Vaccines  Prepared from HBsAg from plasma of persons with chronic HBV infection  Purified using biophysical and biochemical methods  Heat or chemical inactivation step  Safety profile: No transmission of blood- borne pathogens

4. 4 Recombinant Hepatitis B Vaccines  Prepared from HBsAg synthesized by yeast or mammalian cells  Produced in large quantities  Does not require constant supply of human plasma

5. 5 Administration of Hepatitis B Vaccine  Typically given as a three dose series  Fours dose series sometimes used in 1980’s  Schedule flexible  0,1-2,6 month schedule most commonly used  Microgram dose varies by manufacturer and age of recipient  Vaccines can be used interchangeably if given at dose recommended by manufacturer

6. 6 Options for Adding Hepatitis B Vaccine to Infant Immunization Schedule * Will prevent perinatal infection if given at birth 9 moths Measles BCG OPV Birth-1 mo OPV1 DTP1 2 mo OPV2 DTP2 4 mo OPV3 DTP3 6 mo Hep1* Hep2 Hep1 Hep3 Hep2 Hep3 Hep2 Hep3

7. 7 Administration of Hepatitis B Vaccine with other Vaccines Hepatitis B vaccine can be administered with all other infant and childhood vaccines  BCG  DPT  Polio (OPV, IPV)  Measles  Hib  Yellow fever  Hepatitis A

8. 8 Combination Vaccines DPT-Based Combination  DTaP-Hep B and DTwP-Hep B  DTaP-Hep B-Hib  DTaP-Hep B-IPV (in development)  DTaP-Hep B-Hib-IPV (in development)  DTap-Hep B-Hib-IPV-Hep A (in development) Hepatitis B-Based Combinations  Hepatitis B-Hemophilus influenza B  Hepatitis B-Hepatitis A

9. 9 Manufacturers of WHO “Prequalified” Hepatitis B Vaccines Vaccine Hep B (recombinant) Hep B (plasma-derived) DPT-Hep B DPT-Hep B-Hib Manufacturer Glaxo/SKB (Belgium) Merck (USA) Green Cross (Korea) Lucky Goldstar (Korea) Cheil Jedang (Korea) Glaxo/SKB (Belgium)

10. 10 Why Use Combination Vaccines?  Decrease number of immunizations and immunization visits  Increase likelihood child will be fully immunized  Decrease need for cold chain storage, transport, and waste disposal  Simplify management, training, and record-keeping However….  Cost (significantly) more  Cannot be given at birth: Pertussis and Hib cannot be given before 6 weeks of age due to decreased immunogenicity  Precludes use of DTP manufactured in country

11. 11 Costs of Vaccines Purchased Through UNICEF Hep B (recombinant) Hep B (plasma-derived) Hep B (Uniject) 3 DTP-Hep B DTP-Hep B-Hib 3 DTP 2001 0.35 0.43 0.64 1.10 3.50 0.08 2002 0.35 0.61 1.00 3.25 0.08 2003 NA 2 0.23 0.58 0.90 3.10 0.08 Cost per dose 1 (US dollars)Vaccine 1 10-dose vial, unless otherwise specified 2 Not available after 2002 3 Single-dose vials

12. 12 Monovalent vs. Combination Hepatitis B Vaccine: The Armenia Example  Current EPI schedule includes 4 doses DPT  >95% of infants born in health facility, thus giving birth dose of vaccine feasible  Cannot give combination vaccine at birth  Recommend monovalent or combination vaccine?

13. 13 Number of Doses of Hepatitis B Vaccine using Monovalent vs. Combination Vaccine Monovalent (1) Monovalent (2) 3 Monovalent (1) Combination (4) 5 Birth dose Remaining doses Total HB doses Monovalent HB vaccine Combination DTP-HB vaccine HB dose

14. 14 Cost to Vaccinate against Hepatitis B, Diphtheria, Pertussis and Tetanus Using Monovalent vs. Combination Vaccine 1.23 (3) --- 0.32 (4) 1.55 0.43 (1) 4.40 (4) --- 4.83 Monovalent HB Combination DTP Total Cost with monovalent HB vaccine Cost with combination DTP-HB vaccine Vaccine

