2013-05-22-世界卫生组织-Update_of_WHO_biosafety_risk_assessment_and_guidelines_for_the_production_and_quality_control_of_human_influenza_vaccines_against_avian_influenza_A_H7N9_virus_13页_583kb

WHO H7N9 Vaccine Biosafety Guidelines Summary

This document updates WHO guidance for the safe production and quality control of human influenza vaccines targeting the avian influenza A(H7N9) virus.

Key Updates

• Addition of Risk Assessment: Includes specific guidance for laboratory work with characterized candidate vaccine viruses (CVV), missing from previous versions.

H7N9 Virus Characteristics

• Pathogenicity: Identified as low pathogenicity in chickens based on:
  • OIE classification
  • Sequence analysis confirming HA gene consistent with low pathogenic phenotypes
  • No overt disease signs in infected poultry samples
• Mammalian Infection: Replicates efficiently in ferret respiratory tracts but does not cause severe disease. Shows higher potential infectivity and transmissibility in mammals compared to some avian influenza viruses like H5N1 due to binding to mammalian-type receptors.

Vaccine Development Recommendations

• Testing Requirements for candidate vaccine viruses (CVV):
  • HA gene sequencing to confirm low pathogenicity
  • Assay for chicken embryo death
  • Pathogenicity test in ferrets
  • Genetic stability assessment
• Attenuated CVV Criteria:
  1. Consistent HA cleavage site with low pathogenicity
  2. No embryo lethality
  3. Reduced pathogenicity compared to wild-type in ferrets
  4. Maintenance of cleavage site stability after multiple passages
• Exemptions: Reassortant viruses with HA/NA genes identical or nearly identical to previously tested strains may be exempt if deemed safe.

Containment Levels

• Small-scale Laboratory Work:
  • Wild-type H7N9 virus: BSL-3
  • Characterized CVV: BSL-2 with additional operational practices (determined by specific risk assessment)
• Large-scale Production:
  • All work with wild-type and characterized CVV: BSL-3 enhanced

Additional Considerations

• Mammalian Adaptation: Amino acid substitutions in CVV genes may indicate increased infectivity/transmissibility requiring review
• Genetic Stability Testing: Recommended to be performed alongside other safety tests without undue delay, but results may be reviewed urgently if attenuation is lost
• Transmissibility Testing: Not required for CVVs
• Risk Assessment Updates: Laboratories and manufacturers must conduct specific risk assessments and update them as virus characteristics evolve

Testing Procedures (Appendix)

• Ferret Pathogenicity Testing:
  • Uses standardized procedures comparing vaccine vs. wild-type strains
  • Assesses clinical signs, respiratory viral titers, organ replication, and histopathology
  • Attenuated vaccine strains should show reduced clinical signs, lower respiratory replication, and minimal organ involvement

This guidance supports candidate vaccine development and production while ensuring containment appropriate to H7N9 characteristics.