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De Groot Nova Se Immunology Of Vaccines2009

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  • 1. Brown University University of Rhode Island and EpiVax, Providence RI January 2009 Annie De Groot MD Immunology of Vaccines
  • 2. Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now
  • 3. Research and Development Leads to Vaccine Production
    • It currently costs between 200 and 500 million US dollars to bring a new vaccine from the concept stage to market
    • But incentives are present:
      • The vaccine market has increased fivefold from 1990 to 2000
      • Annual sales of 8 billion dollars
      • Less than 2% of the total pharma market but projected to increase
    • Major producers (85% of the market)
      • GlaxoSmithKline (GSK), Merck, Aventis Pasteur, Wyeth, Novartis
    • Main products (>50% of the market)
      • Hepatitis B, flu, MMR (measles, mumps, and rubella) and DTP (diphtheria, tetanus, pertussis)
    • 40% are produced in the United States and the rest is evenly split between Europe and the rest of the world
  • 4. Drug Development Process Laboratory R+D Pre-IND - Safety/Toxicity -> IND filing Phase I - human safety/toxicity Phase II - efficacy Phase III - extended studies / other drug(s) NDA -> FDA Approval Post-licensure surveillance
  • 5. 2008 Success!: New HPV (Cervical Cancer) Vaccine almost 100% effective!
  • 6. 2007 Failure:
    • Merck Ad5 HIV Vaccine
  • 7. Vaccines are Still Big!! Recent Vaccine R and D News
    • November 16, 2007 - - Pfizer buys Coley for $164M
    • August 15, 2008 - - Pfizer inks vaccine pact with Cytos
    • October 3, 2008 - - Crucell wins $70M to develop new vaccines
    • December 29, 2008 - - Novartis pays $20M for CMV program (AlphaVax)
    • January 7, 2009 - - Wyeth in talks to buy vaccine maker Crucell
    • January 8, 2009 - - GSK unveils $300M vaccines plant
    • . . .
  • 8. Why Is Vaccine Research and Development Important?
    • Immunization saves the lives of 3 million children each year.
    • 2 million more children could be saved if existing vaccines were applied on a full-scale worldwide
    • Vaccines have been made for only 34 of the more than 400 known pathogens that are harmful to humans.
    • What is not said: The small molecule R and D is not producing many new drugs – vaccines are seen as a “Pipeline solution”.
  • 9. Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now
  • 10. What does a vaccine do? . . . Trains the immune system to recognize and fight infection . . . Without requiring exposure to the pathogen
  • 11. 10 Steps to Making A Vaccine
      • Define Disease (Chickenpox vs Smallpox)
      • Define Pathogen (Virus vs Parasite)
      • Is there Immunity (If not you are in trouble)
      • Correlates of Immunity one or many? (Ab? Ag? CMI?)
      • Critical Antigens - one or many?
      • Animal Model? Does it predict protection?
      • Prototype Vaccine - Preclinical Proof
      • Safety and Toxicity, GMP, Stability
      • FDA “IND” Approval
      • Post Clinical Phase
          • Clinical trials (Phase I, II, III)
          • Approval (and indication)
          • Distribution / Acceptance / Access
      • Is there Immunity (If not you are in trouble)
      • 4. Correlates of Immunity one or many? (Ab? Ag? CMI?)
  • 12. Basic Principles of Vaccine Immunology Innate immunity (e.g., macrophages, neutrophils, certain molecules) is the first line of defense. It is fast (usually good-to-go) and usually effective. Adaptive immunity (mediated by B and T cells) can be slow to respond (several days). It is highly effective when the innate immune system cannot fully deal with the threat.
  • 13.  
  • 14. Primary response (primary immunization) is relatively: Secondary response (secondary immunization or booster immunization) is relatively: slow (4-7days) small amount of antibody (low concentration of antibody) low affinity antibody IgM first, IgG second (equal amounts of IgM and IgG) fast (2-4 day) large amounts of antibody high affinity antibody mostly IgG
  • 15. Initial SARS Strain 2nd SARS Strain Initial SARS Strain
  • 16. Often, a secondary (memory) response is so fast and effective in removing antigens (pathogens), there are few or no symptoms detected by the infected individual (protective immunity). Secondary responses are the reason we do not get certain infectious diseases more than once. Secondary responses also explain why vaccinations work. For vaccinations, instead of immunizing with something that makes you sick, a vaccine contains antigens prime the immune response.
