Efforts to Improve Nonclinical Guidelines for Enhancing the Safety of Prophylactic mRNA Vaccines in South Korea

Abstract

The emergence of safety concerns regarding novel COVID-19 vaccines four years ago underscored the urgent need for nonclinical safety evaluation methods tailored to the unique characteristics of mRNA vaccines. In response, the World Health Organization (WHO) recommended in 2021 that five key aspects be specifically considered in in vivo safety assessments of mRNA vaccines. However, the current South Korean vaccine guidelines do not fully reflect these considerations, and WHO's recommendations lack specific protocols for their assessment. Therefore, there is a critical need to establish concrete protocols and guidelines for the nonclinical evaluation of prophylactic mRNA vaccines to enhance their safety while aligning with WHO's framework. To address this issue, this study consolidates findings from the “Research on the Development of Toxicity Evaluation Methods for mRNA Vaccines” project, which has been supported by the National Institute of Food and Drug Safety (NIFDS) in South Korea since 2022. The findings aim to contribute to the revision of South Korea's nonclinical evaluation guidelines for mRNA vaccines. For the nonclinical safety assessment, various mRNA vaccine platform components were produced and analyzed. First, characterization, immunogenicity, and efficacy evaluations were conducted for each produced substance to determine its viability as a vaccine candidate. Subsequently, each of the five WHO-recommended factors was assessed. Regarding biodistribution and persistence, we evaluated distribution patterns in normal animals as well as in models representing vulnerable populations and pre-existing conditions. Analytical methods were refined, and target organs were identified to propose a preliminary guideline for mRNA vaccines. For inflammation risk evaluation, studies were conducted on chronic inflammation, mitochondrial toxicity, and toxicity assessments using interleukin-1 receptor antagonist knockout (IL1ra KO) mice, aiming to propose appropriate nonclinical inflammation evaluation methodologies. For general toxicity evaluation, a comprehensive assessment was performed across multiple species, from mice to non-human primates, examining different mRNA platform types, lipid nanoparticle (LNP) components, administration routes, durations, and dosage levels. This enabled an in-depth analysis of target organ toxicities and provided recommendations for improving Good Laboratory Practice (GLP) toxicity studies of mRNA vaccines. Additionally, comparative analyses between normal animals and those with pre-existing conditions were conducted to assess potential differences in toxicity profiles, contributing to the feasibility of utilizing specialized animal models in future assessments. Based on these findings, we will propose a nonclinical safety evaluation protocol for prophylactic mRNA vaccines in South Korea and present a draft guideline as a foundation for assessing future mRNA platform-based vaccines.