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Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
Mahoney Pipeline Status Siem Reap V2a
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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
  • 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!