Mahoney Pipeline Status Siem Reap V2a


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A summary of the situation with dengue vaccine development

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Mahoney Pipeline Status Siem Reap V2a

  1. 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. 2. Brief History <ul><li>1945-1960s: LAV produced in suckling mouse brains </li></ul><ul><li>1970s – 80s: LAV produced in cell culture </li></ul><ul><ul><li>US Army & GSK </li></ul></ul><ul><ul><li>Mahidol University (Thailand) & sanofi pasteur </li></ul></ul><ul><li>1980s – today: chimeric, subunit, DNA </li></ul><ul><ul><li>Acambis, Hawaii Biotech </li></ul></ul><ul><ul><li>U.S. NIH </li></ul></ul><ul><ul><li>U.S. Navy </li></ul></ul><ul><li>1990s – today: Commercial development </li></ul><ul><ul><li>sanofi pasteur and GlaxoSmithKline </li></ul></ul><ul><ul><li>Biotech companies & developing country vaccine manufacturers </li></ul></ul>
  3. 3. Dengue Vaccine Market <ul><li>The success of HBV and pneumococcal vaccines has fundamentally changed the vaccine landscape </li></ul><ul><li>Dengue is a disease only of the tropics but there are important markets </li></ul><ul><li>Several companies are willing to invest large sums </li></ul><ul><li>One company estimates the global dengue vaccine market at $1 billion </li></ul>
  4. 4. Dengue Vaccines – Feasible <ul><li>Type-specific dengue virus (DENV) infection confers protection against disease (infection?) with that serotype </li></ul><ul><li>Infection with two DENV often provides full life-long protection against all four serotypes </li></ul><ul><li>Can produce vaccine candidates </li></ul><ul><ul><li>Adequate virus or antigen yield </li></ul></ul><ul><ul><li>Immunogenic </li></ul></ul><ul><ul><li>Good safety profiles </li></ul></ul><ul><ul><li>Overcome interference (100% seroconversion against all four serotypes in Phase II) </li></ul></ul>
  5. 5. Dengue Vaccines – Challenges <ul><li>Interference </li></ul><ul><ul><li>LAV </li></ul></ul><ul><ul><li>Tetravalent formulation </li></ul></ul><ul><li>Less than ideal assays for anti-DENV </li></ul><ul><ul><li>measure of protection / correlate of protection </li></ul></ul><ul><li>Evaluation – efficacy and safety </li></ul><ul><ul><li>Protection against multiple DENV types </li></ul></ul><ul><ul><li>Differing disease epidemiology </li></ul></ul><ul><ul><li>Safety - theoretical potential for immune enhanced disease (ADE / DHF) </li></ul></ul>
  6. 6. <ul><li>Present Generation (commercial development) </li></ul><ul><ul><li>Cell culture adapted, live attenuated viruses </li></ul></ul><ul><ul><li>Infectious clones </li></ul></ul><ul><ul><ul><li>chimeric viruses </li></ul></ul></ul><ul><ul><ul><li>attenuation by site directed mutagenesis </li></ul></ul></ul><ul><ul><li>Recombinant subunits of DENV envelope proteins </li></ul></ul><ul><li>Next Generation (in development) </li></ul><ul><ul><li>Inactivated dengue viruses </li></ul></ul><ul><ul><li>DNA </li></ul></ul><ul><ul><li>DNA shuffling </li></ul></ul><ul><ul><li>Viral vectored subunits </li></ul></ul><ul><ul><li>Peptide chimeras </li></ul></ul><ul><ul><li>VLPs </li></ul></ul>Types of Dengue Vaccine Candidates
  7. 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. 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. 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. 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. 11. Clinical Trial to Determine Efficacy of sanofi pasteur Yellow Fever-Dengue Chimeric Vaccine <ul><li>Design: blinded, placebo-controlled clinical trial (Phase IIB) </li></ul><ul><li>Vaccines </li></ul><ul><ul><li>Dengue - tetravalent, live attenuated 17D YF- DENV chimera </li></ul></ul><ul><ul><li>Placebo – vaccine diluent </li></ul></ul><ul><li>Administration: 0, 6, 12 months SC </li></ul><ul><li>PI: Prof. Arunee Sabchareon, Mahidol University </li></ul><ul><li>Site: Ratchaburi Province, Thailand </li></ul><ul><li>Sample size: 4002 children ages 4-11 years </li></ul><ul><li>End-point: dengue fever (febrile illness + PCR viremia) </li></ul><ul><li>Duration: 27 cases (~ 2 yrs) + 3 year safety follow-up </li></ul>
  12. 12. Some “educated” guesses on licensure <ul><li>Sanofi pasteur: 2013 </li></ul><ul><li>GSK: ? </li></ul><ul><li>Butantan and Panacea: 2014 – 2015 </li></ul><ul><li>Inviragen and Hawaii: 2014-2015 (both need to find production partners) </li></ul><ul><li>Biological E: ? </li></ul><ul><li>In 2016 there may be two or more licensed vaccines. </li></ul>
  13. 13. Interesting Recent Developments <ul><li>GSK and the Oswaldo Cruz Foundation (FIOCRUZ/Rio de Janeiro) formed joint venture including $35 million for dengue R&D (YF17DD-dengue chimera?) </li></ul><ul><li>Inviragen and SingVax merged and mobilized $15 million to ensure conduct of dengue Phase II. </li></ul>
  14. 14. A promising new candidate <ul><li>Recombinant DEN2E – HBsAg hybrid protein </li></ul><ul><li>Develops antibodies against both DEN2E and HBsAg </li></ul><ul><li>Similar to RTS,S GSK malaria vaccine </li></ul><ul><li>Developed by ICGEB (International Center for Genetic Engineering and Biotechnology), New Delhi </li></ul><ul><li>Encouraged by the U.S.-India Vaccine Access Program </li></ul>
  15. 15. Conclusions <ul><li>Rapid progress is being made on clinical evaluation of dengue vaccine candidates </li></ul><ul><li>Several companies are willing to invest in development </li></ul><ul><li>One vaccine is being evaluated for safety, immunogenicity and efficacy </li></ul><ul><li>Three other vaccines entering Phase I </li></ul><ul><li>Licensure may occur as early as 2013 </li></ul><ul><li>Two or more vaccines may be available in 2016 </li></ul>
  16. 16. We have only three years to prepare for dengue vaccine introduction and implementation!