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THE LONG ROAD TO AN HIV VACCINE (El largo camino hacia una vacuna contra el VIH)

A Multicultural Caribbean United Against HIV/AIDS Santo Domingo, 5-7 March 2004. THE LONG ROAD TO AN HIV VACCINE (El largo camino hacia una vacuna contra el VIH). j. j. José Esparza, MD, PhD WHO-UNAIDS HIV Vaccine Initiative Geneva, Switzerland.

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THE LONG ROAD TO AN HIV VACCINE (El largo camino hacia una vacuna contra el VIH)

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  1. A Multicultural Caribbean United Against HIV/AIDS Santo Domingo, 5-7 March 2004 THE LONG ROAD TO AN HIV VACCINE(El largo camino hacia una vacuna contra el VIH) j j José Esparza, MD, PhD WHO-UNAIDS HIV Vaccine Initiative Geneva, Switzerland

  2. Frequently asked questions about HIV vaccines • How urgently a preventive HIV vaccine is needed? • Why an HIV vaccine has not been developed? • How vaccines are developed? • Where are we with HIV vaccines? • Scientific challenges in the development of an HIV vaccine. • Non-scientific issues on HIV vaccine development • Political support. • Community participation. • Ethical issues. • Future access.

  3. An estimated 34-46 million people were living with HIV/AIDS by the end of 2003, 95% of them in developing countries (70% in Africa) Eastern Europe & Central Asia 1.2-1.8 million North America 790.000-1.2 million Western Europe 520-680.000 East Asia & Pacific 7000.000-1.3 million North Africa & Middle East 470-730.000 Caribbean 350-590.000 South & South-East Asia4.6-8.2 million Sub-Saharan Africa 25-28.2 million Latin America 1.3 - 1.9 million Australia & New Zealand 12-18.000 A safe, effective, affordable and available preventive HIV vaccine is the best long term hope for the control of the HIV/AIDS epidemic, especially in developing countries (complementing other preventive and therapeutic interventions)

  4. HIV Vaccines • The development of an HIV vaccine is one of the most formidable challenges that modern biomedical science is confronting. • Intense international coordination and collaboration will be needed to develop such vaccine, including the conduct of multiple human trials in industrialized and developing countries. • And, when an HIV vaccine is finally developed, international solidarity will be essential to make it available to all populations in need.

  5. A short history of HIV vaccines • 1981: AIDS was described as a new disease. • 1983-1984: HIV discovered as the cause of AIDS. • 1987: First small-scale HIV vaccine trial. • Since then, more than 30 candidate vaccines have been tested in industrialized and developing countries, involving over 10.000 healthy human volunteers. • 1998-2003: First two efficacy trials of HIV vaccines. • gp120 BB in the US, 5400 volunteers. • gp120 BE in Thailand, 2500 volunteers. • Failed to confer protection to the overall population. • 2003: Next phase III trial started in Thailand • 16.000 volunteers

  6. How vaccines are developed? Preclinicaldevelopment Basic research Clinicaltrials Laboratory in vitro & animal studies Human research Safety, Immunogenicity Discovery Exploration Efficacy Vaccine concepts Human trials Phase I/II Phase III Experiments in primates Safety, immunogenicity 1 2 3 4 5 Likelihood of protection in humans 6 1: Recombinant Protein – 2: Synthetic Peptides – 3: Naked DNA 4. Live-recombinant vectors- 5: Whole inactivated virus – 6: Live attenuated virus

  7. HIV vaccine approaches recombinantprotein (gp120) synthetic peptides (V3) naked DNA live-recombinant vectors (viral, bacterial) whole-inactivated virus live-attenuated virus

  8. HIV Vaccines: Pipeline Situation (2004) Vaccine constructs in concept stage ~80 # GMP lots made 25 # Entered Phase II 5 # Entered Phase III 2 # entered phase I trials ~25 # GMP lots made ~25 # entered phase II trials ~5 # entered phase III trials 3 From Larry Corey

