1. HEPATITIS B VIRUS. Discovery and Development. Baruch S. Blumberg Fox Chase Cancer Center, Philadelphia PA, USA

3. HEPATITIS B VIRUS MORPHOLOGY Characteristics Nucleic acid: DNA Classification: hepadnavirus type 1 Serotypes: multiple In vivo replication: reverse transcription in liver and other tissues In vitro propagation: primary hepatocyte culture and transfection by cloned HBV DNA 42 nm 22 nm C HBsAg HBcAgHBV DNA

7. HBV is one of the most common infections in the world. About 600,000 to 1,000,000 deaths per year are attributable to the diseases associated with HBV.

8. (H. Margolis, Center for Disease Control. Paper presented at Third International Conference on Therapies for Viral Hepatitis, Maui, 12/12/99) Virus Number Infected (Millions) Low 15% 34 Case Fatality Rate Total Deaths (Millions) High 25% 100% 371 HIV HBV 34 92.8 55.7 PREDICTED DEATHS FROM PREVALENT CARRIERS OF HIV AND HBV

9. 0 500 1000 1500 2000 2500 25-3435-4445-5455-6465-74 Age group (years) Mortality per 100,000 py M HBV+M HBV-F HBV+F HBV- MORTALITY BY AGE GENDER AND HBV RESPONSE HAIMEN CITY, CHINA G. Chen, W. Lin, F. Shen, U. Iloeje, T. London and A. Evans Inter. J. of epid. 2004, in print

10. CONTROL OF HEPATITIS B VIRUS IN CHINA Z.Y. Xu, T.Q. Yan, S.J. Zhao, et al. Shanghai Medical University “Infant HBV immunization has been implemented into public health service in China since 1986… the seropositivity for HBsAg was reduced from 16.3% (879/5397) of historical controls to 1.43% (70/4886) in cross-sectional study and 1.81% (210/11582) in a cohort study.”

11.  A vaccination program was initiated in 1983 in Afragola, Italy, a community with very high rates of HBV infection and of morbidity and mortality from liver disease (Da Villa, et al., 1992, Da Villa, et al., 1995).  The prevalence of HBsAg in males up to 12 years dropped from 10.5% in 1978 to 0.8 % in 1993 after the vaccination program was in place for ten years.  The prevalence of anti-HBc in dropped from 52.6% to 1.2%.  There was also a drop in the prevalence of HBsAg in the mostly unvaccinated population i.e., males age 13-60. HBsAg dropped from 17.97% in 1978 to 5.5% in 1989. This implies that the reduction of the carrier prevalence in the vaccinated group has an indirect effect on unvaccinated carriers and susceptibles, and suggests that there may an amplification characteristic to the vaccination program. HBV VACCINATION IN ITALY

12. STUDIES ON TAIWAN Hepatocellular Carcinoma: Average annual incidence in the age range 6-14 fell from 0.7/100,000 in 1981-1986 (before vaccination) to 0.36/100,000 in 1990-1994 (after vaccination) (p < 0.01) The annual incidence in children aged 6-9 years fell from 0.52/100,000 in those born in 1974-1984 (pre-vaccination program), to 0.13/100,00 in those born in 1986-1988, (post-vaccination program) (p<0.001)

14. The probability of male or female patients in a single hemodialysis unit remaining HBsAg+ after infection. Males have a 68% probability of becoming chronic carriers when first detected HBsAg-, whereas female patients have a 33% chance.

15. The probability of patients not developing ant-HBs once detected HBsAg+. About 55% of the female patients are likely to eventually develop ant-HBs compared with 30% of males.

16. Parent’s response To HBV Either parent HBsAg + : anti-HBs – Both parents HBsAg - : anti-HBs – Both parents HBsAg - : either parent anti-HBs + Couples (No.) 33 29 154 Live births Male Females 60 (1.8 ± 0.2) 51 (1.8 ± 0.2) 24 (1.6 ± 0.1) 24 (0.7 ± 0.1) 35 (1.2 ± 0.2) 22 (1.4 ± 0.1) Sex ratio 250 (161,429)* 146 (96,230)* 109 (91,131)* PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS ACCORDING TO THE RESPONSES TO HBV OF PARENTS *In parentheses, the 5 percent confidence limits. Blumberg, B.S. Sex differences in response to Hepatitis B Virus, Arthritis and Rheumatism,22, 1261, 1979

17. Hepatitis B and Sex Ratio Notes: This table shows sex ratios among the children of carrier and non-carrier parents in four regions. Data were collected by testing married women and, in all cases except for Greenland, their husbands for HBV. Detailed reproductive histories were also collected. The table represents all births to women in those samples, with generally more than one birth to each women. The last two studies (Greece 2 and France) were designed specifically to test the hypothesis that HBV affects offspring sex ratio, and were run after the original theory was expressed. Location Greenland Kar Kar Island Greece 1 Philippines Greece 2 France HBV Status Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Sons 64 174 63 163 85 287 66 304 52 1006 20 149 60 194 54 206 46 255 41 301 30 955 12 122 Sex Ratio 1.07 0.90 1.17 0.79 1.85 1.13 1.61 1.01 1.73 1.05 1.66 1.22 Daughters From Oster, E. 2005