Noi principii in vaccinare C Leclerc 2014

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Noi principii in producerea si realizarea protocoalelor de vaccinare, videoconferinta Martie 2014 Leclerc C.

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Noi principii in vaccinare C Leclerc 2014

  1. 1. Nouvelles perspectives en vaccinologie AAEIP, Université Paris Sud, 31 Mars 2014 Claude Leclerc
  2. 2. DEVELOPPEMENT of HUMAN VACCINES Live attenuated vaccines Genetically engieneered Purified protein or polysaccharide Killed vaccines Smallpox, 1798 Rabies, 1885 BCG, 1927 Yellow fever, 1935 Polio (oral) Measles Mumps Rubella Adenovirus Typhoid (Ty21a) Varicella Rotavirus Diphteria, 1923 Tetanus, 1927 Pneumococcus Meningococcus Haemophilus influenzae PRP Hepatitis B (plasma derived) Tick-birne encephalitis H. influenzae PRP conjugate Typhoid (Vi) Acellular pertussis Typhoid 1896 Cholera, 1896 Plague, 1897 Pertussis, 1926 (killed bacteria) Influenza, 1936 Rickettsia, 1938 Polio (injected) Rabies (new) Japanese Encephalitis Hepatitis A Hepatitis B (recombinant) Human Papilloma virus Rotavirus 18th Century 19th Century Early 20th Century After World War II (cellular culture)
  3. 3. Vaccines have been made for 36 of >400 human pathogens Immunological Bioinformatics, The MIT press. +HPV & Rotavirus
  4. 4. The different types of vaccines Attenuated Vaccines Killed Vaccines Acellular sub- unit vaccines Pertussis Diphteria Hepatitis B Tetanus Cholera Pertussis Hepatitis A Polio Polio Yellow fever BCG
  5. 5. New and improved technologies and resulting vaccines R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  6. 6. New and improved technologies and resulting vaccines R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  7. 7. New and improved technologies and resulting vaccines R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  8. 8. New and improved technologies and resulting vaccines R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  9. 9. New and improved technologies and resulting vaccines R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  10. 10. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  11. 11. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  12. 12. Dengue epidemiology
  13. 13. Nature Reviews Microbiology 2010 Dengue vaccines under development
  14. 14. Dengue vaccines under development Sanofi Pasteur dengue vaccine enters phase III clinical study in October 2010
  15. 15. The yellow fever 17D virus as a platform for new live attenuated vaccines
  16. 16. Worldwide map of phase II/III dengue clinical trials, and major results obtained so far in humans Guy et al, Vaccine, 2011, 7229-7241
  17. 17. Lancet, Published Online, September 11, 2012
  18. 18. Serotype-specific and overall efficacy of CYD tetravalent dengue vaccine against virologically confirmed dengue disease
  19. 19. Reverse cumulative distribution of serotype-specific PRNT 50 antibody titres curves for DENV serotypes 1–4 by baseline FV-serostatus, pre-vaccination and after two and three doses of CYD-TDV (Full Analysis Set). Vaccine, Volume 31, 2013, 5814 - 5821
  20. 20. sReuters, March 25, 2014
  21. 21. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  22. 22. Schematic representation of the CSP and the RTS,S vaccine P D. Crompton, SK. Pierce, L H. Miller J Clin Invest. 2010
  23. 23. Malaria cuts risk in half in late-stage trial H Waters Nature Medicine Nov 2011
  24. 24. N Eng J Med 2012
  25. 25. Malaria cuts risk in half in late-stage trial H Waters Nature Medicine Nov 2011 31%
  26. 26. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  27. 27. How to discover protective antigens?