  9. HIV candidate vaccines in preclinical development • ALVAC A Aventis/WRAIR/NIAID • DNA+MVA A,D,E WRAIR/NIAID • Salmonella A,A/G IHV/IAVI/NIAID • DNA+Env B,C Chiron/NIAID/SAAVI • VSV B Wyeth-Lederle/NIAID • DNA+lipopetides B Wyeth-Lederle/NIAID • DNA+IL2-Ig B NIAID/VRC/Harvard • MVA B Therion/NIAID • DNA+MVA C SAAVI, NIAID • AAV C Targeted Genetics/CH/IAVI • gp120 C VaxGen/NIAID/WRAIR • VEE-gag C AlphaVax/NIAID/SAAVI • DNA+vaccinia B/C, C ADARC/IAVI/China, Germany • DNA+MVA B-A/G-C Emory/NIAID/CDC • DNA+Adeno A-B-C NIAID/VRC • DNA+fowlpox E UNSW (Australia)/NIAID • DNA+Env multi ABL/NIAID • DNA+protein multi Epimmune/NIAID • BCG +/- vaccinia B, E Japan, Thailand DAIDS, Feb 2003

  10. HIV Vaccine “concepts”tested in clinical trials (1) • Envelope proteins • Recombinant gp 160 in baculovirus/insect cell systems • Recombinant gp160 in mammalian cells • Recombinant gp120 in mammalian cells (multiple products) • Non-envelope proteins • Matrix (p17) and core (p24) proteins in yeast transposons (Ty) • p24 GAG protein produced in mammaliancells • TAT protein produced in E. coli • Peptides • Matrix (p17) peptide (HGP-30) • GAG lipopetides • C4-V3 gp120 peptides • Lipopetides (multiple products) • DNA vaccines • env/rev in plasmid backbone • gag in plasmid backbone • Multiple CTL epitopes in plasmid backbone (several constructs) • Multiple genes in plasmid backbone (several constructs) +

  11. HIV Vaccine “concepts”tested in clinical trials (2) • Poxvirus vectors • Recombinant Vaccinia-gp160 • Recombinant Vaccinia-env/gag/pol • Recombinant Canarypox-HIV (multiple constructs, B, E) • Recombinant Modified Vaccinia Ankara (MVA)-HIV (several) • Recombinant Fowlpox-HVI (AE subtype) • Other viral vectors • Recombinant Adenovirus 5-HIV gag • Venezuelan Equine Encephalitis (VEE) replicon-HIVgagC • Bacterial vectors • Salmonella typhy-HIV • Combinations (prime-boost) • Recombinant gp160 produced in mammalian cells with V3 peptides • Recombinant vacinia-gp160 with rgp160 or rgp120 • Recombinant canarypox-HIV (several) with different boosters (gp120) • DNA vaccines boosted with recombinant viral vectors +

  12. CTL Kill Neutralization HIV Infected Cell The two arms of the immune system:types of vaccine-induced immune responses Humoral immunity (Neutralizing antibodies) Cell-mediated immunity (CTL) (And prime-boost combinations) From Larry Corey

  13. Three “waves” of HIV vaccine paradigms and clinical trials • First “wave” (1987 - mid 1990s): • Induction of neutralizing antibodies • Envelope antigens • Second “wave” (mid 1990s - early 2000s) • Induction of cell-mediated immunity (CD 8 CTL) • Live vectors, DNA vaccines • Prime-boost combinations (pox-vectors + gp120) • Third “wave” (now) • Better/broader immune responses • Novel immunogens and combinations +

  14. Vaccine research and trials in developing countries are necessary because: • The majority of HIV infections occurs in these countries (where a future vaccine would have the most benefit) • Phase III trials need to be conducted in populations with high HIV incidence. • Need to assess vaccine safety, immunogenicity and efficacy in different populations (Different routes of transmission, genetic background, health status). • Genetic and antigenic variability of HIV strains. +

  15. HIV particle and genome MHC gp120 gp41 envelope gp160 lipidbilayer matrix p17 core p24 RT RNA

  16. A B B B B A C B B Other Other E C B A A D A E 3.2% Others 5% (F, G, H, J, NT) D 5.3% A27% C C47.2% B 12.3% Geographical distribution of HIV-1env genetic subtypes (2000) B

