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Martha Lewis Blum, M.D. Ph.D. August 27, 2013

HIV Vaccine. Martha Lewis Blum, M.D. Ph.D. August 27, 2013. Review of Vaccination history (3 slides) how should it work (5 slides). Approaches to an HIV Vaccine goals of vaccination (1 slide) current approaches (5 slides). Highly Publicized HIV Vaccine Trials

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Martha Lewis Blum, M.D. Ph.D. August 27, 2013

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  1. HIV Vaccine Martha Lewis Blum, M.D. Ph.D. August 27, 2013

  2. Review of Vaccination • history (3 slides) • how should it work (5 slides) • Approaches to an HIV Vaccine • goals of vaccination (1 slide) • current approaches (5 slides) • Highly Publicized HIV Vaccine Trials • Merck STEP, RV144, HVTN 505 (3 slides) Why don’t we have one yet?(2 slide)

  3. Vaccine Preventable Diseases From WHO Global Immunization Vision and Strategy 2006-2015.

  4. The Original Vaccine - 1798 How did it work?

  5. Correlates of Immunity: Immune responses associated with control or prevention of disease. Innate Immune responses Adaptive Immune responses Antibody Cell-mediated CD4 helpers CD8 killers Previously could only look for correlates with what we could measure i.e. - Ab titers, now better measures of Cell-mediated immunity

  6. From Pantaleo & Koup; Nature Medicine. 2004. 8: 806-810

  7. Goal of vaccination? Prevention vs. Disease attenuation/treatment

  8. There is no natural protective immunity to HIV. • No evidence of an infected adult clearing the virus once infected. • A vaccine will have to be BETTER than natural immunity if we want to prevent infection.

  9. Types of vaccines Live attenuated virus – MMR, VZV, Flu Killed virus – Polio, HAV, Flu Subunit protein - HBV Virus-like particle - HPV DNA Recombinant viral vectors Combinations

  10. Why don’t “traditional” vaccine strategies work for HIV? Live attenuated Killed Subunit Unsafe, can’t guarantee it is not going to become virulent Too much diversity in envelope, key sites concealed by sugars or structure.

  11. Viral vectors Engineer HIV genes into another non-pathogenic virus Vaccinia Canarypox Fowlpox VEE AAV MVA NYVAC Adenovirus Disadvantages: difficult to produce high titer recombinant virus. may have pre-existing immunity to vector and/or will develop immunity after vaccination.

  12. DNA plasmid vectors Disadvantages: limited response after repeat doses, integration, DNA Ab? From Stevenson 2004. Immunological Reviews 199: 5-8.

  13. Ended (early) in Sept 2007 Used Ad5 viral vector x2 to deliver Gag, Pol, Nef 24/741 cases of HIV in Vaccine group 21/762 cases of HIV in the placebo group Vaccine did promote the development of HIV specific CTL responses but did not prevent infection nor did it decrease viral load. Why did the vaccine-generated CTL responses not work as expected? MERCKSTEP trial

  14. Published results in 2009 Prime-boost combination of 2 vaccines: ALVAC-HIV x4 doses and AIDSVAX B/E boost x2 AIDSVAX is gp120 (B and AE) ALVAC-HIV is Gag Pro (B) and gp120-41 (AE) RV 144The Thai trial Not that the per-protocol and ITT groups had no significant protection. Currently working on what immune response was protective.

  15. DNA prime x2 with Ad5 viral boost x1, with multi-clade Gag, Pol, Env 27/1,250 cases of HIV in vaccine group 21/1,244 cases of HIV in the placebo group Also no effect on viral load of those infected. People with risk factors for acquisition were excluded from this study and it still didn’t work even though it generated plenty of immune responses. Again, why are the vaccine-generated responses not protective? HVTN 505The NIH vaccine

  16. Why don’t we have one yet? • Scientific obstacles • Incomplete understanding of correlates of protection • HIV has several ways of evading immune responses: • 1.) high diversity, each virus is different • 2.) coating of Env to prevent Ab from binding • 3.) Evasion of CTL killing • Unclear which and how many antigens to choose • Results in animals not the same as in humans • Ethical obstacles • Where to test vaccines and on whom • Responsibility for treatment of vaccine trial participants • What end point would be acceptable considering the efficacy of other preventions (circumcision, PrEP)

  17. New Ideas: Give good immune responses to people by gene therapy. Use different viral vectors to produce high level, sustained immune responses. Keep working on figuring out what is a protective immune response and how we can mimic it

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