2004-04-19-世界卫生组织-Report_of_the_Steering_Committee_on_Dengue_and_other_Flaviviruses_vaccines_42页_342kb

WHO Report Summary: Dengue and Other Flaviviruses Vaccines

Steering Committee Meeting, Geneva, 2-3 April 2003

1. Context:

• Objectives: Evaluate progress in dengue (Stages I/II), JE vaccines, and other flaviviruses (yellow fever, West Nile, tick-borne encephalitis).
• Outcomes: Define WHO research priorities and recommend new projects for 2003–4.
• Focus: No clinical trial discussion due to WHO's Task Force managing safety aspects.

2. Plan of Action:

Strategic Priorities:

• Dengue: Safe, effective vaccines suitable for EPI integration.
  • Use infectious clones, nucleic acid vaccines (DNA/RNA), and optimized animal models.
  • Characterize humoral/cellular immunity and T cell epitopes.
• Japanese Encephalitis: Safer, multi-dose vaccines for EPI integration.
  • Standardize neutralization assays and evaluate cross-reactivity across genotypes.
• West Nile/Yellow Fever: Assess vaccine need, efficacy, and safety.
• Tick-Borne Encephalitis: Enhance cross-protection and availability.

Achievements (2002–2003):

• Dengue: Standardized neutralization tests, characterization of T cell responses, challenge studies in monkeys.
• JE: Improved T cell assays, PRNT studies, vaccine trials progressing.

2003–2004 Priorities:

• Dengue: Humoral/cellular immunity assessment, chimeric vaccine formulation.
• JE: Finalize standard reagents, strengthen clinical trial collaboration.

3. Dengue Vaccine Development: (Analyzed as primary focus)

Key Areas:

1. Subunit Vaccines:

   • Recombinant E antigens (20–50 µg/ml yield) induce neutralizing antibodies, but serotype 4 response remains weak.
   • Adjuvants (alum) effective, but higher antigen doses may boost protection.
   • NHP trials confirm protection but require balanced serotype coverage.

2. Chimeric Vaccines:

   • Four-way chimeras (DEN-2 backbone) replicate efficiently; DEN-2/4 immune response is lowest.
   • Genetic stability of attenuating mutations confirmed; no reversion.

3. DNA Vaccines:

   • Gene shuffling (MaxyGen) produces shuffled constructs with mixed efficacy (e.g., prM-E component improves neutralization for all serotypes).
   • Delivery via Biojector enhances antibody persistence.

4. Long-Term Surveillance:

   • Thailand’s tetravalent vaccination did not increase severe dengue risk; additional correlation needed.

4. Japanese Encephalitis (JE) Research:

Genetic Variation and Cross-Protection:

• Goal: Assess cross-immunity across genotypes.
• Findings: JE-IV genotype highly divergent geographically; vaccines may not fully neutralize heterologous strains.

Clinical Evaluations:

• Neutralization Assays: Between genotypes, immunogenicity varies based on strain origin (cell lines used). Refine standards.
• Vaccine Efficacy: Reduces clinical cases, with ~98% effectiveness in vaccinated populations.

5. Other Flaviviruses:

Yellow Fever (YF) Vaccine Safety:

• Concerns over rare viscerotropic/neurotropic side effects linked to age-related susceptibility.

West Nile (WN) Vaccines:

• DNA vaccines effective for horses, Phase I/II trials planned by USDA.
• NNChimeric YF/WN vaccine reduces neurovirulence; Phase III anticipated by 2004–2005.

Tick-Borne Encephalitis (TBE):

• Purified inactivated vaccines effective in Eurasia; new strains require updated research.

7. Confidential Matters

Proposals:

• Dengue DNA Vaccine: Approved for 2-year funding to analyze clonal antibody responses.
• TBE Cross-Efficacy: Revised to focus on human sera studies instead of mouse models.