Control of Hepatitis B and the Revolution in Global Immunization Mark A. Kane MD, MPH Mercer Island, WA
The best way to predict the future is to design it R. Buckminster Fuller
Life can only be understood backwards; but it must be lived forwards. Kierkegaard
Revolution in Global Immunization The early years of this century have brought unprecedented opportunities: New vaccines for the major killers of children and cancer Cervical cancer and other HPV related cancers Rotavirus Diarrhea Pneumococcal Pneumonia Development of cohesive Public Private Partnerships that provide new global financing mechanisms leading to large increases in funding GAVI Dramatic improvement in vaccine delivery infrastructure in the developing world Global control of HPV using the hepatitis B vaccine as a model is achievable with available tools
Major Challenges Remain Shorten time and affordability gap between industrial and developing countries Achieve country financial sustainability Develop new infrastructure to reach adolescents with new vaccines (HPV and future) and booster doses Avoid competition for limited resources between newer vaccines and with screening Deal more effectively with rumors, antivaccine activities, and public resistance to vaccination
Cancer caused by infectious agents worldwide AGENT SITE # CA %CA H Pylori Stomach 592,000 5.5% HPV Cervix, other 561,200 5.2% HBV, HCV Liver 535,000 4.9% HHV-8 Kaposi s sarcoma 54,000 0.9% Schistosoma Bladder 9,00 0.1% HTLV-1 Leukemia 2,700 Total 1,900,000 18% DM Parkin (2006) Int J Cancer
Key Discoveries Jaundice, ascites described by described by ancient Greeks, Chinese and Indians Realization that parenteral exposure to blood could cause jaundice (19 th century) Differentiation of serum or long incubation from infectious or short incubation hepatitis Discovery of Australia Antigen in patients with serum hepatitis Development of blood screening reagents allowed countries to measure carrier prevalence
Key Discoveries (2) Krugman: demonstration that boiled serum from a hepatitis carrier could protect Development of plasma derived hepatitis B vaccine Beasley et al.: proof that hepatitis B was the major cause of liver cancer (10 year study of Taiwan male civil servants) Elucidation of vertical Tx of hep B Demonstration that perinatal transmission could be prevented with HBIG and/or vaccine Development of DNA recombinant vaccines
Globocan 2008 Estimated 694,000 deaths in 2008 Third most common cause of cancer death 69% in Men Mortality Ratio=0.93 great majority in Hepatitis B carriers Reflect population 50 years ago: unvaccinated 2000 birth cohort >1,000,000
Introduction of Hep B vaccine Initial strategy to immunize high risk groups failed (except for HCW s) Depended on knowledge and action of 10 s of thousands of individuals No guaranteed funding Stigma of some risk groups In general high risk strategies are not very effective (flu, adult pneumo) Realization that only routine childhood immunization would have impact on HB disease even in industrial countries Cost (~ $100/3 doses) prohibited consideration of public health use in developing world ITFHBI transferred technology to S. Korea who sells vaccine for $1/dose
Hep B Case Reduction (%) Why vaccinate the general population rather than High-Risk groups only? In the example of hepatitis (Hep) B, universal vaccination was optimal. 1 Modeled reduction in Hep B cases based on various immunization strategies 0% -10% -20% -30% -40% -50% -60% -70% -80% -90% -100% 1990 2000 2015 At-Risk Groups Infants Adolescents Infants and Adolescents Infants, Adolescents, and At-Risk Groups Adapted from Margolis, et al. 1. Margolis H, Alter M, Krugman S. In: Hollinger BF, Lemon SM, Margolis H, eds. Baltimore, Md: Williams & Wilkins; 1991:720 722.
A long decade s journey into night (almost) 1980 s UCI Common Agenda 1990 s Fragmented Agenda routine and supplemental immunization split Polio receives 90% WHO resources competitive zero sum game System decay decreased donor support and interest falling coverage inability to integrate new vaccines Paradigm shift child survival to health reform
A long decade s journey into night (almost) Hepatitis B was introduced in a landscape unfavorable to new vaccine introduction WHO was spending about 90% of non-salary funds on polio and measles control. UNICEF it s not my department and come back when it s $0.25 WHO regions variable in support of HB introduction: sometimes support varied country by country based on personal opinion of staff. Shallow staffing (one person at HQ) and budgeting inadequate for a global effort to introduce a new vaccine
CLASSICAL VACCINE INACTIVATION ATTENUATION PATHOGEN NUCLEIC ACID EXPRESSION MOLECULAR CLONING SUBUNIT VACCINE INSERT VECTOR MUTAGENESIS EXPRESSED PLASMID PEPTIDE VACCINE LIVE RECOMBINANT VECTOR LIVE ATTENUATED NUCLEIC ACID VACCINE
Un homme enceinte s accouche dans son tombeau* *A pregnant man delivers in his grave
Cancer rates, Gambian males 1986-96 incidence per 100,000 140 120 100 80 60 all cancer liver cancer 40 20 0 0-14 15-19 20-24 25-29 30-34 35-39 40-44 age 45-49 50-54 55-59 60-64 65 + (GHIS Reports)
HBsAg prevalence Prevalence of Chronic Hepatitis B Virus Infection Among Children Before and After HepB Vaccine Introduction 16 14 12 10 8 6 4 2 0 Taiwan Shanghai Rural China Gambia Alaska Thailand Children born before hepb introduction Children born after hepb introduction 18 HepB prevention and control: current status 15 May 2007
Cases per 100,000 Effect of Hepatitis B Vaccination on the Incidence of Acute Hepatitis B Alaska, United States 300 250 200 150 100 50 Demonstration Project Routine Immunization 0 1981 1982 1983 1984 1985 1986 1987 1988
Rate ratio Hepatocellular Carcinoma Mortality Rate in Vaccinated and Unvaccinated Cohorts 1.6 1.4 1.2 vaccination 15-100 years of age 1.0 0.8 0.6 0-18 years of age 0.4 0.2 0 75-77 78-80 81-83 84 85-87 88-90 91-93 94-96 97-99 00-02 Year Courtesy of Chang, MH Taiwan Provence
HBsAg prevalence Age specific HBsAg prevalence, 1992 and 2006 serosurveys, China Age groups Liang XF, Bi SL, Yang WZ, Wang LD, Cui G, Cui FQ, et al. Evaluation of the Impact of Hepatitis B Vaccination among Children Born Between 1992 and 2005 in China. Journal of Infectious disease, 2009,200(1):39-47. Liang XF, Bi SL, Yang WZ, Wang LD, Cui G, Cui FQ, et al. Epidemiological Serosurvey of Hepatitis B in China - Declining HBV Prevalence due to Hepatitis B Vaccination. Vaccine, 2009, 27:6550 6557.
