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

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 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 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 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 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 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 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 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 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 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 NA Cost per dose 1 (US dollars)Vaccine 1 10-dose vial, unless otherwise specified 2 Not available after Single-dose vials

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

15 Immunogenicity and Efficacy of Hepatitis B Vaccines

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

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 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 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 hours of birth  Efficacy of hepatitis B vaccine similar when given with and without HBIG

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

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 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 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 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 % 1% 14% 12% 0 13% 1% 50% 74% 85% 67% 68% -- 68% % 0 0.4% 0 1% 0

26 Effectiveness of Routine Infant Hepatitis B Immunization Programs

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 Effect of Hepatitis B Vaccination on the Incidence of Acute Hepatitis B Alaska, United States Cases/100, Demonstration Project 1988 Routine Immunization

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 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