  • 17. Vaccine strategies: B cells need T help
  • 18. Macrophages / APC
  • 19. Two types of T cells: Th and CTL
  • 20. Th cells provide help to B cells
  • 21. CTL cells kill virus infected cells
  • 22. Categories of Vaccines Live attenuated Whole Killed Subunit Epitope-based
  • 23. Categories of Vaccines
    • Live vaccines
      • Are able to replicate in the host
      • Attenuated (weakened) so they do not cause disease
    • Subunit vaccines
      • Part of organism
    • Genetic Vaccines
      • Part of genes from organism
    • Epitope-based vaccines
      • Minimal essential information with least cross-reactive material
  • 24. Live Vaccines
    • Characteristics
      • Able to replicate in the host
      • Attenuated (weakened) so they do not cause disease
    • Advantages
      • Induce a broad immune response (cellular and humoral)
      • Low doses of vaccine are normally sufficient
      • Long-lasting protection are often induced
    • Disadvantages
      • May cause adverse reactions
      • May be transmitted from person to person
  • 25. Subunit Vaccines
    • Relatively easy to produce (not live)
    • Induce little anti-viral T cell response (CTL)
      • Viral and bacterial proteins are not produced within cells
    • Classically produced by inactivating a whole virus or bacterium
      • Heat
      • Chemicals
    • The vaccine may be purified
      • Selecting one or a few proteins which confer protection
    • Example: HPV Vaccine created from two HPV proteins
      • A self-assembling “particle” made of purified protein that is free from whole microorganism cells
  • 26. Subunit Vaccines: Polysaccharides
    • Polysaccharides
      • Many bacteria have polysaccharides in their outer membrane
      • Polysaccharide based vaccines
        • Neisseria meningitidis
        • Streptococcus pneumoniae
      • Generate a T cell-independent response
        • Inefficient in children younger than 2 years old
        • Overcome by conjugating the polysaccharides to peptides
          • This approach used in vaccines against Streptococcus pneumoniae and Haemophilus influenzae.
  • 27. Subunit Vaccines: Toxoids
    • Toxins
      • Responsible for the pathogenesis of many bacteria
    • Toxoids
      • Inactivated toxins
      • Toxoid based vaccines
        • Bordetella pertussis
        • Clostridium tetani
        • Corynebacterium diphtheriae
      • Inactivation
        • Traditionally done by chemical means
        • Altering the DNA sequences important to toxicity
  • 28. Subunit Vaccines: Recombinant
    • The hepatitis B virus (HBV) vaccine
      • Originally based on the surface antigen purified from the blood of chronically infected individuals.
      • Due to safety concerns, the HBV vaccine became the first to be produced using recombinant DNA technology (1986)
      • Produced in bakers’ yeast (Saccharomyces cerevisiae)
    • Virus-like particles (VLPs)
      • Viral proteins that self-assemble to particles with the same size as the native virus.
      • VLP is the basis of a promising new vaccine against human papilloma virus (HPV)
        • Merck
        • In phase III
  • 29. Genetic Vaccines
    • Introduce DNA or RNA into the host
      • Injected (Naked)
      • Coated on gold particles
      • Carried by viruses
        • vaccinia, adenovirus, or alphaviruses
      • bacteria such as
        • Salmonella typhi, Mycobacterium tuberculosis
    • Advantages
      • Easy to produce
      • Induce cellular response
    • Disadvantages
      • Low response in 1st generation
  • 30. Epitope based vaccines
    • Advantages (Ishioka et al. [1999]):
      • Can be more potent
      • Can be controlled better
      • Can induce response to a broad range of proteins and subdominant eptiopes (e.g. against tumor antigens where there is tolerance against dominant epitopes)
      • Can target multiple conserved epitopes in rapidly mutating pathogens like HIV and Hepatitis C virus (HCV)
      • Can be designed to break tolerance
      • Can overcome safety concerns associated with entire organisms or proteins
    • Epitope-based vaccines have been shown to confer protection in animal models ([Snyder et al., 2004], Rodriguez et al. [1998] and Sette and Sidney [1999]) and De Groot (in Press).
