" Scientific, Regulatory and Ethical Issues in International Seminar "HIV Vaccine Research: Ethical and Regulatory Issues" 4-5 October 2006, Brasilia, Brazil " Scientific, Regulatory and Ethical Issues in HIV Vaccine Research: the WHO Perspective" Dr Saladin Osmanov WHO-UNAIDS HIV Vaccine Initiative World Health Organization Geneva, Switzerland

25 years since the first report of the first AIDS cases June 1981: Official registration of the first AIDS cases in USA November 1983 – May 1984 Identification of the human immunodeficiency virus (HIV) as a causative agent of AIDS October-November 1987 The first HIV vaccine trial started

Number of people living with HIV by the end of 2005 Total: 40.3 (36.7 – 45.3) million Western & Central Europe 720 000 [570 000 – 890 000] North Africa & Middle East 510 000 [230 000 – 1.4 million] Sub-Saharan Africa 25.8 million [23.8 – 28.9 million] Eastern Europe & Central Asia 1.6 million [990 000 – 2.3 million] South & South-East Asia 7.4 million [4.5 – 11.0 million] Oceania 74 000 [45 000 – 120 000] North America 1.2 million [650 000 – 1.8 million] Caribbean 300 000 [200 000 – 510 000] Latin America 1.8 million [1.4 – 2.4 million] East Asia 870 000 [440 000 – 1.4 million]

The HIV pandemic continues its accelerated spread at a rate of 14 The HIV pandemic continues its accelerated spread at a rate of 14.000 – 15.000 cases of HIV infection every day and 5.000.000 cases every year More than 95% of cases in developing countries More than 40% of cases among women More than 50% of cases among young people of 15-24 years of age Up to 10% of cases among children younger than 15 years

Scientific, Regulatory and Ethical Issues in relation to HIV/AIDS Vaccine R & D A critical need for a safe, effective and affordable HIV vaccine drives a push for moving multiple vaccine candidates into clinical trials If some of the trails are successful, there would be a need to secure license from local National Regulatory Authorities (NRAs) To facilitate this decision making by NRAs there is a need to develop regulatory frameworks for HIV vaccines addressing multiple scientific, ethical and logistical challenges related to the preparation and conduct of HIV vaccine trials

Scientific Challenges for HIV Vaccine R & D - Genetic variation of HIV - Correlates of immune protection - Role and value of animal models Multiple vaccination strategies to be explored

The current international classification and nomenclature of HIV Types: HIV-1, HIV-2 Groups: M, N, O Subtypes: A-D, F-H, J, K Intersubtype recombinants: Curculating Recombinant Forms: - CRF01_AE, CRF02_AG, etc. - Unique Recombinant Forms

The global proportion of HIV infections caused by different HIV Subtypes and CRFs by 2005

Distribution of HIV Subtypes and CRFs by 2005

Systematic genetic characterization of HIV-1 strains has Impact of HIV-1 Genetic Variability on the Development and Evaluation of HIV vaccines Systematic genetic characterization of HIV-1 strains has proven to be a valuable tool for: - Tracking the dynamics and spread of genetic subtypes of HIV-1 and CRFs on a global basis. - Generation of key data to provide rationale for matching the locally prevalent HIV strains with vaccine candidates. Provision of critical information for improved diagnostic and treatment strategies

Impact of HIV-1 Genetic Variability on the Development and Evaluation of HIV vaccines However, a number of scientific unknowns remain to be addressed: - The molecular epidemiology of HIV-1 is characterized by increasingly complex patterns with a clear shift from pure subtypes to recombinant strains. - The present HIV-1 classification is becoming more and more obsolete, in particular due to the fact that it does not directly reflect/predict biology and immunology of the virus. - Relevance of genetic subtypes and CRFs of HIV-1 for vaccine protection needs to be critically assessed by appropriately designed vaccine efficacy trials.

Potential scenarios of "matched" vs "mismatched" trials in Brazil 1. Complete match between vaccine specificity and a prevalent HIV-1subtype in a study population, e.g. subtype B candidate vaccine among MSM 2. Complete mismatch, e.g. subtype E candidate vaccine among both MSM and IDU 3. Partial match, e.g. subtype C or subtype B candidate vaccine in IDU population in Brazil

Correlates of vaccine induced immune protection В-cell humoral immunity - Binding and neutralizing AB Т-cell mediated immunity - Cytotoxic lymphocytes (CD8+ CTLs) - CD4+Т-helper cells - Cytokine networks and innate immunity - Immune memory Mucosal immunity Combination of all above - Type and quality of immune responses CTL

Potential end-points for HIV vaccine efficacy

Efficacy issues Prevention of infection/disease - Sterilizing immunity - Modification of virus load - Decrease infectiousness (transmission) - Better response to ARV treatment Level of efficacy Efficacy against different virus subtypes Efficacy in different populations Different routes of transmission Different host background: genetic, age, behavioural, social, etc.

