Felgner Jiin, Hernandez-Davies Jenny E, Strahsburger Erwin, Silzel Emily, Nakajima Rie, Jain Aarti, Laster Jacob, Chiang Jui-Lin, Tsai Yali, Felgner Philip L, Davies D Huw, Liang Li
Vaccine Research and Development Center, Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.
Polaris Pharmaceuticals, LLC, San Diego, CA, USA.
NPJ Vaccines. 2025 Jun 11;10(1):123. doi: 10.1038/s41541-025-01153-6.
mRNA vaccines represent a promising alternative to conventional vaccines, as demonstrated by the rapid deployment of mRNA vaccines during the recent COVID-19 pandemic. In this work, we have adapted and fine-tuned various reported mRNA lipid nanoparticle (LNP) synthesis and preparation procedures, evaluated a range of ionizable cationic lipids, and identified top-performing LNP formulations. The impact of uridine modification on mRNA's ability to trigger immune responses has also been explored. Our findings indicate that both unmodified mRNA and N1-methyl pseudouridine-modified mRNA successfully induced an antigen-specific antibody response in mice, while the methoxy uridine-modified mRNA did not. Based on these studies, we constructed a bivalent Fluvid mRNA vaccine, consisting of LNPs encapsulating uridine-unmodified mRNA encoding either a transmembrane domain-deleted hemagglutinin or the full-length native spike protein. This vaccine stimulated robust T cell and B cell immune responses and conferred 100% protective efficacy against challenge with either influenza or SARS-CoV-2 viruses in the mouse model, without compromising efficacy compared to administering each monovalent vaccine individually. Our data suggest that the multivalent mRNA vaccine can offer protection against different viruses by generating humoral and cellular responses against multiple antigens at the same time.
信使核糖核酸（mRNA）疫苗是传统疫苗的一种有前景的替代方案，近期新冠疫情期间mRNA疫苗的迅速部署就证明了这一点。在这项工作中，我们对各种已报道的mRNA脂质纳米颗粒（LNP）合成及制备程序进行了调整和优化，评估了一系列可电离阳离子脂质，并确定了表现最佳的LNP配方。我们还探究了尿苷修饰对mRNA触发免疫反应能力的影响。我们的研究结果表明，未修饰的mRNA和N1-甲基假尿苷修饰的mRNA均能在小鼠体内成功诱导抗原特异性抗体反应，而甲氧基尿苷修饰的mRNA则不能。基于这些研究，我们构建了一种二价流感病毒mRNA疫苗，其由包裹着未修饰尿苷mRNA的LNP组成，该mRNA编码缺失跨膜结构域的血凝素或全长天然刺突蛋白。这种疫苗激发了强大的T细胞和B细胞免疫反应，并在小鼠模型中对流感或新冠病毒攻击提供了100%的保护效力，与单独接种每种单价疫苗相比，效力并未降低。我们的数据表明，多价mRNA疫苗可以通过同时产生针对多种抗原的体液和细胞反应来提供针对不同病毒的保护。
