HIV Vaccine Clinical Trials: In Theory and on the Ground

1. HIV Vaccine Clinical Trials:In Theory and on the Ground Prof. Omu Anzala Program Director Kenya AIDS Vaccine Initiative (KAVI) Department of Medical Microbiology University Of University Kenya 18 October 2009, Paris

2. Outline • Vaccine Development—from the Lab to the Clinic • AIDS Vaccine Design • State of The Field • Clinical Trials in Kenya • Challenges in AIDS Vaccine R&D • Progress: Case Study on Neutralizing Antibodies

3. Vaccine DevelopmentFrom the Lab to the Clinic • Concept • Vaccine design • Testing Political willand finance Researchand development Clinical trials Production Health and other systems Accessand uptake

4. Vaccine DevelopmentFrom the Lab to the Clinic • Laboratory studies • Animal studies • Phase I clinical trials • Less than a hundred volunteers. • Determine safety of the candidate vaccine. • Phase II clinical trials • Several hundred volunteers from low- and high-risk populations. • Determine safety and immunogenicity in a larger population of people. • Efficacy trials (Phase IIB/Phase III clinical trials) • Determine efficacy of preventing HIV/AIDS (does the candidate vaccine prevent HIV infection? and/or delay disease progression?)

5. Supportive Activities for Clinical Trials • Preparations in advance of clinical trials • Incidence studies • Community information [Media, community reps] • Advocacy • Regulatory clearance • During clinical trials • Community advisory boards inputs • DSMB reviews • In parallel with clinical trials • Other clinical and epi-studies, e.g. • Reference ranges • Neutralizing antibody consortium

6. Vaccine Design

7. State of the Field • Trials databases – up to date. • www.iavireport.org/trials-db • www.clincaltrials.gov

8. Clinical Trials in Kenya • Kenya AIDS Vaccine Initiative (KAVI) • Two study sites in Nairobi: • Phase I site at KAVI-KNH • Phase II/III site at KAVI-Kangemi • KAVI has conducted: • 4 Phase I HIV vaccine trials (DNA/MVA) • One Phase II HIV vaccine trials (DNA/rAd5)

9. Results of Efficacy Trials http://www.avac.org/pdf/thai_vax_anticipating_results.EN.pdf

10. Challenges in AIDS Vaccine R&D ISSUE WHAT IT MEANS Scientific challenges • HIV integrates; short window • HIV hyper-variability; clades • Immune correlates of protection are still unknown • HIV suppresses and kills cellsof the immune system • Relevant animal models are lacking • Clinical trials are long and costly • We have to test in people (Thai trial results) • We are tackling an aggressive and fast-moving target • Success will take time Policyandpolitical will • Long-term effort requires long-term, high-level global commitment— leading to action • Market incentives for industry activity lacking • Ethical, regulatory,intellectual-property issues • Health-systems challenges • We need sustained political support • We need to build private-sector engagement • We need to optimize the environment for safe, ethical trials

11. Social Challenges In the Kenya Context Community Concerns (Kenya) • Vaccine safety • Selection criteria for volunteers • Possible side effects • Approvals and clearances from government • Implications of vaccine on volunteer lifestyle • Provision of insurance • Why is Kenya participating • Patent and property rights, royalties

12. Progress: Case Study on Neutralizing Antibodies

13. 2G12 CD4 b12 gp120 2F5 gp41 4E10/Z13 Viral envelope The Neutralizing Antibody Challenge • Most licensed vaccines work by inducing the body to produce antibodies that attack the infecting virus, neutralizing most of it and enabling the immune system to clear remaining virus before the onset of disease • In the blood of certain HIV-infected individuals, scientists have identified special antibodies that are broadly neutralizing—they neutralize many of the types of HIV in circulation worldwide • An AIDS vaccine will almost certainly need to elicit a sufficient amount of these broadly neutralizing antibodies • This is the neutralizing antibody challenge

14. The Antibody Project: Protocol G IAVI Human Immunology Laboratory, London Monogram Biosciences 50 91 81 200 200 200 200 238 200 215 200 Number of donor samples from each site 1. Nearly 2,000 blood samples collected from HIV-positive individuals around the world 2. Samples sent to Monogram Biosciences for neutralization screening

15. 3. Screening results scored using new IAVI algorithm to identify donors of interest The Antibody Project: Identifying Prospects Blood samples collected About 10% are donors of interest About 1% are “elite neutralizers”

16. The Antibody Project: Closing In IAVI Human Immunology Laboratory, London IAVI IAVI NAC at Scripps 4. After data review, new samples requested from donors of interest 5. Samples sent to IAVI Human Immunology Laboratory

17. The Antibody Project: Partners in the Hunt IAVI Human Immunology Laboratory Theraclone HuMabs RockefellerUniversity Monogram* IAVINACat Scripps 6. Samples sent to four partner labs for antibody rescue—each using a different technology *Monogram received new samples to verify neutralization screenings

18. The Antibody Project: Discovery 7. Theraclone is firstto find new broadly neutralizing antibodies 8. Antibodies characterized IAVI Neutralizing Antibody Center at AIDS Vaccine Design and Development Laboratory

19. The Antibody Project: Next Steps IAVI Human Immunology Lab Lipoxen Pepscan Avatar IAVI AIDS Vaccine Design and Development Lab ProSci StrandLife Sciences Chembiotek IAVI Neutralizing Antibody Centerat the Scripps Research Institute Neutralizing Antibody Consortium members Elevation Biotech IAVI Innovation Fund recipients 9. With antibodies characterized, IAVI’s immunogen design partners take over

20. The Antibody Project: The Return Pune Chennai Entebbe IAVI-supported networkof clinicalresearch centers Nairobi Kigali Kilifi Masaka Copperbelt 10. Ultimately, the process comes full circle with clinical testing of vaccine candidates Lusaka Rustenburg Cape Town

21. Questions?