From Discovery to Delivery: Benchwork to Global Health: Shiu-Lok Hu


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Explores relationships and discrepancies between important research-based medical advancements and subsequent real world implementation. Advancements in the management and potential elimination of infectious diseases such as HIV and TB will be addressed, as related to development and implementation of effective diagnostics, vaccines, or treatments.

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  • From Discovery to Delivery: Benchwork to Global Health: Shiu-Lok Hu

    1. 1. In search of HIV vaccine: Progress and Challenges Shiu-Lok Hu Department of Pharmaceutics University of Washington 7th Annual Western Regional International Health Conference April 5, 2009 From Discovery to Delivery: Benchwork to Global Health
    2. 2. As a result of the HIV/AIDS epidemic, life expectancy in Africa has reduced to levels at the beginning of the 20 th century Impact of AIDS on life expectancy in five African countries 1970–2010 Life expectancy at birth (years) Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database. Botswana South Africa Swaziland Zambia Zimbabwe 1970–1975 1975–1980 1980–1985 1985–1990 1990–1995 1995–2000 2000–2005 2005–2010 70 65 60 55 50 45 40 35 30 25 20 4.1
    3. 3. Discovery of HIV Luc Montagnier * Francoise Barré-Sinoussi * Pasteur Institute, France HIV-1 1983; HIV-2 1986 * 2008 Nobel Prize laureates
    4. 4. The ability to propagate HIV in tissue culture helped the identification of the virus as the etiologic agent of AIDS and enabled the development of the first diagnostic test for HIV infection Gallo et al., Science . 1984 May 4;224(4648):500-3. Popovic et al. Science. 1984 May 4;224(4648):497-500. Schupbach et al., Science. 1984 May 4;224(4648):503-5. Sarngadharan et al., Science. 1984 May 4;224(4648):506-8. Schupbach et al., Science. 1984 May 4;224(4648), 607-10.
    5. 5. First antiviral drug against HIV First generation reverse transcriptase (RT) inhibitor: AZT
    6. 6. Percentage of persons surviving through June 2005, by years after AIDS diagnosis cohorts during 1981–2003 and by year of diagnosis — United States Source: CDC. Twenty-Five Years of HIV/AIDS — United States, 1981–2006. MMWR 2006. 2001‒2003 1996‒2000 1993‒1995 1981‒1992 0 25 50 75 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Years after AIDS diagnosis % Figure 12
    7. 7. Percentage of population living with HIV in need of treatment who are receiving antiretroviral therapy Africa, 2007 For every two HIV-infected individuals receiving antiviral therapy, five more become infected The Millennium Development Goals Report, United Nations, 2008
    8. 8. Is it possible? <ul><ul><li>Control of the global HIV/AIDS epidemic will likely depend on the availability of safe and efficacious vaccines </li></ul></ul>
    9. 9. Most successful vaccines made to-date are against pathogens that can elicit protective immunity as a result of natural exposure
    10. 10. <ul><li>Evidence is still lacking for HIV-infected individuals being able to mount an effective immune response to clear infection or to protect against re-infection </li></ul>
    11. 11. Some of the major scientific challenges to AIDS Vaccine Development <ul><li>Virus is highly variable: A moving target </li></ul><ul><li>Virion surface is covered by sugar molecules: Target camouflaged and well protected </li></ul><ul><li>Virus can establish latency and persist in immune privileged sites: May need to stop the initial infectio n </li></ul><ul><li>Specifically target and destroy immune cells: Weakens the mechanisms needed for defense </li></ul>
    12. 12. HIV vaccines approaches *Vaxgen: AIDSVAX ® (gp120 envelope antigen); antibodies *Merck: Recombinant adenovirus (Core antigen) ; cell-mediated immunity recombinant protein (gp120) peptide scaffolds naked DNA live-recombinant vectors (poxvirus, adenovirus, bacterial) whole-inactivated virus live-attenuated virus HIV Vaccine developer* 2 0
    13. 13. Direct evidence indicating the possibility of immune protection against primate lentivirus infection and AIDS has been largely provided by non-human primate models
    14. 14. Sooty mangabey SIVcpz Chimpanzee HIV-1 SIV Sykes monkey Mantled guereza L-Hoest’s monkey Mandrill Red-capped mangabey Vervet monkey Greater spot-nosed monkey Slide courtesy of Beatrice Hahn Origin of HIV: Cross-species transmission of simian immunodeficiency viruses SIVsyk SIVcol SIVlho SIVrcm SIVgsn SIVmnd SIVver SIVsm HIV-2 SIVmac
    15. 15. Improved AIDS-free survival in immunized monkeys after challenge with a chimeric primate immunodeficiency virus (SHIV89.6P) Li et al., J. Virol.82: 638-651, 2008
    16. 16. Protection against primate lentivirus infection or diseases: Lessons from monkey models <ul><ul><li>Protection by immunization against primate lentiviruses is possible </li></ul></ul><ul><ul><li>Live attenuated virus vaccines have generated the most robust protection </li></ul></ul><ul><ul><ul><li>However, safety of this approach remains a major concern </li></ul></ul></ul><ul><ul><li>Several vaccine combinations (heterologous “prime and boost”) have shown to induce complete or partial protection </li></ul></ul><ul><ul><ul><li>Protection against infection </li></ul></ul></ul><ul><ul><ul><li>Reduce viremia and ameliorate disease progression </li></ul></ul></ul>
    17. 17. Can protection in monkey models predict efficacy of HIV vaccines in humans ? <ul><li>Monkeys are not human; SIV not HIV </li></ul><ul><li>Diversity of monkey models: </li></ul><ul><ul><li>Vaccines that work in a given model may not work in another </li></ul></ul><ul><li>Predictive value of protection data in monkey models can only be validated by clinical trial results </li></ul><ul><li>Preclinical models are valuable tools to study the diversity of factors that affect vaccine-induced immunity and protection against primate lentiviruses </li></ul>
    18. 18. Other challenges to HIV vaccine development <ul><li>Liability </li></ul><ul><li>Privacy/insurance </li></ul><ul><li>Risk to benefit ratio </li></ul><ul><li>Market/economic incentive </li></ul><ul><li>Accessibility </li></ul><ul><li>Public acceptance : issues illustrated by the introduction of the successful vaccine against human papilloma virus (cervical cancer) </li></ul>
    19. 19. Microbicides <ul><li>Topical applications that prevent HIV infection </li></ul><ul><li>An alternative to vaccines and other preventive approaches </li></ul><ul><li>Advantages over condoms: greater control by women </li></ul><ul><li>Candidates include specific and non-specific compounds that inactivate the virus or interfere with viral infection </li></ul><ul><li>Proof-of-concept has been demonstrated in animal models </li></ul>
    20. 20. Prophylactic antiviral drug? <ul><li>Efficacy of pre- and post-exposure antiviral drug treatment has been demonstrated in animal models </li></ul><ul><li>Does it work in against acquisition of infection in humans? </li></ul><ul><li>Does it increase the risk of selection for drug-resistant mutants? </li></ul><ul><li>Role in controlling the HIV/AIDS epidemic and improving global health is questionable </li></ul>