1. 25 Years of HIV Vaccine Research: What have we accomplished? José Esparza MD, PhD Senior Advisor on HIV Vaccines Global Health Program The Search for an HIV Vaccine Vienna, July 18, 2010

2. © 2009 Bill & Melinda Gates Foundation | What we have not accomplished  In May 1997 President Clinton announced a comprehensive AIDS vaccine research initiative designed to lead to the development of an AIDS vaccine within 10 years (and the first efficacy was obtained in 12 years!)  However, we are not close to have a practical HIV vaccine that can be used in public health programs around the world.  Our collective goal should be a “practical” vaccine within 10-15 years!  To achieve that goal we need to produce new science AND to harness new and existing science to develop new candidates for clinical trials. 2

3. © 2009 Bill & Melinda Gates Foundation | The Impact of an AIDS Vaccine in Developing Countries Low = 30% efficacy, 20% coverage Medium = 50% efficacy, 30% coverage High = 70% efficacy, 40% coverage Stover J, Bollinger L, Hecht R, Williams C, Roca E: The impact of an AIDS Vaccine in Developing Countries: A New Model and Initial Results. Health Affairs 26(4):1147-1158 (2007)

4. © 2009 Bill & Melinda Gates Foundation | A simplified chronology of HIV Vaccine Research  1981: AIDS identified  1983/4: HIV identified as the cause of AIDS  1987: First phase I HIV vaccine (gp160, MicroGeneSys)  1989: SIV vaccines protect monkeys (R Desrosiers and others)  1991-1992: role of host cell antigens in early NHP protection experiments (J Stott and others)  1990s: Intense effort to develop vaccines to induce antibodies  1990: Begin preparation of trial sites in developing countries  1998: Candidate vaccines failed to induce antibodies that neutralize primary (clinical) isolates  2000s: Intense effort to develop vaccines to induce CMI  1998-2003: Phase III trials of VaxGen gp120 vaccine (Thailand, US)  2004-2007: Phase IIb trials (STEP, Phambili) of Merck Ad5 vectored vaccine  2003-2009: Phase IIb/III trial (RV144) of ALVAC + AIDSVAX in Thailand 4

5. © 2009 Bill & Melinda Gates Foundation | What have we accomplished?  Science Genetic and immunological variability of HIV (R5/X4 variants; clades) Detailed molecular structure of the HIV envelope (target of neutralizing antibodies) Novel broadly neutralizing monoclonal antibodies (PG9/16, VRC01-3, HJ16) Mechanisms of protective immunity in humans (role of antibodies and CMI) Early events of HIV infection (and the small window of opportunity for vaccine prevention) Refinement of NHP models (low dose repeated mucosal challenges) Immunization regimes to induce balanced immune responses (CD4, CD8, antibodies) Design of novel “cross-clade” vaccine inserts (consensus, conserved elements, mosaics) Potential role for non-neutralizing antibodies (i.e., ADCC) Protection at the mucosal portal of entry  Clinical trials Scientifically and ethically possible (provision of other preventive interventions) Slow!!! (only three efficacy trials in 25 years!) Results from efficacy trials are always a surprise (unpredictable). RV144 (a light at the end of the tunnel, but we are not there yet!). 5

6. © 2009 Bill & Melinda Gates Foundation | Efficacy trials present unique opportunities (Esparza, Heyward, Osmanov, 1996 (AIDS 10:S123-S132)  Establish if different vaccine concepts can induce protection in humans.  Validate the primate models presently being used in HIV vaccine research.  Obtain information on immune correlates of vaccine- induced protection.  Explore the significance of viral genetic variability in relation to vaccine-induced protection.  Evaluate different end-points for vaccine efficacy (prevention of infection, establishment of chronic infection, disease)  Generate additional data on vaccine efficacy. 6