MTA-TTK Lendület "Momentum" Peptide-Based Vaccines Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest 1117, Hungary.
Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest 1117, Hungary.
Bioconjug Chem. 2023 Oct 18;34(10):1738-1753. doi: 10.1021/acs.bioconjchem.3c00273. Epub 2023 Aug 22.
The complex immunopathology of() is one of the main challenges in developing a novel vaccine against this pathogen, particularly regarding eliciting protection against both active and latent stages. Multistage vaccines, which contain antigens expressed in both phases, represent a promising strategy for addressing this issue, as testified by the tuberculosis vaccine clinical pipeline. Given this approach, we designed and characterized a multistage peptide-based vaccine platform containing CD4+ and CD8+ T cell epitopes previously validated for inducing a relevant T cell response against . After preliminary screening, CFP10 (32-39), GlfT2 (4-12), HBHA (185-194), and PPE15 (1-15) were selected as promising candidates, and we proved that the pool of these peptides triggered a T cell response in -sensitized human peripheral blood mononuclear cells (PBMCs). Taking advantage of the use of thiol-maleimide chemoselective ligation, we synthesized a multiepitope conjugate (). Our results showed a structure-activity relationship between the conjugation and a higher tendency to fold and assume an ordered secondary structure. Moreover, the palmitoylated conjugate () comprising the same peptide antigens was associated with an enhanced cellular uptake in human and murine antigen-presenting cells and a better immunogenicity profile. Immunization study, conducted in BALB/c mice, showed that induced a significantly higher T cell proliferation and production of IFNγ and TNFα over formulated in the Sigma Adjuvant System.
（）的复杂免疫病理学是开发针对该病原体的新型疫苗的主要挑战之一，特别是在针对活性和潜伏阶段的保护方面。包含在两个阶段中表达的抗原的多阶段疫苗是解决这个问题的一种有前途的策略，正如结核病疫苗临床管道所证明的那样。考虑到这种方法，我们设计并表征了一种基于多阶段肽的疫苗平台，该平台包含先前已验证可诱导针对 的相关 T 细胞反应的 CD4+和 CD8+ T 细胞表位。经过初步筛选，CFP10（32-39）、GlfT2（4-12）、HBHA（185-194）和 PPE15（1-15）被选为有前途的候选物，我们证明了这些肽的组合在致敏的人类外周血单核细胞（PBMCs）中引发了 T 细胞反应。利用硫醇-马来酰亚胺化学选择性连接的优势，我们合成了一种多表位缀合物（）。我们的结果显示了缀合与折叠和呈现有序二级结构的更高趋势之间的结构-活性关系。此外，包含相同肽抗原的棕榈酰化缀合物（）与人类和鼠类抗原呈递细胞中的更高细胞摄取率和更好的免疫原性特征相关。在 BALB/c 小鼠中进行的免疫研究表明，与在 Sigma 佐剂系统中配制的 相比， 诱导了更高的 T 细胞增殖和 IFNγ和 TNFα的产生。
