Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines
Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines
复制标题
DOI：
10.1016/j.omtn.2019.01.013
复制
发表时间：
2019-04-15
影响因子：
8.8
通讯作者：
Brito, Luis A.
中科院分区：
文献类型：
--
作者：
Hassett, Kimberly J.;Benenato, Kerry E.;Brito, Luis A.
mRNA疫苗有潜力解决许多传统疫苗技术无法解决的未满足的医疗需求。有效且耐受性良好的递送技术是充分实现mRNA疫苗潜力的必要条件。临床前和临床研究已经证明，用第一代脂质纳米颗粒（LNP）肌内（IM）递送的mRNA产生稳健的免疫应答。尽管在过去几年中取得了进展，但仍然存在显著的改进机会，因为最先进的LNP被设计用于将siRNA静脉内（IV）递送至肝脏。在这里，我们筛选了一组专有的可生物降解的可电离脂质，当IM给药时，在啮齿动物模型中进行表达和免疫原性。选择化合物的子集，并进一步评价耐受性、免疫原性和在啮齿动物和非人灵长类动物（NHP）中的表达。确定了一种先导制剂，其产生了稳健的免疫应答，耐受性提高。对于疫苗更重要的是，由LNP驱动的先天免疫刺激增加并不等同于免疫原性增加，这说明mRNA疫苗耐受性可以得到改善而不影响效力。
mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency.