Abstract：
BACKGROUND: Poxviruses comprise a group of large double-stranded DNA viruses and are known to cause diseases in humans, livestock animals, and other animal species. The Mpox virus (MPXV; formerly Monkeypox), variola virus (VARV), and volepox virus (VPXV) are among the prevalent poxviruses of the Orthopoxviridae genera. The ongoing Mpox infectious disease pandemic caused by the Mpox virus has had a major impact on public health across the globe. To date, only limited repurposed antivirals and vaccines are available for the effective treatment of Mpox and other poxviruses that cause contagious diseases.
METHODS: The present study was conducted with the primary goal of formulating multi-epitope vaccines against three evolutionary closed poxviruses i.e., MPXV, VARV, and VPXV using an integrated immunoinformatics and molecular modeling approach. DNA-dependent RNA polymerase (DdRp), a potential vaccine target of poxviruses, has been used to determine immunodominant B and T-cell epitopes followed by interactions analysis with Toll-like receptor 2 at the atomic level.
RESULTS: Three multi-epitope vaccine constructs, namely DdRp_MPXV (V1), DdRp_VARV (V2), and DdRp_VPXV (V3) were designed. These vaccine constructs were found to be antigenic, non-allergenic, non-toxic, and soluble with desired physicochemical properties. Protein-protein docking and interaction profiling analysis depicts a strong binding pattern between the targeted immune receptor TLR2 and the structural models of the designed vaccine constructs, and manifested a number of biochemical bonds (hydrogen bonds, salt bridges, and non-bonded contacts). State-of-the-art all-atoms molecular dynamics simulations revealed highly stable interactions of vaccine constructs with TLR2 at the atomic level throughout the simulations on 300 nanoseconds. Additionally, the outcome of the immune simulation analysis suggested that designed vaccines have the potential to induce protective immunity against targeted poxviruses.
CONCLUSIONS: Taken together, formulated next-generation polyvalent vaccines were found to have good efficacy against closely related poxviruses (MPXV, VARV, and VPXV) as demonstrated by our extensive immunoinformatics and molecular modeling evaluations; however, further experimental investigations are still needed.
METHODS: The present study was conducted with the primary goal of formulating multi-epitope vaccines against three evolutionary closed poxviruses i.e., MPXV, VARV, and VPXV using an integrated immunoinformatics and molecular modeling approach. DNA-dependent RNA polymerase (DdRp), a potential vaccine target of poxviruses, has been used to determine immunodominant B and T-cell epitopes followed by interactions analysis with Toll-like receptor 2 at the atomic level.
RESULTS: Three multi-epitope vaccine constructs, namely DdRp_MPXV (V1), DdRp_VARV (V2), and DdRp_VPXV (V3) were designed. These vaccine constructs were found to be antigenic, non-allergenic, non-toxic, and soluble with desired physicochemical properties. Protein-protein docking and interaction profiling analysis depicts a strong binding pattern between the targeted immune receptor TLR2 and the structural models of the designed vaccine constructs, and manifested a number of biochemical bonds (hydrogen bonds, salt bridges, and non-bonded contacts). State-of-the-art all-atoms molecular dynamics simulations revealed highly stable interactions of vaccine constructs with TLR2 at the atomic level throughout the simulations on 300 nanoseconds. Additionally, the outcome of the immune simulation analysis suggested that designed vaccines have the potential to induce protective immunity against targeted poxviruses.
CONCLUSIONS: Taken together, formulated next-generation polyvalent vaccines were found to have good efficacy against closely related poxviruses (MPXV, VARV, and VPXV) as demonstrated by our extensive immunoinformatics and molecular modeling evaluations; however, further experimental investigations are still needed.
摘要：
背景：痘病毒包含一组大型双链DNA病毒，已知可引起人类疾病，家畜动物,和其他动物物种。痘病毒（MPXV；以前的猴痘），天花病毒（VARV），和volepox病毒（VPXV）是正痘病毒科属的流行痘病毒之一。由水痘病毒引起的持续水痘传染病大流行对全球公共卫生产生了重大影响。迄今为止,只有有限的再利用的抗病毒药物和疫苗可用于有效治疗引起传染病的水痘和其他痘病毒。
方法：本研究的主要目标是配制针对三种进化封闭痘病毒的多表位疫苗，即MPXV,VARV,和VPXV使用综合免疫信息学和分子建模方法。DNA依赖性RNA聚合酶（DdRp），痘病毒的潜在疫苗靶标，已用于确定免疫显性B和T细胞表位，然后在原子水平上与Toll样受体2进行相互作用分析。
结果：三种多表位疫苗构建体，即DdRp_MPXV(V1)，DdRp_VARV(V2),设计了DdRp_VPXV(V3)。这些疫苗构建体被发现是抗原性的，非过敏性，无毒,和可溶性具有所需的物理化学性质。蛋白质-蛋白质对接和相互作用谱分析描述了靶向免疫受体TLR2和设计的疫苗构建体的结构模型之间的强结合模式。并表现出许多生物化学键(氢键，盐桥,和非粘合触点)。最先进的全原子分子动力学模拟揭示了疫苗构建体与TLR2在300纳秒的整个模拟中在原子水平上的高度稳定的相互作用。此外,免疫模拟分析的结果表明，设计的疫苗有可能诱导针对靶向痘病毒的保护性免疫。
结论：综合来看，发现配制的下一代多价疫苗对密切相关的痘病毒具有良好的功效(MPXV，VARV,和VPXV)，如我们广泛的免疫信息学和分子建模评估所证明的；然而，还需要进一步的实验研究。
方法：本研究的主要目标是配制针对三种进化封闭痘病毒的多表位疫苗，即MPXV,VARV,和VPXV使用综合免疫信息学和分子建模方法。DNA依赖性RNA聚合酶（DdRp），痘病毒的潜在疫苗靶标，已用于确定免疫显性B和T细胞表位，然后在原子水平上与Toll样受体2进行相互作用分析。
结果：三种多表位疫苗构建体，即DdRp_MPXV(V1)，DdRp_VARV(V2),设计了DdRp_VPXV(V3)。这些疫苗构建体被发现是抗原性的，非过敏性，无毒,和可溶性具有所需的物理化学性质。蛋白质-蛋白质对接和相互作用谱分析描述了靶向免疫受体TLR2和设计的疫苗构建体的结构模型之间的强结合模式。并表现出许多生物化学键(氢键，盐桥,和非粘合触点)。最先进的全原子分子动力学模拟揭示了疫苗构建体与TLR2在300纳秒的整个模拟中在原子水平上的高度稳定的相互作用。此外,免疫模拟分析的结果表明，设计的疫苗有可能诱导针对靶向痘病毒的保护性免疫。
结论：综合来看，发现配制的下一代多价疫苗对密切相关的痘病毒具有良好的功效(MPXV，VARV,和VPXV)，如我们广泛的免疫信息学和分子建模评估所证明的；然而，还需要进一步的实验研究。
