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					   Dengue Vaccine Development


              Harold S. Margolis, MD
      Director, Pediatric Dengue Vaccine Initiative
             International Vaccine Institute
                    Seoul, Korea
                 hsmargolis@pdvi.org


International Meeting on Emerging Infectious Diseases
                    Vienna, Austria
                 February 13-16, 2009
         Dengue Vaccines
        Where are We Today ?

No vaccine licensed
High levels of country interest – prevention and
vaccines
Low levels of awareness about dengue vaccine
development in the “vaccine community”
A number of candidates - strong ‘pipeline’
Candidates in different stages of evaluation
A large-scale efficacy trial has begun
Dengue Vaccines – Feasible

Type-specific dengue virus (DENV)
infection confers protection against
disease (?infection) with that serotype

Can produce vaccine candidates
– Adequate virus or antigen yield
– Immunogenic
– Good safety profiles
Dengue Vaccines – Challenges

Tetravalent formulation
– Interference - live vaccines
Less than ideal antibody assays
–   measure of protection / correlate of protection

Evaluation – efficacy and safety
– Protection against multiple DENV types
– Disease epidemiology differs by region / hemisphere
– Safety - theoretical potential for immune enhanced
    disease (ADE / DHF)
Dengue Vaccine Use – Challenges

 Product profile not ideal (live attenuated)
 – More than one dose required in 2nd year of
   life
 – Administered subcutaneously
 Vaccine delivery
 – catch-up immunization
 Crowded immunization schedule
Types of Dengue Vaccine Candidates

 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
       Dengue Vaccine Candidates

 Developer /
                                   Approach
  Producer
                 4 chimeras composed of yellow fever 17D virus
  Acambis/
                 non-structural genes + respective DEVN 1,2,3 or
Sanofi Pasteur   4 envelop genes

WRAIR / GSK      Cell culture passage of clinical isolates

                 DENV-2 attenuated virus + 3 chimeras composed
CDC/InViragen/
                 of DENV-2 non-structural genes + respective
  Shantha        DENV 1,3, or 4 envelop genes
                 Genetically engineered, stable mutations in 3’
                 non-coding region of DENV-1, 2, 4 vaccine
    NIAID        candidates. DENV-3 candidates = DENV-4/DEN-3
                 chimeras
                 80% preM expressed in Drosophila S2 cell lines,
Hawaii Biotech   alum adjuvant +/- NS1
           Status of Dengue Vaccines
                            Process           Evaluation
Developer     Producer      Develop   Phase    Phase     Phase
                             ment       I         II      IIB-III

Acambis     SanofiPasteur                                   2009
                Glaxo
 WRAIR                                                       ?
              SmithKline
                                               Mid-2009
                                              Tetravalent
             Biological E
   NIH                                2010

               Butantan               2010

               Panacea                 ?
              InViragen /             Mid -
  CDC
               Shantha                2009
 Hawaii        Hawaii                  Q1-
 Biotech       Biotech                2009
      Chimeric Flavivirus Vaccine Technology
          Yellow fever 17D or Dengue genome cloned as cDNA
 5’       C prM E E
          C prM                      structural genes
                                 Non-Nonstructural genes          3’
                                          Exchange coat protein genes
prM   E                   prM     E       of dengue 1,2,3,4 (wild-type)

 5’        C                          Non-structural genes       3’

               Chimeric cDNA –> transcribe to RNA
 5’                                                              3’

                         Transfect mRNA
                                               Envelope = heterologous
                                                        virus
               Grow virus
               in cell culture                 RNA replicative ‘engine’ =
                                                  YF 17D or DENV
               Safety Considerations
            Live / Chimeric Vaccines – I

Reversion to virulence (17D →wt YF)
 – In vitro - high stability of chimeras in passage and
    production
 – In vivo - few mutations, conservative, not associated
    with increased neurovirulence in monkeys
Mosquito transmission
 – 100-1000-fold less replication than wt virus after
    intrathoracic inoculation
 – No virus in saliva or transmission
Vaccine 2002; 3043-3046
                Safety Considerations
                Chimeric Vaccines – II


Recombination with other Flaviviruses / viruses
 – Created recombinants of CY-JE and wt Kunjin virus - no
    increased neurovirulence or viscerotropism
 – Created recombinants of CY-DEN and wt YF Asibi strain -
    recombinant viruses more attenuated than the wt parent in
    mosquitoes
 – Only intergenotypic DEN recombination observed in
    nature
 – Low level short duration viremia following vaccination
Vaccine 2002; 3043-3046
                Safety Considerations
                Chimeric Vaccines – III

