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Mahoney Pipeline Status Siem Reap V2a

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A summary of the situation with dengue vaccine development

A summary of the situation with dengue vaccine development

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  • 1. The Dengue Vaccine Landscape Harold S. Margolis, MD Richard Mahoney, PhD* Pediatric Dengue Vaccine Initiative International Vaccine Institute Seoul, Korea Asia Pacific Dengue Prevention Board Siem Reap, Cambodia, Oct 8-10, 2009 *Any errors are solely mine.
  • 2. Brief History
    • 1945-1960s: LAV produced in suckling mouse brains
    • 1970s – 80s: LAV produced in cell culture
      • US Army & GSK
      • Mahidol University (Thailand) & sanofi pasteur
    • 1980s – today: chimeric, subunit, DNA
      • Acambis, Hawaii Biotech
      • U.S. NIH
      • U.S. Navy
    • 1990s – today: Commercial development
      • sanofi pasteur and GlaxoSmithKline
      • Biotech companies & developing country vaccine manufacturers
  • 3. Dengue Vaccine Market
    • The success of HBV and pneumococcal vaccines has fundamentally changed the vaccine landscape
    • Dengue is a disease only of the tropics but there are important markets
    • Several companies are willing to invest large sums
    • One company estimates the global dengue vaccine market at $1 billion
  • 4. Dengue Vaccines – Feasible
    • Type-specific dengue virus (DENV) infection confers protection against disease (infection?) with that serotype
    • Infection with two DENV often provides full life-long protection against all four serotypes
    • Can produce vaccine candidates
      • Adequate virus or antigen yield
      • Immunogenic
      • Good safety profiles
      • Overcome interference (100% seroconversion against all four serotypes in Phase II)
  • 5. Dengue Vaccines – Challenges
    • Interference
      • LAV
      • Tetravalent formulation
    • Less than ideal assays for anti-DENV
      • measure of protection / correlate of protection
    • Evaluation – efficacy and safety
      • Protection against multiple DENV types
      • Differing disease epidemiology
      • Safety - theoretical potential for immune enhanced disease (ADE / DHF)
  • 6.
    • Present Generation (commercial development)
      • Cell culture adapted, live attenuated viruses
      • Infectious clones
        • chimeric viruses
        • attenuation by site directed mutagenesis
      • Recombinant subunits of DENV envelope proteins
    • Next Generation (in development)
      • Inactivated dengue viruses
      • DNA
      • DNA shuffling
      • Viral vectored subunits
      • Peptide chimeras
      • VLPs
    Types of Dengue Vaccine Candidates
  • 7. Chimeric Flavivirus Vaccine Technology Envelope = heterologous virus RNA replicative ‘engine’ = YF 17D or DENV 5’ 3’ C Non-structural genes prM E prM E Exchange coat protein genes of dengue 1,2,3,4 (wild-type) Yellow fever 17D or Dengue genome cloned as cDNA 5’ 3’ C prM E Non-structural genes C prM E Nonstructural genes 5’ 3’ Chimeric cDNA –> transcribe to RNA Grow virus in cell culture Transfect mRNA
  • 8. Dengue Vaccine Candidates (Commercial) Approach Developer / Producer Subunit - 80% E expressed in Drosophila S2 cell lines, +/- NS1, alum adjuvant Hawaii Biotech Genetically engineered, stable mutations in 3’ non-coding region of DENV-1, 2, 4 vaccine candidates. DENV-3 candidates = DENV-4/DEN-3 chimeras U.S NIH (and licensees) DENV-2 attenuated virus + 3 chimeras composed of DENV-2 non-structural genes + respective DENV 1,3, or 4 envelope genes CDC/InViragen Cell culture passage of clinical isolates U.S. Army/ GSK 4 chimeras composed of yellow fever 17D virus non-structural genes + respective DENV 1,2,3 or 4 envelope genes Acambis/ Sanofi Pasteur
  • 9. Clinical Trials to Evaluate Efficacy of Dengue Vaccines Vaccine 2002; 3043-3046 Guidelines for Clinical Evaluation of Dengue Vaccine in Dengue Endemic Areas. Vaccine 2008;26:4113-4119 http://whqlibdoc.who.int/hq/2008/WHO_IVB_08.12_eng.pdf
  • 10. Dengue Vaccine Status Butantan Panacea Biological E 4Q 2010 3Q 2009 Hawaii 4Q 2009 Inviragen 1Q 2010 4Q 2010 or 1Q 2011 1Q 2010 ? NIH ? GSK 2009 sanofi pasteur Phase IIb Phase II Phase I Process Development Developer Clinical Development
  • 11. Clinical Trial to Determine Efficacy of sanofi pasteur Yellow Fever-Dengue Chimeric Vaccine
    • Design: blinded, placebo-controlled clinical trial (Phase IIB)
    • Vaccines
      • Dengue - tetravalent, live attenuated 17D YF- DENV chimera
      • Placebo – vaccine diluent
    • Administration: 0, 6, 12 months SC
    • PI: Prof. Arunee Sabchareon, Mahidol University
    • Site: Ratchaburi Province, Thailand
    • Sample size: 4002 children ages 4-11 years
    • End-point: dengue fever (febrile illness + PCR viremia)
    • Duration: 27 cases (~ 2 yrs) + 3 year safety follow-up
  • 12. Some “educated” guesses on licensure
    • Sanofi pasteur: 2013
    • GSK: ?
    • Butantan and Panacea: 2014 – 2015
    • Inviragen and Hawaii: 2014-2015 (both need to find production partners)
    • Biological E: ?
    • In 2016 there may be two or more licensed vaccines.
  • 13. Interesting Recent Developments
    • GSK and the Oswaldo Cruz Foundation (FIOCRUZ/Rio de Janeiro) formed joint venture including $35 million for dengue R&D (YF17DD-dengue chimera?)
    • Inviragen and SingVax merged and mobilized $15 million to ensure conduct of dengue Phase II.
  • 14. A promising new candidate
    • Recombinant DEN2E – HBsAg hybrid protein
    • Develops antibodies against both DEN2E and HBsAg
    • Similar to RTS,S GSK malaria vaccine
    • Developed by ICGEB (International Center for Genetic Engineering and Biotechnology), New Delhi
    • Encouraged by the U.S.-India Vaccine Access Program
  • 15. Conclusions
    • Rapid progress is being made on clinical evaluation of dengue vaccine candidates
    • Several companies are willing to invest in development
    • One vaccine is being evaluated for safety, immunogenicity and efficacy
    • Three other vaccines entering Phase I
    • Licensure may occur as early as 2013
    • Two or more vaccines may be available in 2016
  • 16. We have only three years to prepare for dengue vaccine introduction and implementation!