2011-10-22-世界卫生组织-Recommendations_to_assure_the_quality,_safety_and_efficacy_of_Group_A_Meningococcal_Conjugate_vaccines,_Annex_2,_TRS_No_962_57页_613kb

Summary of Annex 2: Recommendations to assure the quality, safety and efficacy of group A meningococcal conjugate vaccines

Core Content

This document provides comprehensive recommendations for the manufacturing, nonclinical and clinical evaluation, and regulatory oversight of group A meningococcal conjugate vaccines (MenA-CVs). It outlines the scientific and regulatory standards necessary to ensure the quality, safety, and efficacy of these vaccines, which are critical for protecting against meningococcal disease, particularly in vulnerable populations such as infants and young children.

Main Views

1. Introduction and Background

• Group A meningococcal vaccines were previously known as meningococcal polysaccharide vaccines, but their limited immunogenicity in young infants and lack of immunological memory have restricted their use in routine immunization programs.
• Conjugate vaccines (e.g., MenC) have shown better immunogenicity and long-term protection, especially in infants, due to T-cell-dependent immune responses.
• The development of MenA conjugate vaccines is important due to the epidemic patterns of group A meningococcal disease, particularly in sub-Saharan Africa and during the Hajj pilgrimage in Saudi Arabia.

2. General Considerations

• Group A meningococcal vaccines are conjugated to protein carriers to enhance immunogenicity and induce immune memory.
• Non-conjugated polysaccharide vaccines are less effective in young children and do not induce immune memory.
• The licensure of MenA conjugate vaccines is based on:
  • Elicitation of bactericidal antibody response;
  • Evidence that the immune response is T-cell-dependent;
  • Non-inferiority in reactogenicity compared to other licensed vaccines.

3. Special Considerations

• Conjugate vaccine production is more complex than polysaccharide vaccines due to the need for chemical activation and carrier protein selection.
• International reference materials are not currently available for group A meningococcal conjugate vaccines.
• The use of animal-derived components is discouraged unless approved by national regulatory authorities, and must comply with WHO guidelines on transmissible spongiform encephalopathies.

Key Information

Part A: Manufacturing Recommendations

A.1 Definitions

• Group A meningococcal conjugate vaccine is defined as group A saccharide covalently linked to a carrier protein.
• International name is "Group A meningococcal conjugate vaccine", while the proper name should reflect the language of the country of origin.
• Master seed lot and working seed lot are defined as bacterial suspensions used for vaccine production and should be maintained under appropriate storage conditions.

A.2 General Manufacturing Recommendations

• Good Manufacturing Practices (GMP) for pharmaceuticals and biological products should be followed.
• Standard operating procedures (SOPs) and validation of production steps must be submitted to regulatory authorities for approval.
• Biosafety Class 2 handling is required for Neisseria meningitidis due to its potential to cause human infection.

A.3 Production Control

A.3.1 Control of Polysaccharide

• Strains used for polysaccharide production must be approved and characterized.
• Serological assays and 1H NMR spectroscopy are recommended for identity verification.
• Moisture content, polysaccharide content, protein impurity, nucleic acid impurity, endotoxin content, and O-acetyl content must be tested and controlled.
• Polysaccharide content should be at least 8.0% of dry weight as determined by the Chen assay.
• O-acetylated polysaccharide is preferred, with a minimum of 2 mmol/g of saccharide.
• Molecular size distribution should be monitored using HPSEC or gel filtration to ensure manufacturing consistency.

A.3.2 Control of Carrier Protein

• Microorganisms and culture media for carrier protein production should be non-toxic and non-allergenic.
• Animal-derived materials must comply with WHO guidelines and be approved by national regulatory authorities.

A.4 Records and Retained Samples

• Comprehensive records must be maintained for all manufacturing and control steps.
• Retained samples should be kept for traceability and retesting.

A.5 Labelling and Distribution

• Labelling must clearly identify the vaccine and its components.
• Distribution and transport must be conducted under conditions that ensure stability and safety.

Part B and Part C: Nonclinical and Clinical Evaluation

• Nonclinical evaluation includes immunogenicity testing and physicochemical analysis.
• Clinical evaluation focuses on immune response assessment, safety, and efficacy.
• Postmarketing studies and surveillance are recommended to monitor long-term effectiveness and adverse events.

Part D: Recommendations for National Regulatory Authorities

• National regulatory authorities should ensure that manufacturing and control methods are validated and consistent with clinical trial data.
• Official lot release and certification should be based on comprehensive testing and quality assurance.

Appendices

• Appendix 1 provides a model summary protocol for manufacturing and control.
• Appendix 2 offers a model certificate for vaccine release.

Conclusion

These recommendations serve as scientific and advisory guidelines for manufacturers and regulatory authorities. They emphasize the importance of quality control, safety, and efficacy in the production of group A meningococcal conjugate vaccines. Modifications to these recommendations are allowed but must not compromise vaccine safety or efficacy.