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Desenvolvimento de Vacinas Anti-HIV: Cenário Internacional e Perspectivas para o Brasil

Desenvolvimento de Vacinas Anti-HIV: Cenário Internacional e Perspectivas para o Brasil. Prof Dr Alberto José da Silva Duarte DEPARTAMENTO DE DERMATOLOGIA FACULDADE DE MEDICINA DA USP. ANTI-HIV VACCINE. PATHWAYS FOR VACCINE DEVELOPMENT ( *). 5 – 10 years. 3 – 5 years. 1 – 3 years.

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Desenvolvimento de Vacinas Anti-HIV: Cenário Internacional e Perspectivas para o Brasil

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  1. Desenvolvimento de Vacinas Anti-HIV: Cenário Internacional e Perspectivas para o Brasil Prof Dr Alberto José da Silva Duarte DEPARTAMENTO DE DERMATOLOGIA FACULDADE DE MEDICINA DA USP

  2. ANTI-HIV VACCINE

  3. PATHWAYS FOR VACCINE DEVELOPMENT (*) 5 – 10 years 3 – 5 years 1 – 3 years Basic and advanced research Industry Phases I/II Phase III test Development and concept trial Production Evaluation of safety and immunogenicity Efficacy Test * TIME NECESSARY FOR DEVELOPMENT: MINIMUM 9 E MAXIMUM 18 YEARS

  4. TIME BETWEEN ETIOLOGIC AGENT IDENTIFICATION AND REGISTER OF AN EFFICIENT PROPHYLACTIC VACCINE Vaccine Etiologic agent discovery Year of FDA approval Years until approval Malaria Typhoid fever Haemophilus infl.. Pertussis Polio Measles Hepatitis A Hepatitis B HPV HIV 1893 1884 1889 1906 1908 1953 1973 1965 1981 1983 ( - ) 1989 1926 1995 1955 1995 1995 1981 2006 ??? ( - ) 105 92 89 47 42 22 16 25 ???

  5. ESTIMATIVE OF PEOPLE LIVING WITH HIV/AIDS WORLD AND BRAZIL WORLD BRAZIL 20 MILLIONS AIDS 371.000 ASYMPTOMATIC 40.3 MILLIONS 650.000 4.9 MILLIONS OF NEW INFECTIONS IN 2005 3.1 MILLIONS OF DEATHS IN 2005 UNAIDS, 2005; MINISTÉRIO DA SAÚDE/DST/Aids, Jun/2005

  6. Eastern Europe and Central Asia 1,6 milhões Western and Central Europe 720.000 North America 1,2 milhões East Asia 870.000 North Africa and Middle East 510.000 Caribbean 300.000 South and South-East Asia 7,4 milhões Sub-Saharan Africa 25,8 milhões Oceania 74.000 Latin America 1,8 milhões ESTIMATIVE OF PEOPLE LIVING WITH HIV/AIDS WORLDWIDE 2005 TOTAL: 40,3 millions WHO

  7. AZT DDI DDC D4T Zidovudine Didanosine Zalcitabine Stavudine 1990 1987 1992 1994 3TC SQV IDV RTV NVP DLV NFV Lamivudine Saquinavir Indinavir Ritonavir Nevirapine Delavirdine Nelfinavir 1995 1996 1997 1995 EFV ABV AMP LPV/R Tenofovir Atazanavir T20 Efavirenz Abacavir Amprenavir Lopinavir 1998 1998 2000 2001 2003 2005 EVOLUTION OF THE TREATMENT ANTI-HIV Nucleoside Analogues Protease inhibitors Nucleoside Non analogues Nucleotide Analogues Fusion inhibitors

  8. SURVIVAL AND AIDS EVENTS – ADEE 3002 HC /FMUSP KAPLAN - MEIER TEST 1.00 0.75 0.50 HAART 0.25 0.00 0 5 10 15 2000 1989 TIME IN YEARS CASSEB et al, AIDS PAT. CARE AND STD., 2004

