Issues and Questions in HIV Vaccine Trials

1. Issues and Questions in HIV Vaccine Trials Noreen Jack MB.BS, MPH

2. years-decades 1-3 yrs. 5-15 yrs. Vaccine Development Process Application Concept Exploration Basic & Exploratory Research Product Development Animal Studies IND Candidate vaccine Phase 0 Phase I Phase II Phase III Virology Immunology Molecular Biology PLA 5

3. Scientific Issues and Questions

4. Overview of AIDS Vaccine Designs Whole inactivated Live Attenuated HIV peptide Recombinant protein subunit Live virus vector DNA Live bacterial vector

5. Chimps are not a perfect model Immunize with HIV-1 surface (env) protein gp120; gp160 Raise neutralizing antibody response Protect against subsequent infection 1990 Encouraging results in 3 chimps; confirmed in subsequent small studies But Chimps can clear HIV-1 infection on their own Macaques is important in current vaccine research Assessment of safety and immunogenicity in a model closely related to humans IL2/Ig adjuvanted DNA vaccines or DNA prime followed by MVA boost elicited control over viral replication and protection from CD4 loss Recently differences in allele (Mamu-A*01) influence immune response and poorer viral control Animal Models do not always predict responses in humans

6. Geographic Distribution of HIV-1 Subtypes – 1990’s B,A,C,D,E,F,G,H B,A,D,E C,B,E A,C,D,E,F,G,H E,B B,E,F,C B U.S. Military HIV Research Program

7. Relevance of HIV-1 Strains • Vaccines that produce CD8-CTLs recognize some HIV strains of other clades • Samples from Ugandan volunteers given Clade B based ALVAC 205 responded to Clade A and D peptides • Does it lead to cross-protection? Dual infections B/C;B/E and recombinants can occur • Vaccines producing Abs; subunit vaccines • No neutralization of strains beyond vaccine strain • New strategies: combining immunogens from different clades to create “cocktail” vaccines-multiclade vaccines

8. Advantages for immune escape (env) • Surface glycosylation obstructs receptor-binding sites and conserved regions are concealed or inaccessible • Results in the lack of cross-neutralization within same clades or between different clades • Lab-adapted strains don’t neutralize “primary isolates” • New approach-designing vaccine immunogens computationally based on consensus or ancestral strains

9. What arm of immune response correlates with protection from infection or disease? • Both cellular and humoral responses may be required • Humoral responses control early viral replication and prevent viral entry into target cells • Cellular immune responses play a role in the control of replication • Envelope subunit vaccine (gp160 or gp120) produces better antibody responses • Vector vaccines as ALVAC and Ad5 vector produces better cellular immune responses • How do we achieve both?

10. What Strategies result in the best immune responses: Prime Boost • The administration of one type of vaccine followed or together with another vaccine • ALVAC 1452 and gp120 or gp160 • DNA and MVA • DNA and vector Ad5 • Ad5 and ALVAC 205 • The purpose is to enhance the immune response and develop both antibody and CTL immune responses enhancing the overall effect

11. Need for trials in humans • Phase I to define safety • Phase II to define immunogenicity and safety • Phase III to determine efficacy and safety • An expanded global trials capacity is required • Efficacy trials require large number of volunteers : 5,000 to 15,000 • Training of staff in the conduct of clinical trials. Retaining staff • Infrastructure needs include laboratory supports in country that can meet quality standards • Local in-country ethical review board capacity

12. HIV VACCINE TRIALS NETWORK International and US Sites to test HIV Vaccines New York, NY Baltimore, MD Boston, MA Chicago, IL Fairfax, VA Washington, DC Port-au-Prince, Haiti Rochester, NY Providence, RI • Global initiative • Many sites St. Louis, MO Nashville, TN *Yunnan, China Seattle, WA Nanning, China San Francisco, CA Birmingham, AL Kingston, Jamaica Chiang Mai, Thailand *Tegucigalpa, Honduras Santo Domingo, Dominican Republic *Pune, India San Juan, Puerto Rico Blantyre, Malawi Port of Spain, Trinidad & Tobago Gaborone, Botswana Lima, Peru Soweto, South Africa Sao Paulo, Brazil Rio de Janeiro, Brazil Durban, South Africa *Potential Expansion Sites *Capetown, SA

13. Study and Operational Issues • Eligibility criteria based on US criteria not readily applicable to many international settings • Risks criteria • Medical criteria especially based on hematology and biochemistries norms for Caucasians • This delays recruitment and enrollment • Difficulties with shipping samples-often delays. Sites should have the capacity to perform in country sample processing and some laboratory assays

14. Ethical Considerations • Prevent social harms • Vaccine induced HIV antibodies may lead to an HIV antibody positive result • Difficulties include discrimination • Problems with immigration and obtaining insurance where an HIV test is required • Misdiagnosis during hospitalization or other situations where HIV testing may be needed • Mechanisms to prevent social harms include PCR test to distinguish from true infection and providing support for the volunteer as required

15. Ethical Considerations • Legacy of Tuskegee/the term “Guinea Pigs” impacts on community education and recruitment efforts especially in developing countries • Is there an obligation to provide antiretroviral treatment for volunteers who become HIV-infected? • For a efficacy trial to reach a conclusion, people have to become infected • Researchers conducting a vaccine trial must do everything to prevent people from becoming infected: risk reduction counseling • Participants in a vaccine trial may believe they are protected

16. Advocacy, Community awareness and education • Develop and maintain Community Advisory Boards (CABs) • Increase community awareness of HIV prevention including HIV vaccines. • Usually there is misinformation • There is distrust of developed countries motives for the development of HIV vaccines • Concerns of safety and long term consequences • Community awareness assists recruitment providing understanding and support for volunteers

17. Funding and Economic Issues • Adequate resources for infrastructure, to train and fund researchers and increase community awareness to conduct scientifically/ethically sound trials • For industry, there is more profit in drugs • Preclinical development: $100,000,000 • Clinical testing: $100,000,000 (NIH) • R&D companies may see few incentives given the challenges and uncertainties • What are the implications of success? If a HIV vaccine becomes available would it be affordable to developing countries? How will it be distributed?

18. Summary • HIV Vaccine development is one of the many challenges of the HIV pandemic • Since 1980’s the small successes have informed today’s knowledge and the new vaccine designs and strategies • Continue efforts require increased resources, commitment and collaboration of many