Different HIV vaccine strategies Peptides Recombinant proteins DNA vaccines Vectored vaccines (virus or bacterial vectors) Prime-boost combinations Attenuated vaccines Whole Inactivated vaccines

Role and Value of Animal Models The currently available animal models do not provide for go/no-go check point in pre-clinical research. Important questions need to be resolved, e.g.: - Which model mimics more closely the HIV infection in humans? - Different models produce controversial results. Which are most appropriate? Need for key improvements to model Creating a more human exposure model Repetitive low dose vaginal challenges

Evolution of strategic approaches to HIV vaccine R & D First generation of HIV vaccines (1987-1990 ) - Induction of neutralizing/binding AB - HIV-1 envelope derived antigens (rgp160, rgp120, peptides) Second generation of HIV vaccines ( 1990-2000) - Induction of T-cell immunity (CD8+, CD4+/CTL) - Vectored and DNA vaccines - "Prime-boost" combinations Third generation of HIV vaccines (2000-present) - Stimulation of more potent and broad spectrum of anti-HIV responses - Candidate vaccines derived on functionally important epitopes based on the globally prevalent HIV strains (subtypes A, B, C, D, CRF01_AE,etc.)

More than 30 vaccine candidates tested in phase I/II trials Major lessons learnt from phase I/II clinical trials with the first and second generation of HIV vaccines in 1987-2003 More than 30 vaccine candidates tested in phase I/II trials With participation of more than 7,000 HIV-negative volunteers Trials were conducted both in developed and developing countries, including USA, Europe, Thailand, Brazil, Uganda, Kenya, Cuba, China Practically, all vaccine candidates were highly safe. However, immunogenicity and duration of immune responses were far less than optimal, in particular with vaccines targeting T-cell immunity

Lessons learnt from the first phase III efficacy trials rgp120 BB (AIDSVAX B/B) (VaxGen) USA, Canada, the Netherlands 5.418 volunteers, mostly MSM with only a small control group involving women with high risk for HIV Start: June 1998 Completed: February 2003 rgp120 BE (AIDSVAX B/E) (VaxGen) Thailand 2.545 volunteers (IDUs) Start: March 1999 Completed: January 2004 Phil Berman Don Francis

Results from the first HIV vaccine phase III trials Both phase III trials did not show any significant level of efficacy. However, these trials have also demonstrated that: Phase III trials can be successfully conducted in high risk volunteers, including IVDUs and MSM Large numbers of volunteers can be recruited and followed up Trial endpoints occur throughout the trial and not just clustered in the first half of the trial Behavioural counseling is effective and no evidence of increased risk in either IVDUs or MSMs, but residual risk group persists Attention needs to be directed to adequate recruitment of women and minorities in large efficacy trials

The third on-going phase III trial in Thailand rgp120 BE (VaxGen) + ALVAC (Pasteur Merieux) 16,000 volunteers Expected efficacy: 50% protection agains HIV infection Or control of viral replication and reduced viral load set point Start: September 2003 End: January 2008

Challenges for Generation of Functional Humoral Immunity Renewed, concentrated and cooperative effort towards the development of immunogens capable of inducing functional humoral immunity Not just binding antibody New effort in increasing sensitivity, specificity, and reproducibility of neutralization assays Expanded work in understanding native gp160 - structure pre/post binding and stability Increasing preclinical focus on immunogens inducing functional Ab (generation of ADCC, neutralization of primary isolates)

New generation of HIV vaccines Recombinant proteins/peptides Lipopeptides Gp120/gp140 (subtypes A,B,C, CRFs, etc.) Oligomeric proteins Env gp140 (subtypesA,B,C, CRFs and others) Regulatory proteins of HIV (e.g.,Tat, Nef)

Challenges for Targeting Cellular Immunity Establish baseline anti-vector immunity Need strategies to overcome pre-existing immunity Establish gold standard to measure cellular immunity (CD8+ T cells) Increased sensitivity of assays must be linked to functional standards or validated through animal model protection studies Improve assessment of CD4+ T cell function Need to standardize lab platforms for immune assessment around the globe SOPs Tech transfer Specimen processing, storage and shipment