  9. NUMBER OF PERINATAL HIV INFECTIONS BY YEARS - 1985-2003, USA 1992 Number of cases Year of diagnosis

  10. ESTIMATIVE OF PREVALENCE AND DEATH BY AIDSUSA (1985 – 1999)*

  11. > 80% OF INFECTED PEOPLE DO NOT HAVE ACCESS TO THE HAART Coverage (%) 75–100 50–74.9 25–49.9 10–24.9 <10 Data not available ACCESS TO ANTI-RETROVIRAL TREATMENT June 2005 WHO

  12. HISTORY (INCOMPLETE) OF THE DEVELOPMENT OF AN EFFICIENT ANTI-HIV VACCINE (2001 – 2006) • 1987 – First trial Phase I - USA. • 1987 to 2006 - 19 years of research, 35 vaccine candidates, produced by 26 manufactures, with more than 85 Phase I/II trials, sponsored by 16 institutions, involving more than 10.000 volunteers of31 countries. • 2003 – Phase III trial (rgp120) not efficient • 2004 – Bangkok - 2006 – 2 phase III trials (Ad5; ALVAC + gp120) 1 I/IIa phase trial(DNA+Ad ou Pox) New vaccine designs Adapted from José Esparza, IAC 2004 & IAVI

  13. 90 80 70 Neutralizing Ac 60 50 T cell response 40 30 20 10 0 1983-87 1988-92 1993-97 1998-02 2003-06 STRATEGIES TO OBTAIN AN ANTI-HIV VACCINE Adapted from Barré-Sinoussi, XVI AIDS International Conference, Toronto, 2006

  14. Atenuated live virus PROPOSAL OVERVIEW TO OBTAIN AN ANTI - HIV/AIDS VACCINE Modified from Basic Concepts in HIV Vaccinology; Gaston Djomand, MD; HVTN Core, FHCRC, October, 2003

  15. NEW STRATEGIES PRIME-BOOST (BIMODAL) PRIME BOOST LIVE-VIRUS VECTOR OR DNA ENVELOPE SUB-UNID OR LIVE-VIRUS VECTOR

  16. PHASE I/IIa TRIALS FOR ANTI-HIV VACCINES DNA Vectors DNA Vectors Adeno Viral Vectors - Pox Proteins - Subunidad Peptides - Subunidad Others AIDS VACCINE BLUEPRINT / IAVI, 2006

  17. a proof of concept to evaluate whether cell-mediated immune responses elicited by the Ad 5 vectors containing three HIV genes (gag-pol-nef) confers any benefit. Both trials showed the vaccine had no effect in preventing HIV infection and no effect in suppressing viral load Phase IIB. 3000 subjects. Initial data are expected in late 2007 or early 2008.Subtype B gp120 alone failed to prevent HIV infection or suppress viral load em previous human efficacy trials Phase III. The trial is being conducted in Thailand. 16,000 volunteers The vaccine is safe and that subjects not previously exposed to Ad 5 generated significant cell-mediated immune responses to the HIV antigens gag, pol, nef Priming with a canarypox vector and then subsequently boosting with gp120 provides additional benefit 2nd phase IIB. Soulth Africa. Subtype C. VACCINE CANDIDATES ON CLINICAL TRIAL OR PHASES IIB AN/OR III Candidatos Questões científicas Status Candidatos Questões científicas Status AIDS VACCINE BLUEPRINT / IAVI, 2006

  18. Conclusion: Pre-existing immunity against viral vector vaccine limits its immunogenicity EFFECT OF ADENOVIRUS 5 (Ad 5) NEUTRALIZING ANTIBODIES ON IMMUNE RESPONSE

  19. CANDIDATES FOR PREVENTIVE VACCINE TRIALS TESTED FROM 2001 YEAR 2001 2002 2003 2004 2005 2006 PHASE TOTAL I 6 2 17 11 12 6 54 I/II 1 1 2 1 5 II 1 2 4 1 III 1 3 2 0 TOTAL 6 3 20 15 13 7 66 Obs.: 2 other phase II trials and III were done in 1998 and 1999 Fonte: www.iavi.org/trialdh; Boletim VACINAS anti HIV/AIDS – nº13 – GIV, Junho, 2005