15. 15 Immunogenicity and Efficacy of Hepatitis B Vaccines

16. 16 Immunogenicity of Hepatitis B Vaccine  Protective response to vaccine defined as an anti- HBs titer >10 mIU/ml  Seroconversion rates >95% after three doses of vaccine  Similar seroconversion rates with plasma-derived and recombinant vaccines

17. 17 Factors Associated with Decreased Immunogenicity of Hepatitis B Vaccine  Older age  Immunosuppressive illnesses (HIV infection, chronic liver disease, chronic renal failure, diabetes)  Obesity  Smoking Major Factors Minor Factors

18. 18 Immunogenicity of Hepatitis B Vaccine by Age: United States (n=528) * Anti-HBs >10 mIU/ml Source: Roome AJ. JAMA.24; 1993

19. 19 Comparison of Immunogenicity of Monovalent and Combination Hepatitis B Vaccines Hepatitis B vaccines equally immunogenic when administered in monvalent and combination form Source: Giammanco. Vaccine 1998; Papaevangelou Vaccine 1995; Pichichero CID 1997 79 of 80 (99%) 37 of 39 (95%) 367 of 368 (99%) 238 of 251 (95%) Proportion of children seroprotected (anti-HBs>10mIU/ml) after three doses of vaccine DTaP-HB-Hib

20. 20 Efficacy of Hepatitis B Vaccines Pre-exposure prophylaxis  Efficacy in preventing HBV infection ~95% if vaccinated before exposure Post-exposure prophylaxis  Efficacy in preventing perinatal infection ~95% if vaccinated within 12-24 hours of birth  Efficacy of hepatitis B vaccine similar when given with and without HBIG

21. 21 Prevention of Perinatal HBV Infection With Hepatitis B Vaccine Poovorawan. Pediatr Infect Dis J, 1992;11:816-21 Protective efficacy >94% with all regimens N=59N=65N=59N=60

22. 22 Long-Term Protection with Hepatitis B Vaccine  Vaccine provides long-term protection  Immunity persists despite loss of anti-HBs  documented protection up to 15 years – lifelong protection likely – continued follow-up needed to determine duration of protection Booster doses of hepatitis B vaccine NOT currently recommended

23. 23 Mechanism of Long-Term Protection with Hepatitis B Vaccine Primary vaccination series Immune memory Anamnestic antibody response Rapid rise in anti-HBs Protection from infection Exposure to HBV

24. 24 Serologic Response to Booster Dose of Hepatitis B Vaccine Primary series Booster dose (simulating natural infection) Source: Williams and Goldstein, CDC 2 weeks post-booster 4 weeks post-booster 1 year post-booster

25. 25 Long-Term Protection with Hepatitis B Vaccine Among Vaccinated Infants and Children Country Anti-HBc Positive HBsAg Positive Anti-HBs >10 mIU/mln Years f/u China Hong Kong Taiwan Italy Gambia Italy 15 12 10 9 10 6% 1% 14% 12% 0 13% 1% 50% 74% 85% 67% 68% -- 68% 52 148 805 118 53 675 474 2% 0 0.4% 0 1% 0

26. 26 Effectiveness of Routine Infant Hepatitis B Immunization Programs

27. 27 Effectiveness of Hepatitis B Vaccination Programs  Incidence of acute hepatitis B  Prevalence of chronic HBV infection  Incidence of hepatocellular carcinoma Routine infant hepatitis B immunization programs decrease:

28. 28 Effect of Hepatitis B Vaccination on the Incidence of Acute Hepatitis B Alaska, United States 0 50 100 150 200 250 300 Cases/100,000 19811982 1983198419851986 1987 Demonstration Project 1988 Routine Immunization

29. 29 Chronic HBV Infection Among Children Before and After Routine Infant Hepatitis B Immunization: Alaska, United States Prevalence HBsAg among children < 5 years old Hepatitis B vaccination commenced in 1980’s Hep B3 coverage=93% 3% 0 Source: McMahon. Am J Med 1983; Harpaz. JID 2000.

30. 30 Effect of Routine Hepatitis B Immunization on the Incidence of Hepatocellular Carcinoma Among 6-14 Year Olds : Taiwan Routine infant immunization Source: Chang MH. NEJM 1997 High-risk infant immunization