Potential adverse events from YF chimeras
 – Neurovirulence and neuroinvasivness
      Less neurovirulent than YF 17D virus (mice, monkeys)
      Not neuroinvasive (mice, hamsters, monkeys)
 – Viscerotropism - extraneural pathology
      CYD - no liver foci in monkeys compared to a few foci
      for 17D
      CYD - lower growth than 17D in Hepatic cell lines


Vaccine 2002; 3043-3046
                Safety Considerations
                Dengue Vaccines – IV


Potential for Antibody Dependent Enhanced
Disease (ADE)
 – Follow-up of adults and children previously
   vaccinated with monovalent ant tetravalent vaccines
     N ~400 – not likely to detect a rare event
     None with DHF with second dengue infections




Vaccine 2002; 3043-3046
Dengue Vaccine Evaluation
           Dengue Epidemiology
     Challenges to Vaccine Evaluation



 Multiple virus types (serotypes)
 Incidence: high endemic + periodic epidemics
 Highly seasonal
 Peak age of incidence varies by region



Vaccine 2002; 3043-3046
“Guidelines for Clinical Evaluation of Dengue
    Vaccine in Dengue Endemic Areas”

             Issue                        Recommendation
 Disease (DF) identification    Fever surveillance

 1° end-point (statistical)     Dengue fever (fever + viremia)
 2° end-points (descriptive)    Severe dengue (DHF)

 Correlate (s) of protection    Post-hoc analysis (PRNT + other assays)

 Protection against multiple Statistical endpoint likely only for single
 DENV types                  DENV type in any one site.
                                Sample of participants for short and long-
 Antibody response
                                term follow-up (up to 5 yrs)
                                Cohort to remain blinded for 3-5 yrs (no
 Safety
                                crossover) + expanded trials
 Vaccine 2008;26:4113-4119
Vaccine Evaluation – The PDVI Field
         Site Consortium
  Multiple sites in Asia and the Americas
  Laboratory-based dengue fever incidence data
  Population-based, fever surveillance to identify
  cases over a wide range of ages
  Comparable case definitions and laboratory
  testing algorithms and methods
  GCP monitoring for surveillance
  GLP with internal and external quality control
PDVI Field Site Consortium, 2009


                                                      Ratchaburi
                                                       Thailand
                                  Kampong Cham
                                    Cambodia
                                                                    Khamphaeng Phet
                 Puerto Rico                                           Thailand


                                          Kolkata, India                       Guadalupe
 Managua                                                                       Philippines
Nicaragua

      Medellin                                         Long Xuyen
     Colombia                                            Vietnam     My Tho
                                          Colombo
                                          Sri Lanka                  Vietnam
                         Brazil
sanofi pasteur CYD23 Phase IIB Trial

 Design: blinded, placebo-controlled efficacy & safety
 Vaccines
–   Dengue - tetravalent, live attenuated 17D YF- DENV chimera
–   Placebo – inactivated rabies (Verorab®)
 Administration: 0, 6, 12 months SC
 PI: Arunee Sabchareon, Faculty of Tropical Medicine,
 Mahidol University
 Site: Ratchaburi Province, PDVI funded field site
 Sample size: 4002 children ages 4-11 years
 End-point: dengue fever (febrile illness + PCR viremia)
–   Vaccine 2008;26:4113-4119
 Duration: 27 cases (~ 2 yrs) + 3 year safety follow-up
sanofi pasteur CYD23 Phase IIB Trial

 Staged Trial
– Initial Stage (now) – active detection of adverse events
   (n=150)
– Second stage (March 2009) – after review of adverse
   events by Data Safety Monitoring Committee (n=3850)
 Case identification
– Fever surveillance at home, schools, medical facilities
– Acute serum specimen collection ( < 7 days after fever)
– Convalescent specimen collection ( 7 -14 days after
   fever onset)
– Full clinical data collected
– Final diagnosis = virologic (PCR)
Creating an Enabling
    Environment
                          The PDVI
 A product development partnership (PDP)
 Founded at meeting of stakeholders in Ho Chi
 Minh City, December 2001
 Funded by Rockefeller Foundation and Bill and
 Melinda Gates Foundation
 Program of the International Vaccine Institute,
 Seoul, Korea

                     www.pdvi.org
Vaccine 2002; 3043-3046
          PDVI Goals

To accelerate development, evaluation
and introduction of dengue vaccines
To make safe and effective dengue
vaccines available to populations in
dengue endemic countries to reduce
disease incidence
   THANK YOU
  Vaccine          Vaccine
 Evaluation        Access


           PDVI

  Product          Supportive
Developmen          Research
     t
    Strategic Partnerships
          Advocacy
       www.pdvi.org

				
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