2016-05-24-世界卫生组织-Recommendations_to_assure_the_quality,_safety_and_efficacy_of_recombinant_human_papillomavirus_virus-like_particle_vaccines,_Annex_4,_TRS_No_999_87页_376kb

Summary of WHO Recommendations for Recombinant HPV VLP Vaccines

Core Content

These WHO Recommendations provide guidance on the quality, safety, and efficacy of recombinant human papillomavirus (HPV) virus-like particle (VLP) vaccines. They are an updated version of the 2006 WHO Guidelines and include new information based on real-world experience with licensed vaccines and the development of extended valency vaccines.

Main Sections and Key Points

Part A: Manufacturing Recommendations

• Definitions and Reference Materials:

  • The international name of the vaccine is "recombinant human papillomavirus virus-like particle vaccine" followed by type specificity and the name of the recombinant protein.
  • Proper names are used in the country of origin.
  • The use of the international name is limited to vaccines that meet specific quality criteria.

• General Manufacturing:

  • Emphasizes the importance of standardized processes and quality control at each stage of production.
  • Includes control of source materials, VLP production, purification, and final formulation.

• Control of Source Materials:

  • Ensures that all materials used in vaccine production are of high quality and free from adventitious agents (e.g., bacteria, fungi, viruses).

• Control of VLP Production:

  • Focuses on maintaining consistency and purity in VLP production.
  • Includes monitoring of expression systems and the use of appropriate cell substrates.

• Control of Purified Monovalent Antigen Bulk:

  • Ensures that the antigen is pure and of consistent quality.
  • Includes biochemical and immunological characterization.

• Control of Adsorbed Monovalent Antigen Bulk:

  • Addresses the adsorption of antigens onto adjuvants.
  • Highlights the importance of pooling and homogeneity.

• Control of Final Bulk:

  • Ensures that the final formulation is uniform and safe.
  • May be prepared from multiple adsorbed monovalent antigen bulks.

• Filling and Containers:

  • Recommends using appropriate containers and ensuring sterility during filling.

• Control Tests on Final Lot:

  • Specifies tests required to ensure the vaccine meets all quality and safety standards.

• Records and Retained Samples:

  • Emphasizes the importance of documentation and sample retention for traceability and quality assurance.

• Labelling and Distribution:

  • Provides guidelines for proper labelling and safe distribution and transport.

• Stability Testing:

  • Recommends stability testing and proper storage conditions to determine expiry dates.

Part B: Nonclinical Evaluation

• Product Characterization and Process Development:

  • Includes detailed characterization of VLPs and the development of robust manufacturing processes.

• Pharmacodynamic Studies:

  • Evaluates the immune response and the mechanism of action of the vaccine.

• Toxicology Studies:

  • Assesses the safety of the vaccine and its components, including adjuvants and cell substrates.

Part C: Clinical Evaluation

• Immunological Data:

  • Highlights the importance of measuring immune responses, including neutralizing antibodies.

• Virological Data:

  • Focuses on the detection and quantification of neutralizing antibodies using assays such as EIA and pseudovirion neutralization.

• Histological Data:

  • Recommends the use of histological endpoints like CIN2-3 and adenocarcinoma in situ to assess vaccine efficacy.

• Vaccine Efficacy Evaluation:

  • Suggests using composite endpoints to evaluate overall treatment effects.

• Cross-Protection:

  • Addresses the potential for vaccines to protect against multiple HPV types.

• Safety:

  • Emphasizes the need for safety assessments, including the evaluation of preservatives and their impact on immunogenicity.

• Post-Licensing Evaluation:

  • Recommends ongoing monitoring of vaccine safety and efficacy after licensure.

Part D: Recommendations for National Regulatory Authorities (NRAs)

• General Recommendations:

  • NRAs are advised to adopt or modify these recommendations while ensuring the vaccine is at least as safe and efficacious as per the guidelines.

• Official Release and Certification:

  • NRAs should establish clear criteria for the release and certification of vaccine lots.

Key Information

• HPV Overview:

  • HPV is a group of DNA viruses that cause various epithelial diseases, including cervical cancer and genital warts.
  • High-risk HPV types (e.g., 16, 18) are associated with cervical cancer, while low-risk types (e.g., 6, 11) are linked to warts and RRP.

• VLP Characteristics:

  • L1 VLPs are non-infectious, self-assembled, and highly immunogenic.
  • Conformational epitopes are essential for neutralizing antibody production.

• Current Vaccines:

  • Bivalent vaccine: Contains L1 VLPs of types 16 and 18, formulated with AS04 adjuvant.
  • Quadrivalent vaccine: Contains L1 VLPs of types 6, 11, 16, and 18, formulated with amorphous aluminium hydroxyphosphate sulfate adjuvant.
  • 9-valent vaccine: An extended version of the quadrivalent vaccine, including types 31, 33, 45, 52, and 58.

• Vaccine Administration:

  • Currently administered via intramuscular injection.
  • Future research may explore alternative routes (e.g., nasal, oral) to avoid needles.

• Preservatives and Adjuvants:

  • Preservatives may be used, but their impact on immunogenicity must be evaluated.
  • Thiomersal, an organo-mercury compound, may destroy neutralizing epitopes and should be avoided.

• Clinical Efficacy:

  • Efficacy is assessed using histological endpoints (e.g., CIN2-3) and type-specific persistence of HPV.
  • Immunobridging studies may be used to extrapolate efficacy between different formulations or populations.

• Immunological Correlates of Protection (ICPs):

  • Functional antibodies above a threshold GMT or GMC are considered ICPs for many vaccines.

• Regulatory and Laboratory Needs:

  • NRAs and NCLs must ensure that all testing and regulatory requirements are met.
  • Guidance is provided on the use of international reference materials and the standardization of HPV testing.

Conclusion

These WHO Recommendations aim to ensure that recombinant HPV VLP vaccines are manufactured, tested, and evaluated to the highest standards of quality, safety, and efficacy. They reflect the latest scientific knowledge and include updates on terminology, production methods, and clinical evaluation approaches. The document is intended to serve as a scientific and advisory guide for both manufacturers and NRAs, with the flexibility to adopt or modify recommendations as needed, provided that the safety and efficacy of the final product are not compromised.