Progress in addressing issues in relation to: HIV Variability and Improving Cellular Immunogenicity Pox Vectors Canary Pox (A, B, E) Fowl Pox (B, E) MVA (A,B,C,D,E,CRF02) SAAVI VRC Aaron Diamond Emory Oxford Therion Eurovac USMHRP NYVAC, Tan/Tan Eurovacc Other Vectors Salmonella (B,C) WRAIR IHV Adenovirus VRC (A,B,C) Merck (B) Semliki Forest (A,B,C) VEE (C gag) SAAVI Alphavax VSV Yale AAV Johnson Measles Polio Simbis Virus Chiron DNAs Wyeth (B) Emory (CRF02,B,C) U of Penn (A,C,D,E) Eurovacc(C) Oxford (A) SAAVI (C) Karolinska (A,D) Aaron Diamond(C) Chiron (C)

Need to conduct multiple efficacy trials, especially in developing countries

Current Challenges for HIV Vaccine R & D Clinical trial issues Numerous clinical trials need to be conducted in developed and developing countries Criteria to move forward candidate vaccines through phase I-III trials and novel approached to the trial design (IIa, IIb trials ?) - Definition of trial end-points and expected vaccine effects - Trial to determine vaccine efficacy in diverse populations: ethnicity, gender and age, with a special focus on women and adolescents

Current Challenges for HIV Vaccine R & D Regulatory and ethical aspects - Production of candidate vaccines for clinical trials (GMP) - Immunogenicity and potency measurement - Safety monitoring Regulatory and ethical review, approval and oversight Ensuring the required standards (GCP, GLP) Access to care and treatment Potential licensing and immunization strategies

Current Challenges for HIV Vaccine R & D Clinical trial site development - Need for comprehensive site development in developing countries and integration of HIV vaccine research into national strategic planning, with a special focus on capacity building, training and infrastructure development Broad and effective community involvement Advocacy and policy development Addressing issues of future access to and public health use of HIV vaccines (not only financial aspects) Cooperation and the development of regional frameworks (e.g. AAVP) Novel paradigms for international collaboration and partnerships (Global HIV Vaccine Enterprise)

National Capacity Building Logistical Issues related to the conduct of HIV vaccines trials in developing countries Government willingness & commitment Public (media) attention National Capacity Building - Clinical trial and Laboratory expertise Data management Community involvement International collaboration Epidemiology Virus Monitoring Regulatory & Ethical Frameworks Scientific infrastructure Availability of cohorts Social behaviour expertise

National AIDS Vaccine Plans and Strategies Brazil: Second generation (2000) Initiated in 1992 in Brazil, Thailand and Uganda. Continued in several other countries. Facilitate trials by describing policies, approval mechanisms, and research priorities.

New Generation of National AIDS Vaccine Plans/Strategies NORMATIVE FRAMEWORK Political Legal Regulatory Ethical Logistical TECHNICAL COMPONENTS Virology Epidemiology Socio/ behavioural Clinical trials Media/ PR Etc SUPPORTING ENVIRONMENT Community support HIV/AIDS Prevention Access to care, incl. ART Infrastructure/ human resources Etc

Supporting AIDS vaccine activities in developing countries Media Handbook Ethics Guidelines

Considerations with regard to different scenarios: Addressing future introduction, cost-effectiveness and delivery of HIV vaccines Considerations with regard to different scenarios: - Introduction of the first "imperfect" HIV vaccines (sub-optimal efficacy, impact of genetic variability, different modes of transmission, multiple host and population factors) Development of cost-effective and targeted interventions and immunization strategies (women, adolescents, high-risk groups), as part of the overall HIV prevention, treatment and care programmes Production of sufficient quantities and affordable price

The African AIDS Vaccine Programme (AAVP) The AAVP is a network of African scientists and community, working together to promote and facilitate HIV vaccine research and evaluation in Africa, through capacity-building and regional and international collaboration (“the voice of Africa”). Activities being developed and implemented through six thematic working groups: Advocacy, information and resource mobilization. Biomedical sciences (laboratory and clinical). Population studies (Epidemiology and Socio-Behavioural issues). Ethics, Law and Human Rights. National Strategic Planning. Community.

Increasing participation of African countries in HIV vaccine trials 2000 2006 2008 > 4 000 volunteers ? 12 countries 400 volunteers 8 countries 15 trial sites 50 volunteers 1 country 2010 >10 000 volunteers

Klausner et al. Science 2003, 300:2036-2039

New Opportunities, Evolving Partnerships, Commitment and Collaboration and New Paradigms Unity of Mission Development of a globally effective HIV vaccine Shared vision Concentrated and comprehensive focus on developing countries in sub-Saharan Africa, Asia and Latin America Unique opportunity but new challenges to all sponsors Coordinate Optimize - site development Share - knowledge, personnel, sites, safety data Unify - single immunologic evaluative platform