David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky School of Medicine, Lexington, KY 40506, USA.
Viruses. 2023 Feb 15;15(2):538. doi: 10.3390/v15020538.
It is clear that new approaches are needed to promote broadly protective immunity to viral pathogens, particularly those that are prone to mutation and escape from antibody-mediated immunity. Prototypic pathogens of this type are influenza and SARS-CoV-2, where the receptor-binding protein exhibits extremely high variability in its receptor-binding regions. T cells, known to target many viral proteins, and within these, highly conserved peptide epitopes, can contribute greatly to protective immunity through multiple mechanisms but are often poorly recruited by current vaccine strategies. Here, we have studied a promising novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP), which was previously recognized for its ability to generate anti-tumor immunity through the induction of potent cytotoxic CD8 T cells. Using a preclinical mouse model, we have assessed an R-DOTAP nanoparticle adjuvant system for its ability to promote CD4 T cell responses to vaccination with recombinant influenza protein. Our studies revealed that R-DOTAP consistently outperformed a squalene-based adjuvant emulsion, even when it was introduced with a potent TLR agonist CpG, in the ability to elicit peptide epitope-specific CD4 T cells when quantified by IFN-γ and IL-2 ELISpot assays. Clinical testing of R-DOTAP containing vaccines in earlier work by others has demonstrated an acceptable safety profile. Hence, R-DOTAP can offer exciting opportunities as an immune stimulant for next-generation prophylactic recombinant protein-based vaccines.
很明显，需要新的方法来促进对病毒病原体的广泛保护免疫，特别是那些容易发生突变和逃避抗体介导免疫的病原体。这种类型的典型病原体是流感和 SARS-CoV-2，其受体结合蛋白在其受体结合区域表现出极高的可变性。众所周知，T 细胞可以针对许多病毒蛋白，并且在这些蛋白中，高度保守的肽表位可以通过多种机制极大地促进保护性免疫，但目前的疫苗策略往往不能很好地招募它们。在这里，我们研究了一种有前途的新型纯对映体特异性阳离子脂质 1,2-二油酰基-3-三甲基铵丙烷（R-DOTAP），它以前因其通过诱导有效的细胞毒性 CD8 T 细胞产生抗肿瘤免疫的能力而受到认可。使用临床前小鼠模型，我们评估了 R-DOTAP 纳米颗粒佐剂系统在促进重组流感蛋白疫苗接种产生 CD4 T 细胞反应的能力。我们的研究表明，R-DOTAP 始终优于基于角鲨烯的佐剂乳剂，即使在引入具有强大 TLR 激动剂 CpG 时，在通过 IFN-γ 和 IL-2 ELISpot 测定量化时，也能够引发肽表位特异性 CD4 T 细胞。其他人早期的临床 R-DOTAP 疫苗试验表明其具有可接受的安全性。因此，R-DOTAP 可以为下一代预防性重组蛋白疫苗提供令人兴奋的免疫刺激机会。