  20. PHASE TRIALS I/II DONE IN BRAZIL UP TO 2004 YEAR PLACE 1995 2003 2004 RECOMBINANT PROTEIN / RECOMBINANT VECTOR SYNTHETIC PEPTIDE ADENOVIRUS VECTOR RIO DE JANEIRO ADENOVIRUS VECTOR SÃO PAULO SYNTHETIC PEPTIDE BELO HORIZONTE * DENDRITIC CELLS RECIFE * Therapeutic vaccine

  21. VACCINE TRIALS 2004 AMERICAS Additional sites currently in implementation Fonte: www.iavi.org/trialdh; Boletim VACINAS anti HIV/AIDS – nº13 – GIV, Junho, 2005

  22. VACCINE TRIALS 2004 AFRICA, ASIA, EUROPE AND OCEANIA Additional sites currently in implementation Fonte: www.iavi.org/trialdh; Boletim VACINAS anti HIV/AIDS – nº13 – GIV, Junho, 2005

  23. MODELS HIV VACCINE MODELSUMMARY LIMITATIONS Live-virus vector Inactivated virus Recombinant subunit Peptides DNA Live-bacteria vector Pathogenicity CTLs & nAb nAb  CTLs e nAb Low immunogenicity Little experience X X X X

  24. WHY IS SO DIFFICULT TO DEVELOP AN EFFICIENT ANTI-HIV VACCINE? • Viral complexity and diversity • Anti-HIV immune response • Viral escape or adaptive mechanisms • HIV reservoires • Lack of experimental models mimeting human infection • Ethical issues • Political problems • Economical issues

  25. WHICH ELEMENTS ARE INVOLVED IN AN EFFICIENT ANTI-HIV VACCINE? A) Neutralizing antibodies B) Specific cellular immune response C) Both

  26. IMMUNE RESPONSE ANTI-HIV NEUTRALIZING Ab Viral Membrane Antibody Antibody CCR5 CD4 membrane of the target cell Poignard et al Annu. Rev. Immunol., 19:253-274, 2001 Parren and Burton Adv. Immunol., 77:195-262, 2001.

  27. IMMUNE RESPONSE ANTI-HIV NEUTRALIZING Ab Viral Membrane Antibody CD4 CCR5 membrane of the target cell Poignard et al Annu. Rev. Immunol., 19:253-274, 2001 Parren and Burton Adv. Immunol., 77:195-262, 2001.

  28. WHY IS SO DIFFICULT TO INDUCE ANTI-HIV NEUTRALIZING ANTIBODIES? • Mutation of epitopes with loss of Ab recognition. • Large number of subtypes with low cross-reactivity. • Replication virus can differ up to 10% in its genetic sequence at the same individual. • High level of glicosilation blocks the Ab access. • The majority of crucial neutralizing sites (CD4 /co-receptor binding site) are not access to the Ab.

  29. carbohidrates derived from host cell (silent facie) Facie not neutralizing neutralizing Facie WHY IS SO DIFFICULT TO INDUCE ANTI-HIV NEUTRALIZING ANTIBODIES? gp120 of the viral envelope gp120/gp41 of the viral envelope

  30. From here on another > 15 millions will be spent Spending of > 15 millions USD 7. Phase I 8. Phase II 9. Phase III 10. Phase IV Safety and Immunogenicity Primary Objectives Safety and Immunogenicity Protection efficacy Safety and efficacy Healthy adults Volunteers (10-100) Target population Volunteers(50-500) Target population Volunteers (1000-50,000) Vaccines and epidemiologic studies Subjects: CURRENT MODEL FOR ANTI-HIV VACCINE DEVELOPMENT pre-clinical studies 1. Discovery of antigen formulations for HIV and SIV 4. Immunogenicity challenge models of SIV and SHIV in none human primates 2. HIV and SIV trials In mice 3. SIV (GLF) antigens production 6. Toxicity evaluation 5. GMP production of HIV antigens Clinical studies of HIV antigens

  31. FINAL CONSIDERATIONS THE ANTI-HIV VACCINE PIPELINE Cellular Immunity Neutralizing ab Mucosal immunity Mechanism combined Open closed closed closed Current Pipeline IdealPipeline AIDS VACCINE BLUEPRINT / IAVI, 2006

  32. FINAL CONSIDERATIONS CHALLENGES FOR PROPHYLATIC VACCINE DEVELOPMENT • High viral diversity. • The vaccine must reach all populations, regardless of race or social condition. • High cost for development and clinical tests. • Existance of efficient treatment. • Difficulties of large scale volunteer recruitment.

