25 Years of HIV Vaccine Research: What have we accomplished?

José Esparza MD, PhDSenior Advisor on HIV VaccinesGlobal Health Program

The Search for an HIV VaccineVienna, 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.

© 2009 Bill & Melinda Gates Foundation |

The Impact of an AIDS Vaccine in Developing Countries

Low = 30% efficacy, 20% coverageMedium = 50% efficacy, 30% coverageHigh = 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

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!).

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.