2013-01-01-世界卫生组织-Recommendations_to_assure_the_quality,_safety_and_efficacy_of_influenza_vaccines_human,_live_attenuated_for_intranasal_administration,_Annex_4,_TRS_No_977_76页_935kb

Key Findings from WHO Recommendations for Influenza Vaccines (Intranasal, Live Attenuated)

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Annex 4 Recommendations to assure the quality, safety and efficacy of influenza vaccines (human, live attenuated) for intranasal administration

This comprehensive update by WHO encompasses significant advancements since the original 1979 recommendations. This document outlines manufacturing standards, nonclinical evaluation, clinical assessment protocols, national regulatory requirements, and dedicated guidance for pandemic situations applicable to intranasal, live attenuated influenza vaccines (LAIV). The pillar themes are safety assurance through validated processes, evidence-based efficacy demonstration, sensitivity to rapidly evolving influenza strains, and harmonization for global application.

Critical Recommendations:

1. Replacement of Traditional Egg-based Strain Selection: The previous 1979 protocol relies on outdated egg-based strain selection and potency units (EID50). This designation is deprecated by the influenza expert committee on biological standardization for live attenuated vaccines in favor of a modern approach that incorporates reverse genetics for vaccine development. Stringent criteria exist for attenuation phenotype retention in vaccine seed strains prepared from potentially highly pathogenic avian influenza viruses.

2. Emphasis on Cell Culture Substrates: The document explicitly allows for cell culture-based manufacturing and recognizes certain requirements for substrates used in this method. Prospective manufacturers are expected to engage with these, including requirements for animal-cell substrate qualification, testing for adventitious agents, and stability protocols for these substrates analogous to those specified for egg substrates.

3. Novel Testing Paradigms: Guidance updated to exclude reliance on animal testing for assessing adventitious agents (based on the elimination of WHO responsibility for such tests). Where testing is needed for vaccines derived from substrates sourced through specific routes (non-SPF eggs), the document details tailored testing panels and procedures.

4. Quality Control Parameters:

   • Concludes a focus on measured infectivity (potency) expressed in TCID50, EID50, or PFU per dose, explicitly including viral growth in cell culture for the TCID50 endpoint. Inclusion also mandates testing for endotoxin and residual moisture (for lyophilized vaccines).

   • Advocates comprehensive specification of product components, aligning with stringent manufacturing protocol validation to ensure safety and efficacy.

   • Mandates traditional and contemporary testing for sterility, adventitious agents, infectivity, identity, and attenuation for master and working seed lots, monovalent pools, and final bulk products.

5. Documentation Standards: A comprehensive summary and protocol template (Detail 30 shows its controversial nature) substitutes traditional lengthy records, providing a structured summary requiring evidence review by national regulatory authorities. Establishment approval necessitates comprehensive pre-validation of processes and procedures.

6. Product Consistency: Manufacturing methods must remain unchanged unless explicitly validated and approved by authorities, despite modifications to strain selection criteria determined through careful assessment of their impact on vaccine characteristics.

7. COVID-19 Pandemic Context: The context of COVID-19 import
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