  • 31. Therapeutic vaccines
    • Vaccines to treat the patients that already have a disease
    • Targets
      • Tumors
      • AIDS
      • Allergies
      • Autoimmune diseases
      • Hepatitis B
      • Tuberculosis
      • Malaria
      • Helicobacter pylori
    • Concept
      • suppress/boost existing immunity or induce immune responses.
  • 32. Cancer vaccines
    • Break the tolerance of the immune system against tumors
    • 3 types
      • Whole tumor cells, peptides derived from tumor cells in vitro, or heat shock proteins prepared from autologous tumor cells
      • Tumor-specific antigen–defined vaccines
      • Vaccines aiming to increase the amount of dendritic cells (DCs) that can initiate a long-lasting T cell response against tumors.
    • Therapeutic cancer vaccines can induce antitumor immune responses in humans with cancer
    • Antigenic variation is a major problem that therapeutic vaccines against cancer face
    • Tools from genomics and bioinformatics may circumvent these problems
  • 33. Allergy vaccines
    • Increasing occurrence of allergies in industrialized countries
    • The traditional approach is to vaccinate with small doses of purified allergen
    • Second-generation vaccines are under development based on recombinant technology
    • Genetically engineered Bet v 1 vaccine can reduce pollen-specific IgE memory response significantly
    • Example of switching a “wrong” immune response to a less harmful one.
  • 34. Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now
  • 35. TETANUS
  • 36. SMALLPOX
  • 37. POLIO
  • 38. Wild Poliovirus, 1988
  • 39. Wild Poliovirus, 2004
  • 40. Progress in Polio Eradication New Polio Cases linked to Nigerian Boycott, 2005 10 steps to making a vaccine
    • Pathogen
    • Correlates of immunity
    • Critical antigens
    • Animal model
    • Delivery method
    • Preclinical confirmation
    • FDA Approval
    • Clinical Trial
    • Distribution
    • Acceptance
  • 41. Wild Poliovirus, 2006
  • 42. Wild Poliovirus, 2007
  • 43. Can we Eradicate Polio?
  • 44. Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now
  • 45. EMERGING INFECTIOUS DISEASES SINCE 1990
    • 1993 (US) - Hantavirus pulmonary syndrome (Sin nombre virus)
    • 1994 (US) – Human granulocyte ehrlichiosis
    • 1995 (Worldwide) - Kaposi sarcoma (HHV-8)
    • 1995 (US) – Cyclosporiasis from raspberries
    • 1996 (England) – Variant Creutzfeld-Jakob disease (vCJD)
    • 1997 (Japan) – Vancomycin-intermediate S. aureus
    • 1998 (Malaysia) – Nipah virus
    • 1999 (US) - West Nile encephalitis (West Nile virus)
    • 2001 (US) - Anthrax attack via letters
    • 2001 (Netherlands) – Human metapneumovirus
    • 2002 (US) – Vancomycin-resistant S. aureus
    • 2003 (China  worldwide) - Severe acute respiratory syndrome (coronavirus)
    • 2003 (US) - Monkeypox
    • What’s next?