  17. February 2004 Clinical trials in developing countries(1993-2002) • 1993 China II V3 branched peptide 23 • 1994 Thailand II V3 branched peptide 30 • 1994 Brazil II V3 branched peptide 30 • 1995 Thailand I/II rgp 120 B (MN) 30 • 1995 Thailand I/II rgp 120 B (SF2) 54 • 1996 Cuba I V3-multi-epitope peptide 30 • 1997 Thailand II rgp 120 BE (SF2/CM235) 380 • 1998 Thailand II rgp 120 BE (MN/A244)* 92 • 1999 Uganda II ALVAC vcp205 40 • 1999 Thailand III rgp 120 BE (MN/A244) 2 .545 ( Phase III) • 2000 Thailand I/II ALVAC vCP1521 + rgp 120 BE 60 • 2000 Thailand I/II ALVAC vCP1521 + orgp 160 E 70 • 2000 Thailand I/II ALVAC vCP1521 + rgp 120 BE* 125 • 2001 Kenya I DNA-HIVA 18 • 2001 Haiti II ALVAC vCP1452 + rgp120 BB 40 • 2001 Trinidad II ALVAC vCP1452 + rgp 120 BB 40 • 2001 Brazil II ALVAC vCP1452 + rgp 120 BB 40 • 2002 Perú II ALVAC vCP1452 + rgp 120 BB 40 • 2002 Kenya I MVA-HIVA 18

  18. February 2004 Clinical trials in developing countries(2003-2004) • 2003 Uganda II DNA-HIVA + MVA-HIVA 50 • 2003 Botswana I DNA-multi-epitope B 12 • 2003 Kenya II DNA-HIVA + MVA-HIVA 120 • 2003 South Africa II MVA-HIVA 55 • 2003 South Africa I VEE-vectored C gag 40 • 2003 South Africa MRKAd-5 gag B • and Malawi I/II MRKAd-5 gag 87 • 2003 Brazil • and Peru I/II MRKAd-5 gag B 87 • 2003 Thailand I/II MRKAd-5 gag B 87 • 2003 Haiti (+PR) I/II MRKAd-5 gag B 87 • 2003 Thailand III ALVAC vCP1521 + rgp 120 BE 16.000 (Phase III) • 2004? Rwanda II DNA-HIVA+ MVA-HIVA ? • 2004? Thailand I DNA-AE+FPV-AE 14 • 2004? Thailand II DNA-AE+FPV-AE 160 • 2004? Uganda II DNA gag,pol,nefB/envABC+Adeno 30

  19. What have we learned from the trials conducted thus far? • Trials can be conducted with high scientific and ethical standards (also in developing countries) • Candidate vaccines are safe (only minor side effects). • Candidate vaccines induce anti-HIV specific immune responses: Neutralizing antibodies and/or cell-mediated immunity (although, the quality and quantity of these immune responses may need to be improved). • The first generation of HIV vaccines (based on monomeric envelope gp120 protein) did not show significant protective efficacy in two phase III trials conducted in US and in Thailand. • More Phase I, II and III trials are need to obtain more information on the safety, immunogenicity and protective efficacy of new HIV candidate vaccines. • Efficacy trials can also provide important information on what type of immune response can protect against HIV/AIDS (immune correlates of protection) , and that information will help on the design of the next generation of vaccines.

  20. Important scientific questions • People infected with HIV develop strong immune responses against the virus, but that immunity can not control the replication of HIV or prevent progression to AIDS. • Question: What type of immune responses should be induced by vaccines to prevent HIV infection or AIDS? (Imune correlate of protection) • There are many genetic variants (subtypes) of HIV. • Question: Do we need specific vaccines for each subtype? • Monkeys can be (partially) protected with experimental vaccines. • Question: Can these vaccines also protect humans (need phase III trials) • Many types of candidate HIV vaccines (and combinations) are been developed and tested. • Question: Are these vaccines sufficient to protect humans (to be learned from phase III trials). If the answer is not: can we develop better vaccines?

  21. Multiple HIV vaccine trials are needed to test the safety, immunogenicity and protective efficacy of: • Different types of candidate vaccines (and prime-boost combinations). • Against different HIV subtypes. • In different populations (different routes of transmission, genetic background, health status). These trials need to be conducted in both industrialized and developing countries

  22. Different phases of International Site Development • Before 1992: “Epidemiological” assessments: • Studies to obtain (epidemiological) baseline data for determining the feasibility of conducting trials in international settings. • NIH PAVEs (Preparation for AIDS Vaccine Evaluation) • From 1992: First “National AIDS Vaccine Plans”: • WHO sponsored plans in Brazil, Rwanda, Thailand, and Uganda. • Including: policies, mechanisms for approval and preparatory research. • From ~1998: More comprehensive National Vaccine Strategies: • More proactive role for “host” countries (Example: SAAVI) • Consideration of non-vaccine issues in site development (including other preventive and therapeutic interventions) • From ~2001: Regional Vaccine Strategies: • African AIDS Vaccine Programme (AAVP) • From 2004: A Caribbean HIV Vaccine Strategy?

