1. " 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

2. 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

3. Number of people living with HIV by the end of 2005
Total: 40.3 (36.7 – 45.3) million
Western & Central Europe
[ – ]
North Africa & Middle East
[ – 1.4 million]
Sub-Saharan Africa
25.8 million
[23.8 – 28.9 million]
Eastern Europe & Central Asia
1.6 million
[ – 2.3 million]
South & South-East Asia
7.4 million
[4.5 – 11.0 million]
Oceania
74 000
[ – ]
North America
1.2 million
[ – 1.8 million]
Caribbean
[ – ]
Latin America
1.8 million
[1.4 – 2.4 million]
East Asia
[ – 1.4 million]

4. The HIV pandemic continues its accelerated spread at a rate of 14
The HIV pandemic continues its accelerated spread at a rate of – cases of HIV infection every day and 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 years of age
Up to 10% of cases among children younger than 15 years

5. 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

6. 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

7. 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

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

9. Distribution of HIV Subtypes and CRFs by 2005

10. 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

11. 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.

12. 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

13. 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

14. Potential end-points for HIV vaccine efficacy

15. 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.

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

17. 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

18. Evolution of strategic approaches to HIV vaccine R & D
First generation of HIV vaccines ( )
- Induction of neutralizing/binding AB
- HIV-1 envelope derived antigens (rgp160, rgp120, peptides)
Second generation of HIV vaccines ( )
- 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.)

19. 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
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

20. 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

21. 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

22. 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

23. 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)

24. 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)

25. 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

26. 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)

27. Need to conduct multiple efficacy trials, especially in developing countries

28. 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

29. 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

30. 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)

31. 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

32. 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.

33. 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

34. Supporting AIDS vaccine activities in developing countries
Media Handbook
Ethics Guidelines

35. 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

36. 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.

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

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

39. 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