HDT Bio, 1616 Eastlake Avenue E #280, Seattle, WA 98102, USA.
HDT Bio, 1616 Eastlake Avenue E #280, Seattle, WA 98102, USA.
Mol Ther. 2023 Aug 2;31(8):2360-2375. doi: 10.1016/j.ymthe.2023.06.017. Epub 2023 Jul 3.
RNA vaccines possess significant clinical promise in counteracting human diseases caused by infectious or cancerous threats. Self-amplifying replicon RNA (repRNA) has been thought to offer the potential for enhanced potency and dose sparing. However, repRNA is a potent trigger of innate immune responses in vivo, which can cause reduced transgene expression and dose-limiting reactogenicity, as highlighted by recent clinical trials. Here, we report that multivalent repRNA vaccination, necessitating higher doses of total RNA, could be safely achieved in mice by delivering multiple repRNAs with a localizing cationic nanocarrier formulation (LION). Intramuscular delivery of multivalent repRNA by LION resulted in localized biodistribution accompanied by significantly upregulated local innate immune responses and the induction of antigen-specific adaptive immune responses in the absence of systemic inflammatory responses. In contrast, repRNA delivered by lipid nanoparticles (LNPs) showed generalized biodistribution, a systemic inflammatory state, an increased body weight loss, and failed to induce neutralizing antibody responses in a multivalent composition. These findings suggest that in vivo delivery of repRNA by LION is a platform technology for safe and effective multivalent vaccination through mechanisms distinct from LNP-formulated repRNA vaccines.
RNA 疫苗在对抗由传染性或癌症威胁引起的人类疾病方面具有重要的临床应用前景。自扩增复制子 RNA（repRNA）被认为具有增强效力和节省剂量的潜力。然而，repRNA 是体内固有免疫反应的有效触发物，这可能导致转基因表达减少和剂量限制的反应原性，正如最近的临床试验所强调的那样。在这里，我们报告说，通过使用局部阳离子纳米载体制剂（LION）递送多个 repRNA，可以在小鼠中安全地实现多价 repRNA 疫苗接种，这需要更高剂量的总 RNA。LION 进行的多价 repRNA 肌肉内给药导致局部分布，伴随着局部固有免疫反应的显著上调，并在没有全身炎症反应的情况下诱导抗原特异性适应性免疫反应。相比之下，脂质纳米颗粒（LNPs）递送的 repRNA 显示出广泛的分布、全身炎症状态、体重减轻增加，并未能在多价组合物中诱导中和抗体反应。这些发现表明，LION 体内递送 repRNA 是一种安全有效的多价疫苗接种平台技术，其机制与 LNP 配方的 repRNA 疫苗不同。
