Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Pharmaceutical Science Research Center, Shiraz University of Medical Science, Shiraz, Iran.
Infect Genet Evol. 2021 Nov;95:105084. doi: 10.1016/j.meegid.2021.105084. Epub 2021 Sep 20.
Human papillomavirus (HPV) is the main cause of cervical cancer, the 4 prominent cause of death in women globally. Previous vaccine development projects have led to several approved prophylactic vaccines available commercially, all of which are made using major capsid-based (L1). Administration of minor capsid protein (L2) gave rise to the second generation investigational prophylactic HPV vaccines, none of which are approved yet due to low immunogenicity provided by the L2 capsid protein. On the other hand, post-translation proteins, E6 and E7, have been utilized to develop experimental therapeutic vaccines. Here, in silico designing of a therapeutic and prophylactic vaccine against HPV16 is performed.
In this study, several immunoinformatic and computational tools were administered to identify and design a vaccine construct with dual prophylactic and therapeutic applications consisting of several epitope regions on L2, E6, and E7 proteins of HPV16.
Immunodominant epitope regions (aa 12-23 and 78-78 of L2 protein, aa 11-27 of E6 protein, and aa 70-89 of E7 protein) were employed, which offered adequate immunogenicity to induce immune responses. Resuscitation-promoting factors (RpfB and RpfE) of Mycobacterium tuberculosis were integrated in two separate constructs as TLR4 agonists to act as vaccine adjuvants. Following physiochemical and structural evaluations carried out by various bioinformatics tools, the designed constructs were modeled and validated, resulting in two 3D structures. Molecular docking and molecular dynamic simulations suggested stable ligand-receptor interactions between the designed construct and TLR4.
Ultimately, this study led to suggest the designed construct as a potential vaccine candidate with both prophylactic and therapeutic applications against HPV by promoting Th1, Th2, CTL, and B cell immune responses, which should be further confirmed in experimental studies.
人乳头瘤病毒（HPV）是宫颈癌的主要病因，也是全球女性第四大死亡原因。以前的疫苗开发项目已经导致了几种已批准的预防性疫苗上市，这些疫苗均基于主要衣壳蛋白（L1）制成。而对次要衣壳蛋白（L2）的使用则催生了第二代研究性预防性 HPV 疫苗，但由于 L2 衣壳蛋白提供的免疫原性较低，这些疫苗均尚未获得批准。另一方面，E6 和 E7 等翻译后蛋白已被用于开发实验性治疗性疫苗。在此，我们对 HPV16 的治疗性和预防性疫苗进行了计算机辅助设计。
在这项研究中，我们使用了多种免疫信息学和计算工具来识别和设计一种具有双重预防性和治疗性应用的疫苗构建体，该构建体包含 HPV16 的 L2、E6 和 E7 蛋白上的多个表位区域。
我们选择了免疫优势表位区域（L2 蛋白的 aa12-23 和 78-78、E6 蛋白的 aa11-27 和 E7 蛋白的 aa70-89），它们具有足够的免疫原性以诱导免疫反应。结核分枝杆菌的复苏促进因子（RpfB 和 RpfE）被整合到两个单独的构建体中，作为 TLR4 激动剂充当疫苗佐剂。在经过各种生物信息学工具进行理化和结构评估后，对设计的构建体进行了建模和验证，生成了两个 3D 结构。分子对接和分子动力学模拟表明，设计的构建体与 TLR4 之间存在稳定的配体-受体相互作用。
最终，这项研究表明，所设计的构建体具有预防和治疗 HPV 的双重应用潜力，它可以通过促进 Th1、Th2、CTL 和 B 细胞免疫反应，可作为一种潜在的疫苗候选物，这需要在实验研究中进一步证实。
