2009-05-10-世界卫生组织-WHO_Working_Group_on_Technical_Specifications_for_Manufacture_and_Evaluation_of_Dengue_Vaccines_36页_198kb

Dengue Vaccine WHO Working Group Meeting Report Summary (Geneva, May 11-12, 2009)

This report summarizes the findings and agreed conclusions from an international expert meeting focused on revising WHO guidelines for tetravalent live dengue vaccines.

Key Points:

1. Purpose & Scope:

   • Review current issues in dengue disease, vaccine pipeline, manufacturing, clinical evaluation, and environmental risk assessment.
   • Initiate revision of WHO guidelines for production and quality control (QC) of candidate tetravalent live dengue vaccines.
   • Determine if new guidelines are needed for nonclinical/clinical evaluation and environmental risk assessment (ERA).
   • Focus the revision exclusively on live recombinant tetravalent dengue vaccines.
   • New guidelines to include: ERA, nonclinical evaluation, and clinical evaluation.

2. Dengue Disease & Epidemiology:

   • Dengue is a major global public health concern (100+ countries, >1 billion people at risk).
   • No specific treatment; prevention (vector control) is challenging. Vaccination offers potential.
   • Aedes mosquitoes are primary vectors.
   • Dengue is caused by four serotypes (DENV-1,2,3,4).

3. Vaccine Pipeline Focus:

   • Live attenuated vaccines are the primary focus for pipeline and guideline revision.
   • Examples: Live attenuated vaccines from PDK cells (some withdrawn/abandoned), WRAIR/GSK/FrCell lines, NIH (DEN4∆30), Acambis/Sanofi Pasteur (ChimeriVax™), Hawaii Biotech (DENVax).
   • Critical Requirement: Tetravalent vaccines must induce protective neutralizing antibodies to all four serotypes to avoid Antibody-Dependent Enhancement (ADE) risks.

4. Quality Control (QC) for Live Vaccines:

   • Ensure genetic stability of attenuated mutations following WHO legal basis for vaccine regulation.
   • Key QC elements:
     • Genetic Stability: Confirm presence of attenuation markers (mutations/deletions) throughout development stages using methods like sequencing (e.g. TaqMAMA).
     • Potency: Viral infectivity measured (e.g. PFU, focus-forming units).
     • Phenotypic Stability: Phenotype correlation with genotype.
   • Proposed QC testing matrix agreed upon (Table 3).

5. Environmental Risk Assessment (ERA):

   • Recommended for all live recombinant dengue vaccines.
   • Factors considered: Genetic stability, transmission potential, recombination risk, host range, vector competence.
   • Need for guidance, noting differing national regulatory authority (NRA) requirements and WHO's potential role.

6. Clinical Evaluation:

   • Lend emphasis to establishing robust clinical endpoints (dengue diagnosis, pre-existing immunity).
   • Focus on bridging studies, especially identifying suitable animal models (non-human primates, human challenge studies).
   • Data safety monitoring boards are essential.

Conclusions from Revision:

• Update WHO recommendations for NRAs and manufacturers to assure quality, safety, and efficacy of dengue vaccines.
• Integrate ERA, nonclinical, and clinical evaluation into the standards.
• Provide the foundation for WHO technical specifications for prequalification.