2015-11-05-世界卫生组织-Recommendations_to_assure_the_quality,_safety_and_efficacy_of_poliomyelitis_vaccines_inactivated_,_Annex_3,_TRS_No_993_86页_467kb

Summary of WHO Recommendations for Inactivated Poliomyelitis Vaccine (IPV)

Core Content

This document outlines the WHO Recommendations for the quality, safety, and efficacy of inactivated poliomyelitis vaccines (IPV), replacing the previous Annex 2 of the WHO Technical Report Series, No. 910. It is intended as scientific and advisory guidance for national regulatory authorities (NRAs) and manufacturers of biological products. While NRAs may adopt or modify these recommendations, any changes must ensure that the product is at least as safe and efficacious as per the original guidelines.

The recommendations cover manufacturing, nonclinical evaluation, clinical evaluation, and specific guidance for NRAs. They also include terminology definitions, appendices, and reference materials for standardized testing and production.

Main Sections and Key Points

Part A. Manufacturing Recommendations

• Definitions:

  • Provides clear definitions for key terms such as "final bulk", "final lot", "cell bank", "master cell bank", "working cell bank", "virus master seed lot", "virus sub-master seed lot", and "virus working seed lot".
  • Includes the international name and proper name of the vaccine, with the international name being "poliomyelitis vaccine (inactivated)".

• General Manufacturing Requirements:

  • Applies WHO Good Manufacturing Practices (GMP) for pharmaceutical and biological products.
  • Includes guidance on the safe production of IPV, particularly when using wild-type poliovirus or attenuated Sabin strains.

• Control of Source Materials:

  • Emphasizes the importance of controlling the source of virus strains and cell cultures.
  • Highlights the need for proper characterization of virus seed lots, especially those derived from Sabin strains or recombinant DNA technology.

• Control of Vaccine Production:

  • Recommends validation of production conditions using a full range of tests, including in vivo and in vitro potency tests.
  • Suggests periodic testing of monovalent pools with mutant analysis (e.g., MAPREC) to ensure consistency and stability.

• Filling and Containers:

  • Ensures that final containers are filled from a single final bulk and are homogeneous in terms of contamination risk.

• Control Tests on the Final Lot:

  • Requires testing of the final lot for potency, safety, and purity, including D-antigen content and neutralizing antibody levels.

• Records and Retained Samples:

  • Mandates detailed records and retained samples for traceability and quality assurance.

• Labelling and Distribution:

  • Specifies clear labelling and appropriate storage conditions to ensure vaccine stability and shelf life.

Part B. Nonclinical Evaluation

• Characterization of Seed Lots:

  • Focuses on Sabin-based IPV (sIPV) and IPV derived from recombinant DNA technology.
  • Recommends characterization of virus strains used for seed lot production.

• Antigenic Profile:

  • Ensures that the antigenic profile of the vaccine is consistent and representative of the target virus types.

• D-Antigen Content:

  • Defines D-antigen as the native virus particles that are the target of neutralizing antibodies.
  • Currently measured using ELISA.

• Immunogenicity in Animal Models:

  • Suggests the use of animal models to assess immunogenicity and vaccine efficacy.

• Nonclinical Safety Studies:

  • Includes biocontainment and biosafety measures to prevent accidental release of wild-type or vaccine-derived polioviruses.

Part C. Clinical Evaluation

• Immunogenicity Studies:

  • Recommends clinical trials to assess the immunogenicity of the vaccine.

• Concomitant Administration with Other Vaccines:

  • Addresses the interaction of antigens and adjuvants in combined vaccines (e.g., DT-based vaccines).

• Pre-Licensure Safety Data:

  • Requires pre-licensure safety data to support vaccine approval.

• Post-Marketing Surveillance:

  • Encourages ongoing monitoring of vaccine safety and efficacy after market release.

Part D. Recommendations for NRAs

• General Recommendations:

  • Encourages NRAs to ensure quality control and biocontainment during vaccine production.

• Official Release and Certification:

  • Highlights the importance of official release and certification of final lots to ensure public health safety.

Key Information

• IPV Development and Use:

  • IPV has been used since 1955 and is now a key tool in polio eradication.
  • Countries have increasingly switched from OPV to IPV to reduce the risk of vaccine-associated paralytic poliomyelitis (VAPP).

• VAPP and cVDPV:

  • VAPP is a rare adverse event associated with OPV, with an estimated 2–4 cases per million birth cohort annually.
  • Circulating vaccine-derived poliovirus (cVDPV) can emerge from OPV strains, particularly Sabin type 2, and is a threat to eradication.

• Global Polio Eradication Initiative (GPEI):

  • The GPEI aims to eradicate poliomyelitis by 2018.
  • Key strategies include withdrawal of OPV, introduction of bivalent OPV (bOPV), and routine use of IPV for long-term risk management.

• Biocontainment and Biosafety:

  • After the elimination of wild-type poliovirus, wild-type strains must be contained to prevent reintroduction.
  • Sabin strains are being considered for IPV production due to their attenuated nature, but containment measures must be validated.

• Testing and Validation:

  • The in vivo potency assay in rats is now standardized and used to characterize vaccine potency.
  • D-antigen content is determined using ELISA.
  • MAPREC testing is recommended for monitoring genetic stability of Sabin-derived strains.

• International Standards:

  • The International Reference Preparations (IRPs) and International Standards (ISs) are used to standardize potency and immunogenicity testing.
  • These standards are available from NIBSC in the UK.

• New Technologies:

  • Recombinant DNA technology is being explored for safe vaccine production.
  • Transgenic mice (TgPVR) are used for immunogenicity and efficacy testing, but not for lot release.

Conclusion

These WHO Recommendations aim to ensure the quality, safety, and efficacy of inactivated poliomyelitis vaccines, particularly in the context of polio eradication and the transition from OPV to IPV. They emphasize standardized production, robust testing, and biocontainment measures to minimize risks and support global health goals. The use of Sabin strains and recombinant-derived strains is encouraged, with appropriate validation and testing protocols. NRAs and manufacturers are advised to follow these guidelines and justify any modifications to ensure product safety and effectiveness.