  • 46. Emerging Diseases Worst Case Scenario What are the critical elements
    • Highly infectious pathogen
    • Circumstances that permit transmission
      • Crowding
      • Travel
      • Vectors
    • Lack of preparedness
    • Lack of treatment
    • Lack of vaccine
  • 47. EMERGING INFECTIOUS DISEASES SINCE 1990
    • 1993 (US) - Hantavirus pulmonary syndrome (Sin nombre virus)
    • 1994 (US) – Human granulocyte ehrlichiosis
    • 1995 (Worldwide) - Kaposi sarcoma (HHV-8)
    • 1995 (US) – Cyclosporiasis from raspberries
    • 1996 (England) – Variant Creutzfeld-Jakob disease (vCJD)
    • 1997 (Japan) – Vancomycin-intermediate S. aureus
    • 1998 (Malaysia) – Nipah virus
    • 1999 (US) - West Nile encephalitis (West Nile virus)
    • 2001 (US) - Anthrax attack via letters
    • 2001 (Netherlands) – Human metapneumovirus
    • 2002 (US) – Vancomycin-resistant S. aureus
    • 2003 (China  worldwide) - Severe acute respiratory syndrome (coronavirus)
    • 2003 (US) - Monkeypox
    • 2004 (Asia) – Avian influenza (H5N1)
  • 48. The FLU
  • 49. Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now
  • 50. The Old Way of Making Vaccines shake and bake
  • 51. The New Way of Making Vaccines
  • 52. The Even Newer Way In vitro screening epitope Bioinformatics
  • 53. Less than the entire pathogen is required Hepatitis Virus or Vaccine Epitope Subset = Immunome Immune system ‘ filter’
  • 54. T cell epitope At Intersection of Immune Response
  • 55. EpiVax: Accelerating Vaccines and Biologics Research and Development Anne S. De Groot 1, 2,3, L.Moise 1, 3 , J.A. McMurry 1 , W. Yang 1 , William Martin 1 1 EpiVax, Inc. 2 Brown Medical School and 3 University of Rhode Island [email_address] http://www.EpiVax.com
  • 56. We think about what a vaccine does. . . . . . Trains the immune system to recognize and fight infection . . . Without requiring exposure to the pathogen using “epitopes” = chains of amino acids
  • 57. Current Vaccine–Related NIH Funding 1R43AI058376 "A novel Smallpox Vaccine Derived from the VV/VAR Immunome“ 1R43AI065036 "A Genome-Derived, Epitope-Driven H pylori Vaccine“ 1R43AI058326 "A Genome-Derived, Epitope-Driven Tularemia Vaccine" 1R43AI075830-01 “ Optimization of a Multivalent Tuberculosis Vaccine” 7R01AI050528 (new R21: Optimization of HIV Vaccine Delivery) Epitope Driven HIV Vaccine Development Unfunded : Influenza, HPV, EBV
  • 58. EpiVax Genome-derived, epitope-driven vaccine approach : In Silico EpiMatrix / ClustiMer / OptiMatrix [class I and class II alleles] Conservatrix / BlastiMer/. EpiAssembler/ VaccineCAD In Vitro HLA binding assay ELISpot - ELISA - Multiplex ELISA - FACS - T regulatory T cell profiling In Vector DNA prime/peptide (pseudoprotein boost) vaccines Vaccine delivery / formulation optimization / detolerizing delivery agents In Vivo HLA DR3, DR4 transgenic mice HLA class I transgenic mice Vaccination, Comparative studies
  • 59. Prime-boost Smallpox Vaccine Immunization Sacrifice Birth 1. epitope DNA vaccine prime 2. epitope peptide boost 1. control DNA prime 2. control peptide boost Week 0 Week 8-14 IFN-gamma and multiplex ELISA Challenge Lethal Intratranasal Challenge 3 mice week 16 Week 18
  • 60. Results: 100% survival of Vaccinated mice vs. 17% of placebo 100% 100% 0 20 40 60 80 100
  • 61. No significant weight loss in vaccinated mice – surviving mice in placebo arm are regaining weight
  • 62. HIV Vaccine Development The GAIA HIV Vaccine •  In Development since 1998 - More than 300 epitopes mapped • Highly Variable Pathogen – Conserved epitopes • HLA Diversity -- 6 HLA supertypes • T cell help -- Immunogenic consensus sequence epitopes • Validation in HLA transgenic mice -- Good progress.
  • 63. Better Vaccines and Health for All Our Hope for the Future
  • 64. Fearless Science
  • 65. QUESTIONS EpiVax: Science without Fear/ Fearless Science