  28. 28. Identification of new target antigens: impact of genomics Whole genome sequences of most bacterial pathogens and parasites completed E. coli K-12 B. burgdorferi B. subtilis M. tuberculosis R. prowazekii H. influenzae C. pneumoniae C. trachomatis N. gonorrhoeae S. aureus H. pylori P. horikoshü E. faecalis N. meningitidis S. epidermitis M. genitalium S. pneumoniae L. pneumophila P. falciparum S. pyogenes M. pneumoniae T. pallidum L. major P. aeruginosa T. cruzi M. leprae P. aerophilum V. cholerae
  29. 29. Genomic-based vaccine development Whole genomic sequence Computer prediction Expression of recombinant proteins DNA preparation In silico vaccine candidates Immunogenicity testing in animal models Vaccine development
  30. 30. 600 potential vaccine candidates identified 350 proteins successfully expressed in E.coli 344 proteins purified and used to immunize mice 355 sera tested 91 novel surface-exposed proteins identified 28 novel proteins have bactericidal activity Meningoccocal B Vaccine: A Genomic Approach 5 vaccine candidates Rappuoli et al, 2002 Clinical trials
  31. 31. 2000 2013
  32. 32. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  33. 33. Front Immunol 2014 Structural vaccinology
  34. 34. A new computational method to design epitope-focused vaccines, illustrated with a neutralization epitope from RSV  Nature 507, 201–206 (13 March 2014)
  35. 35. Nature 507, 201–206 (13 March 2014) Induction of neutralizating antibodies against RSV
  36. 36. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  37. 37. Overview of the problems and methodologies of systems vaccinology Seminars in Immunology, 2013, 209 - 218
  38. 38. R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
  39. 39. Alum adjuvants are non-cystalline gels based on aluminum oxyhydroxide (referred to as Aluminum hydroxide gel), aluminum hydroxyphosphate (referred to as aluminum phosphate gel) or various proprietary salts such as aluminum hydroxy- sulfate) Alum is used in several licensed vaccines including: •  diphtheria-pertusis-tetanus •  diphtheria-tetanus (DT) •  DT combined with Hepatitis B (HBV) •  Haemophilus influenza B •  inactivated polio virus •  Hepatitis A (HAV) •  Streptoccucus pneumonia •  Menngococccal •  Human papilloma virus (HPV) Vaccines containing Alum Adjuvant
  40. 40. Dendritic cells initiate antigen-specific immune responses •  most efficient of all APCs •  high MHC class I, II & costimulators •  efficient cross presentation •  stimulate naïve T cells (CD4, CD8) All immunization strategies must target DCs Initiate Ag-specific immune responses
  41. 41. Multiple inducers of DC maturation Immature DC Mature DC various T cell responses Microbial products / TLR ligands Viral products Inflammatory cytokines Signaling receptors
  42. 42. Antigen-presenting cells serve as the bridge between innate and antigen-specific responses 2003, 2, 727-735
  43. 43. Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Nov 2011 Vaccine adjuvants
  44. 44. Innate immune responses
  45. 45. Innate Lymphoid Cells (ILC)
  46. 46. T cell differentiation pathways Coomes S M et al. Open Biol. 2013;3:120157 ©2013 by The Royal Society
  47. 47. Therapeutic vaccines for chronic infections or cancers
  48. 48. Cancer, a worldwide burden  1st cause of mortality in France  In Europ, in 2012: - 1.75 million deaths from cancer -  3.45 million new cases of cancer  In the world, in 2012: - 8.2 millions deaths - 14 million new cases diagnosed
  49. 49. Cancer, a cell disease uncontrolled proliferation Tumor Surgery ChimiotherapyRadiotherapy Anti-angiogenic drugs
  50. 50. Immune responses can control the growth of tumor cells The immunosurveillance theory “It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provoke an effective immunological reaction, with regression of the tumor and no clinical hint of its existence” British Med Journal, April 1957Burnet
  51. 51. Tumor specific/associated antigens Overexpressed self antigens Differentiation antigens Mutated self antigens Non self oncoviral antigens Altered self antigens: Abnormal post- translational/ transcriptional modification: underglycosylation
