2006-05-31-世界卫生组织-WHO_Informal_consultation_on_scientific_basis_of_specifications_for_production_and_control_of_Japanese_Encephalitis_vaccines_inactivated_for_human_use_19页_178kb

Summary of WHO Informal Consultation on Inactivated Japanese Encephalitis Vaccines (June 2006)

Core Content

The World Health Organization (WHO) convened an informal consultation in June 2006 to initiate the revision of its recommendations for the production and control of inactivated Japanese encephalitis (JE) vaccines for human use. The meeting aimed to update scientific standards in response to recent developments in vaccine technology, particularly the shift from mouse brain-derived substrates to continuous cell lines such as Vero cells. Attendees included experts from national regulatory authorities, control laboratories, and vaccine manufacturers globally.

Main Objectives

• Review the scientific basis of current WHO recommendations for inactivated JE vaccines.
• Discuss the scientific basis for nonclinical and clinical evaluation of vaccines produced using continuous cell lines.
• Identify the need for developing appropriate standards and standardized assays for inactivated JE vaccines.

Key Information

1. Vaccine Background and Public Health Importance

• JE is a significant public health issue in Asia, affecting over 3 billion people.
• It causes approximately 50,000 clinical cases annually, with high mortality and long-term sequelae, primarily in children under 10 years.
• Vaccination is the only effective long-term method for JE control and prevention.
• Current vaccines include inactivated ones from mouse brain, PHK cells, and Vero cells, as well as live attenuated vaccines.

2. Biological Standardization

• WHO aims to ensure vaccine quality, safety, and efficacy through technical specifications and international standards.
• The recommendations are advisory and help in harmonizing vaccine licensure globally.
• A threshold of neutralizing antibodies ≥1:10 is now accepted as evidence of protection.
• WHO has ongoing initiatives to develop regional reference preparations for inactivated JE vaccines.
• The Developing Countries Vaccine Regulators Network (DCVRN) and Sentinel Countries Network are being established to support regulatory systems and post-marketing surveillance.

3. Clinical Development of Vero Cell-Derived JE Vaccines

• Vero cell-derived JE vaccines are being developed and show promising results.
• They are free of preservatives, single-dose, and freeze-dried.
• These vaccines have demonstrated 100% seroconversion rates in clinical trials, comparable to mouse brain-derived vaccines.
• Common adverse events include local reactions and mild fever, with no serious adverse events reported.
• Boosters significantly increase antibody titers, as measured by PRNT₅₀ assays.
• The vaccine is currently licensed in China and used in large quantities, with a focus on safety and immunogenicity testing.

4. Current Issues in Vaccine Development

4.1 Cell Substrates

• Cell substrates used in vaccine production include primary cells, diploid cells, and continuous cell lines (e.g., Vero cells).
• The characterization of cell substrates is essential to ensure identity, purity, and safety.
• Key aspects of characterization include growth pattern, morphology, microbial sterility, and viral contamination testing.
• Cell bank systems are used to ensure a consistent supply of cell substrates and to prevent contamination.

4.2 Potency Testing

• The current potency test involves immunizing mice with two doses of test and reference vaccines and measuring neutralizing antibody titers via PRNT₅₀ assays.
• The new method uses Vero cells and computer-assisted analysis (Bioassay Assist), improving consistency and accuracy.
• The use of homologous virus strains in challenge tests was recommended to enhance the reliability of potency assessments.
• Alternative methods for potency expression, such as median effective dose (ED₅₀) and probit models, were also discussed.

5. Regulatory Perspectives

5.1 China

• Inactivated JE vaccines in China are being phased out due to the availability of live attenuated vaccines.
• Vero cell-derived inactivated vaccines are under development, with some already in production and others in clinical trials.
• QC tests in China include sterility, virus titration, inactivation, identity, pH, formaldehyde content, thiomersal content, potency, and thermostability.

5.2 India

• Dr Keshaw (Panacea Biotec, India) discussed the use of Vero cells and the importance of characterizing them to ensure vaccine safety.
• He emphasized the need for standardized testing procedures and the role of WHO guidelines in supporting regulatory compliance.

Conclusion

The meeting highlighted the importance of updating WHO recommendations to reflect advances in vaccine technology, particularly the use of Vero cell substrates. It also emphasized the need for harmonized standards, rigorous testing protocols, and improved regulatory systems to ensure vaccine quality, safety, and efficacy. The scientific basis for nonclinical and clinical evaluation was identified as a critical area for revision, with a focus on potency assays, cell substrate characterization, and the inclusion of appropriate international standards.