1. Thorny Issues in HIV Vaccine Trials Saul Walker Policy Advisor IAVI

2. Thorny Issues? Vaccine positivity (including insurance) Clades Partial efficacy and end-points Cohort selection Phase 2b or not Phase 2b Placebo selection Standards of Care for trial participants in developing countries

3. Vaccine positivity Vaccines often intended to induce antibodies –Standard HIV tests may show +ve for vaccine induced response –Possible to determine true and vaccine positivity through selective tests, such as PCR –Volunteers provided with information and directions for future testing Insurance –ABI recognised issue of vaccine positivity –Assumptions that volunteers are ‘high risk’

4. Clades Genetic variability in HIV produced numerous clades

5. Clades

6. Genetic variability in HIV produced numerous clades Variability challenging for vaccine design but don’t know how important clade issue is –Animal data showing cross reactivity for a number of candidates –Only clinical data will be conclusive Potential for multi-clade vaccines –VRC has an ABC product Some parts of virus relatively well conserved Broad protection a key objective

7. Efficacy Types of Immunity –Sterilising Immunity (V s ): protection from infection –Disease mitigation (V p ): infection but delays or prevention of disease progression –Reduced Infectiveness (V i ): lower VL leading to reduced transmission End points –For V p focus has been on viral set point and/or time to treatment – V i more difficult to design ethical trial Limited Efficacy –Some of the people all of the time or all of the people some of the time –Efficacy and Effectiveness: potential for behavioral reversals

8. Cohort Selection Adolescents –A key group that could benefit from a vaccine –Consent issues and parental sensitivities Discordant couples –Treatment for positive partner? –Possible European cohorts Vulnerable groups –IDUs, sex workers, MSMs …. Service men/women etc –Adding to existing stigma

9. Phase 2b Trials Need to accelerate development and time to field while managing investment risks –Novel trial designs and strategies Phase 2b - ‘Proof of concept’ –Shorter trial designed to show efficacy > 0 –Expand into Phase 3 trial for license –Reduces initial trial costs but can increase total time –Reduces manufacturing investment risks –Designs that expand into Phase 3

10. Placebo Selection Compare gold standard with gold standard + vaccine –Under trial conditions, gold standard can dramatically reduce incidence –Availability of limited efficacy vaccines could make trials impractical Phase 2b to Phase III transition? –Availability of new prevention options, such as microbicides

11. Standards of Care in Developing Countries Trial participants package of care including primary care and HIV prevention Treatment beyond trial not an ethical obligation for prevention trials –‘morally praiseworthy’ Emerging consensus of ‘how’ not ‘if’ –Practical issues: who, when, how long, ensuring provision, cost –Agreement on shared responsibilities Sustainability Trial/community disparities

12. Standards of Care in Developing Countries Consultation essential –Policy development evolved in discussion with WHO- UNAIDS, other sponsors, researchers and NGOs –IAVI undertaken consultations in Uganda and India consultations

13. IAVI SOC Policy - Commitments Ongoing consultation on detail and implementation Support primary healthcare and HIV prevention services to an agreed standard for trial participants for the duration of the trial* Support access to treatment, care and support, including ART when recommended by treatment guidelines, for participants who become HIV infected during a trial* –Initial commitment of 5ys ART after start of treatment recommended –Funding for therapy through an Escrow Account or appropriate national scheme. Treatment guidelines will be agreed with country stakeholders before trial initiation with WHO guidelines providing a baseline IAVI will ensure referral to local support services for volunteers who are HIV-infected and who are screened out before enrolment *unless sufficiently covered under and existing national programme

14. IAVI SOC Commitments IAVI will work actively with country and international stakeholders to support opportunities for trial related investments to provide benefit to communities in which trials take place –Capacity building –Link trial activities with local HIV/AIDS programmes and health services IAVI will work with country and international stakeholders to support; –Sustained provision of treatment, care and support for trial participants who have become HIV infected during a trial –Opportunities to build on trial related investments to provide sustained community health benefits