  52. 52. The concept of therapeutic anti-cancer vaccines   Induction of specific immune responses against tumor specific/associated antigens to kill tumor cells or prevent their growth without affecting normal cells
  53. 53. Tumor vaccines - Whole tumor cells: + BCG or DETOX, e.g. Melacine vaccine (cell lysates), CancerVax ( irradiated melanoma cell lines), M-Vax (hapten-treated autologous cells) and gene- modified, irradiated tumor cells (GM-CSF) - Tumor antigens: MAGE-1, MAGE-3, MART-1/Melan-A, tyrosinase, gp100, MUC-1, CEA, etc. - Peptide vaccines: mutated ras, mutated p53, Her-2/neu, MART -1, gp100, MUC-1 - Heat shock proteins - DNA vaccines - Dendritic cell vaccines
  54. 54. Response rate = 3. 8% Current human cancer vaccines show very low objective clinical response rate Rosenberg, Yang & Restifo Nature Med 10:909 (2004)
  55. 55. Response rate = 3. 8% Current human cancer vaccines show very low objective clinical response rate Rosenberg, Yang & Restifo Nature Med (2004) Benefit of passive immunotherapy (antibodies) in cancer patients Lack of efficacy of most current therapeutic cancer vaccines
  56. 56. Problems Tumor derived antigens are weakly immunogenic Need for better adjuvants or immunisation strategies
  57. 57. Dendritic cells initiate antigen-specific immune responses •  most efficient of all antigen-presenting cells •  stimulate naïve T cells (CD4, CD8) All immunization strategies must target DCs
  58. 58. An Approach to Initiating Immunity to Cancer: Dendritic Cells Loaded with Tumor Antigens ex vivo DC precursors expanded immature DCs add disease- related antigens maturing DCs presenting antigen(s) Tumor- specific T cells responding to dendritic cells
  59. 59. 2010: FDA panel passes first cancer vaccine
  60. 60. Original Article Sipuleucel-T Immunotherapy for Castration- Resistant Prostate Cancer Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore, M.D., E. Roy Berger, M.D., Eric J. Small, M.D., David F. Penson, M.D., Charles H. Redfern, M.D., Anna C. Ferrari, M.D., Robert Dreicer, M.D., Robert B. Sims, M.D., Yi Xu, Ph.D., Mark W. Frohlich, M.D., Paul F. Schellhammer, M.D., for the IMPACT Study Investigators N Engl J Med Volume 363(5):411-422 July 29, 2010
  61. 61. Source: www.provenge.com/ Provenge clinical trials : prostate cancer
  62. 62. Source: www.provenge.com/ Provenge clinical trials : prostate cancer
  63. 63. Cancer vaccine pipeline
  64. 64. Problems Tumor derived antigens are weakly immunogenic Need for better adjuvants or immunisation strategies
  65. 65. CD8+ T cell CD4+ T cell Dendritic cell Induction of optimized T cell responses by in vivo dendritic cells targeting Antigen targeting Maturation signals 2 1 Adjuvant
  66. 66. CyaA: a new proteinic vector targeted to dendritic cells Bordetella pertussis Dermonecrotic Toxin BrkA FHA TCF FIM TCT Pertussis Toxin cAMP Pertactin Adenylate cyclase Toxin Dendritic Cell CD11b/CD18 AC domain RTX domain 1 400 1706 Internalization Endosomes Cytosol CyaA binds to CD11b allowing efficient targeting to dendritic cells Guermonprez et al, J. Exp. Med, 2001 Adenylate cyclase (CyaA)
  67. 67. Recombinant CyaA + Activation of CD8+ Cytotoxic T lymphocytes Dendritic Cell ϕ CD11b/CD18 Antigen Th CD4+ MHC-II endosomes lysosomes ϕ ϕ MHC class II presentation Activation of CD4+ Helper T lymphocytes MHC class I presentation Endoplasmic Reticulum CTL CD8+ MHC-I/β2 ϕ Translocation Endocytosis Antigens grafted in CyaA are delivered to both MHC class I & MHC class II presentation pathways
  68. 68. Immunisation in mice and non-human primates by recombinant CyaA carrying a variety of antigens (such as from M. tuberculosis or HIV) stimulates strong CTL and Th1 responses, even in the absence of adjuvant. Préville et al, Cancer Res, 2005, Mascarell et al, J. Virol 2005, Majlessi et al, Inf Immun, 2005, Hervas-Stubb et al, Inf Immun, 2006, Mascarell et al, Vaccine 2006, Berraondo et al, Cancer Res, 2007, Fayolle et al, Vaccine 2010. CyaA: a new proteinic vector targeted to dendritic cells
  69. 69. 80 HPV infection life cycle Few months to few years Up to 20 years Goodman A., Wilbur D. C.
  70. 70. Human papilloma virus

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