Countries Using HepB Vaccine in National Immunization Schedule, 2010 No (7 countries [of which 3 given at adolescence] or 4%) Source: WHO/IVB database, 193 WHO Member States. Data as of September 2011. Date of slide: 21 September 2011 Yes (177 countries or 92%) Yes (Part of the country) (2 countries or 1%) Yes (Risk groups) (7 countries or 4%) The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2011. All rights reserved 22 Hepatitis B Standard presentation 2009 November 28, 2012
Log GNP/Capita Impact of income on programme implementation: Hepatitis B Brunei Hong Kong Singapore Coverage >70% HBsAG > = 5% Hep B in EPI Hep B unavailable $6000 Jordan Bulgaria Saudi Arabia Taiwan Rep of Korea South Africa $500 Fijj Mongolia Togo DPR Korea Zimbabwe Zambia Ghana Kenya Thailand Philippines Indonesia China Benin Uganda Viet Nam Malawi Tanzania Log Population 10 Million 50 Million
HB vaccine: Universal Immunization Policy 1999 National programme Planning
Million doses Slow introduction of Hep B and Hib vaccines into developing countries 200 150 GAVI Fund established HepB -- all developing countries 100 50 0 Hep B licensed in U.S. Hib licensed in U.S. 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 HepB -- all developing countries, excl. India, China, Indonesia Hib -- all developing countries * WORLD BANK DATA GAVI forecasts*
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 number of countries % coverage Country introduction HepB* and global infant HepB3 coverage, 1989-2010 200 150 100 50 23 31 35 39 43 51 60 64 70 81 121 137 148 154 159 165 171178179 179** 107 94 100 80 60 40 20 0 0 Number of countries introduced HepB HepB3 coverage Source: WHO/UNICEF coverage estimates 2010 revision. July 2011; and IVB Database, 193 WHO Member States. Date of slide: 2 August 2011 * Year of introduction can be the year of partial introduction ** Includes India and the Sudan with partial introduction excluding 3 countries where HepB administered for adolescence 26 Italy November, 2011
% coverage Global Immunization 1989-2010, 3 rd dose of Hepatitis B coverage in infants global coverage at 75% in 2010 100 90 80 70 60 50 40 30 20 10 0 0 1 1 3 4 7 11 13 14 15 18 30 33 38 45 49 54 59 64 68 73 75 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Global African American Eastern Mediterranean European South East Asian Western Pacific Source: WHO/UNICEF coverage estimates 2010 revision. July 2011; 193 WHO Member States. Date of slide: 2 August 2011 27 Italy November, 2011
Over five million future deaths prevented Results from routine immunisation and one-off tactical investments, by vaccine Source: These estimates and projections are produced by the WHO Department of Immunization, Vaccines and Biologicals, based on the most up to date data and models available as of November 2010 Basic facts about GAVI DATE
Birth dose issues Only 50% of countries offer birth dose but coverage varies dramatically Perinatal transmission has different patterns in Asia and elsewhere Home vs institutional births Delivery at institutional births not difficult but contraindications and administrative issues Coverage of home births very low Qualified vaccinators and cold chain issues Extensive research on out of cold chain storage Monovalent cheap but GAVI doesn t provide it Next major step in Global Hep B control
Introducing a new vaccine is a political decision Each country makes its own decisions Local epidemiology and burden of disease Level of knowledge about disease and vaccine in medical community, public and the media Successful demonstration projects in the country or region Global and regional WHO recommendations The position of GAVI, UNICEF, and bilateral donors Economic modelling of cost effectiveness and impact
Introducing a new vaccine is a political decision Competing priorities for immunization resources Position of womens health in national priorities Cost of the vaccine The affordability of the vaccine to the country The behavior of other countries in the region and the world The strength of internal advocacy for introduction of the vaccine into the public sector The success of the vaccine in the private sector Influence of global and local vaccine producers
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