Ndeupen Sonia, Qin Zhen, Jacobsen Sonya, Estanbouli Henri, Bouteau Aurélie, Igyártó Botond Z
Thomas Jefferson University, Department of Microbiology and Immunology, Philadelphia, PA.
bioRxiv. 2021 Jul 23:2021.03.04.430128. doi: 10.1101/2021.03.04.430128.
Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against coronavirus disease in 2019 (COVID-19). Clinical trials and ongoing vaccinations present with very high protection levels and varying degrees of side effects. However, the nature of the reported side effects remains poorly defined. Here we present evidence that LNPs used in many preclinical studies are highly inflammatory in mice. Intradermal injection of these LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate. In summary, here we show that the LNPs used for many preclinical studies are highly inflammatory. Thus, their potent adjuvant activity and reported superiority comparing to other adjuvants in supporting the induction of adaptive immune responses likely stem from their inflammatory nature. Furthermore, the preclinical LNPs are similar to the ones used for human vaccines, which could also explain the observed side effects in humans using this platform.
基于含信使核糖核酸的脂质纳米颗粒（LNPs）的疫苗是一种很有前景的新平台，两种主要的抗2019冠状病毒病（COVID-19）疫苗都采用了该平台。临床试验和正在进行的疫苗接种显示出非常高的保护水平以及不同程度的副作用。然而，所报告副作用的性质仍不清楚。在此，我们提供证据表明，许多临床前研究中使用的LNPs在小鼠中具有高度炎症性。皮内注射这些LNPs会引发快速且强烈的炎症反应，其特征为大量中性粒细胞浸润、多种炎症途径的激活以及各种炎性细胞因子和趋化因子的产生。相同剂量经鼻给药的LNP在肺部引发了类似的炎症反应，并导致高死亡率。总之，我们在此表明，许多临床前研究中使用的LNPs具有高度炎症性。因此，它们强大的佐剂活性以及与其他佐剂相比在支持适应性免疫反应诱导方面所报告的优势可能源于其炎症性质。此外，临床前使用的LNPs与用于人类疫苗的LNPs相似，这也可以解释使用该平台的人类中观察到的副作用。
