2013-05-14-世界卫生组织-Recommendations_to_assure_the_quality,_safety_and_efficacy_of_live_attenuated_yellow_fever_vaccines,_Annex_5,_TRS_No_978_74页_1mb

Summary of WHO Recommendations on Yellow Fever Vaccine Quality, Safety, and Efficacy

Introduction and Historical Context

• The recommendations update previous WHO guidelines for live attenuated yellow fever vaccines, developed based on evolving virology, safety concerns, and global disease burden.
• First formulated in 1958, revised in 1975 and 1995, and updated in 2013 to incorporate new potency units (International Units, IU) and enhanced evaluation criteria.
• Yellow fever remains a public health concern in endemic regions, with vaccination being key for prevention, especially for travelers and residents in high-risk countries.

Virus Characteristics and Vaccine Background

• Yellow fever virus is an RNA virus with a single serotype and multiple genotypes; vaccines are derived from the 17D strain.
• Serious adverse events include yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and yellow fever vaccine-associated neurological disease (YEL-AND), which are rare but require careful monitoring.
• Two substrains (17D-204 and 17DD) are commonly used, with the 17D-213 substrain also in use in some regions. Neurotropism and viscerotropism are assessed in monkeys to ensure vaccine safety.

Manufacturing Recommendations

• Seed Virus Qualification: Requires certification through nonclinical and safety tests, including neurovirulence and viscerotropism assessments in nonhuman primates.
• Production Controls: Strict microbiological testing for adventitious agents (e.g., bacteria, mycoplasma, viruses like ALV) and potency determination using cell culture titration in IU/dose.
• Quality Parameters: Include sterility, residual moisture, stabilizers, and endotoxin levels. Records must ensure batch consistency.

Nonclinical Evaluation

• Tests in Animals: Assess neurotropism, viscerotropism, and immunogenicity using nonhuman primates to compare with reference strains.
• Immunogenicity Studies: Demonstrate neutralizing antibody induction in preclinical models, with controls and dose-response analyses.

Clinical Evaluation

• Immunogenicity: Measure neutralizing antibodies (e.g., through PRNT or LNI) to show noninferiority compared to licensed vaccines, with endpoints based on GMTs and seroconversion rates.
• Safety: Include trials in healthy adults, with exclusion criteria for high-risk groups (e.g., infants under 6 months, immunocompromised). Post-marketing surveillance for rare events like YEL-AND and YEL-AVD is emphasized.

Regulatory Recommendations for National Authorities

• Lot Release: Vaccines must meet WHO Part A and national requirements; NRAs should certify release based on potency, stability, labeling, and safety tests.
• Surveillance: Enhanced monitoring for adverse events and periodic stability studies are required.
• Labeling: Must specify virus substrain, potency, contraindications, and storage conditions to ensure proper use.

Rare Adverse Events

• YEL-AVD and YEL-AND are uncommon but serious; factors like age and genetic predisposition may increase risk.
• Post-licensure surveillance helps identify contributing cofactors, with no link found between vaccine mutations and these events.

Key Conclusions

• WHO recommendations ensure uniform global standards for safety, efficacy, and quality, facilitating international vaccine exchange and use.

• Updates to potency units and evaluation protocols reflect scientific advancements, balancing efficacy with minimal risk.

• Considerations for special populations (e.g., HIV-positive individuals, breastfeeding mothers) support safer public health interventions.