  33. FINAL CONSIDERATIONS WHY BELIEVE IN THE POSSIBILITY TO OBTAIN A EFFICIENT VACCINE? • Advances on viral diversity and its biology . • Knowlege of exposed but not infected people (Discordant couples, commercial sexual workers who do not get HIV infection). • Recognition of slow progression patients. • High technological advance to develop vaccine. • Efficient vaccine development despite less current knowledge

  34. FINAL CONSIDERATIONS IMPACT OF THE VACCINE ON HIV NEW INFECTIONS AIDS VACCINE BLUEPRINT / IAVI, 2006

  35. 1. Establishment and implementation : a. Central repository of reagents and materials; b. Crioconservation of biological specimens; c. Epidemiological studies to determine prevalence and incidence of HIV infection; d. Local and national data base development with clinical, epidemiological and genetic data; e. Training in clinical-epidemiological research 3. Support of vaccine sites already established; 4. Implementation of new sites based on epidemiological data. 2. Investment of national technical-scientifical knowledge; NECESSARY ACTIONS TO STUDY ANTI-HIV VACCINE IN BRAZIL

  36. 6. Incentive for therapeutic vaccines; • Why therapeutic vaccines: • a) Can help already infected patients • b) May increase the knowlegde of anti-HIV immune response • c) Can establish a new model of vaccine monitoring 7. Stimulous to study prophylactic vaccines: a) To invest in national vaccine products b) To invest in national phase I studies c) To invest in vaccinal products already in the market. NECESSARY ACTIONS TO STUDY ANTI-HIV VACCINE IN BRAZIL

  37. Universidade de São Paulo Faculdade de Medicina Departamento de Dermatologia Laboratório de Investigação Médica Unidade 56 (LIM56) e-mail: lim56@lim56.fm.usp.br Tel: (0XX11) 3066- 7457 Fax: (0XX11) 3081-7190

  38. 2. IMMUNE RESPONSE ANTI-HIV CYTOTOXICITY

  39. CD4 3. ESCAPE MECHANISM: HIV / CD4+ cell Infection

  40. 3. ESCAPE MECHANISM: HIV-1 Decreasing of the MHC-I expression induced by nef RESPONSE ALONG THE HIV DISEASE PROGRESSION NORMAL RESPONSE

  41. 3. ESCAPE MECHANISM: NEF down regulated MHC-I and CD4 Trono D.,8th CROI-2001

  42. 2. EFFECT OF THE CTL OVER SIV VIRAL LOAD Ac anti-CD8+ Células T CD8+ Viral load(copies/ml) Weeks Schmitz et al, 1999 Jin et al, 1999

  43. 1. RETROVIRIDAE FAMILY PHYLOGENETICAL TREE HIV-1 and HIV-2 had same origin from primates

  44. 1. HIV GENOMA AND MAJOR ANTIGENS

  45. b) Pool of lalent cells infected by HIV with competent replicant virus 3. OTHERS MECHANISMS FOR VIRAL ADAPTATION

  46. a) latent Pool of cells Infected by HIV containing replicant virus b) HIV virions CD trapped into dendritic cells CD 4. LATENT RESERVOIR

  47. 1. HIV GENOMA HIV Electronic Microscopy

  48. Vpr Vpr Vpu Vpu Tat1 Tat1 Tat2 Tat2 Vif Vif Rev1 Rev1 Rev2 Rev2 Gag Gag Nef Nef Pol Pol Env 1. HIV GENOMA REGULATORY GENS STRUCTURAL GENS

  49. HIV: TYPES, GROUPS, SUBTYPES AND RECOMBINANTS LIM/56 - FMUSP

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