  23. Development of WHO-sponsored National AIDS Vaccine Plans” (1990-1992) • Fifteen countries around the world assessed (1-2 weeks site visits of multi-institutional teams). • WHO AIDS Vaccine Advisory Committee recommended to initially focus on four countries (Brazil, Rwanda, Thailand and Uganda). • National Plans developed through a process of extensive consultation and consensus building among all stakeholders (national and international). • The outcomes of the process were a better understanding and buying-in of the process and a document that describes the “rules of the game”. The WHO-UNAIDS sponsored National AIDS Vaccine Plans greatly facilitated the conduct of trials in developing countries

  24. WHO-SPONSORED “NATIONAL AIDS VACCINE PLANS” (from 1992) • Definition of national policy: • Including HIV vaccines as an integral part of the national response to HIV/AIDS. • Establishment of mechanisms for submission, review, approval and monitoring of research proposals: • Scientific • Ethical • Implementation of “preparatory” research: • Virus isolation and characterization • Epidemiology and cohort development • Socio-behavioural studies • Clinical trials capacity • Data- Management • Public Information

  25. Brazil: Second generation (2000) Thailand: First generation (1993) “National AIDS Vaccine Plans”

  26. The HIV vaccine controversy in Brazil (1991)

  27. Brazil: From the “guinea pigs” syndrome (1991) to community engagement (2003) Third world countries will test vaccines against AIDS:“Oh Boy, what an honour!”

  28. Early media reaction to a proposed HIV vaccine trial in Thailand (1991) The Nation (Bangkok), 2 November 1991

  29. The HIV vaccine controversy in Uganda (1996)

  30. Uganda (1996): In preparation for first trial in Africa. Thailand (1999): Annual HIV Vaccine Workshops Building National Consensus through discussions with all stakeholders

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

  32. “National AIDS Vaccine Plans” NORMATIVE FRAMEWORK Political Legal Regulatory Ethical Logistical TECHNICAL COMPONENTS Virology Epidemiology Socio/ behavioural Clinical trials Media and PR Etc SUPPORTING ENVIRONMENT Community support HIV/AIDS Prevention Access to care, including ART Infrastructure and human resources Etc

  33. 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 participation. A model for a Caribbean Strategy?

  34. Future challenges on site development • Need to increase clinical trial capacity worldwide (identified as a priority by the Gates Foundation-driven “Global HIV Vaccine Enterprise”). • Multiple sites needed to test different candidate vaccines, against different HIV subtypes, in populations with different transmission partners. • Comprehensively developed sites could be used for vaccines and other HIV preventive research (including microbicides). • Consider impact of scaling-up ART on vaccine trials: HIV incidence, level of care, etc. • Need to ensure that the “most appropriate” candidate vaccines are tested in the “most appropriate” sites, regardless of whom developed the product or strengthened the site. This will require intense international collaboration and coordination (a a great deal of good-will from all partners).

  35. HIV vaccines: The way forward • More basic research is needed to obtain scientific knowledge required for rational vaccine development. • Additional clinical trials must be conducted to obtain information on: • Type of immune response(s) required for protection. • Type of protection conferred by different candidate vaccines (protection against infection or against disease). • Relevance of HIV genetic subtypes for vaccine induced protection. • Clinical trials and laboratory research should be part of an iterative process leading to incremental knowledge and better vaccines. • Urgent need to increase world-wide effort on HIV vaccine research and development, with better coordination and collaboration.

  36. In conclusion • An HIV vaccine (complementing other interventions) remains the best long-term hope for the control of the AIDS pandemic, especially in developing countries. • Present activities to develop an HIV vaccine should increase significantly, to produce a vaccine with the required urgency. • For this, a better coordinated effort is needed to accelerate HIV vaccine development, and this effort should involve the full participation of developing countries. • And once a vaccine is developed, international solidarity will be essential to make it available to all countries and populations in need.

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