Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
BioIndustrial Division, Butantan Institute, Sao Paulo Secretary of Health, São Paulo, Brazil.
Front Immunol. 2021 Dec 21;12:788185. doi: 10.3389/fimmu.2021.788185. eCollection 2021.
Control of human ascariasis, the most prevalent neglected tropical disease globally affecting 450 million people, mostly relies on mass drug administration of anthelmintics. However, chemotherapy alone is not efficient due to the high re-infection rate for people who live in the endemic area. The development of a vaccine that reduces the intensity of infection and maintains lower morbidity should be the primary target for infection control. Previously, our group demonstrated that immunization with crude antigens in mice induced an IgG-mediated protective response with significant worm reduction. Here, we aimed to develop a multipeptide chimera vaccine based on conserved B-cell epitopes predicted from 17 common helminth proteomes using a bioinformatics algorithm. More than 480 B-cell epitopes were identified that are conserved in all 17 helminths. The -specific epitopes were selected based on their reactivity to the pooled sera of mice immunized with crude antigens or infected three times with infective eggs. The top 35 peptides with the strongest reactivity to immune serum were selected to construct a chimeric antigen connected in sequence based on conformation. This chimera, called ASCVac-1, was produced as a soluble recombinant protein in an expression system and, formulated with MPLA, was used to immunize mice. Mice immunized with ASCVac-1/MPLA showed around 50% reduced larvae production in the lungs after being challenged with infective eggs, along with significantly reduced inflammation and lung tissue/function damage. The reduced parasite count and pathology in infected lungs were associated with strong Th2 immune responses characterized by the high titers of antigen-specific IgG and its subclasses (IgG1, IgG2a, and IgG3) in the sera and significantly increased IL-4, IL-5, IL-13 levels in lung tissues. The reduced IL-33 titers and stimulated eosinophils were also observed in lung tissues and may also contribute to the ASCVac-1-induced protection. Taken together, the preclinical trial with ASCVac-1 chimera in a mouse model demonstrated its significant vaccine efficacy associated with strong IgG-based Th2 responses, without IgE induction, thus reducing the risk of an allergic response. All results suggest that the multiepitope-based ASCVac-1 chimera is a promising vaccine candidate against sp. infections.
控制人类蛔虫病，这是一种在全球范围内最普遍的被忽视的热带病，影响着全球 4.5 亿人，主要依赖于驱虫药物的大规模投药。然而，由于生活在流行地区的人再次感染率高，单纯的化疗效果并不理想。开发一种既能降低感染强度，又能保持较低发病率的疫苗，应该是感染控制的首要目标。以前，我们的研究小组证明，用粗抗原免疫小鼠可以诱导一种 IgG 介导的保护性反应，显著减少蠕虫数量。在这里，我们旨在基于生物信息学算法，从 17 种常见的蠕虫蛋白质组中预测的保守 B 细胞表位，开发一种多肽嵌合疫苗。鉴定出 480 多个在所有 17 种蠕虫中保守的 B 细胞表位。根据它们对用粗抗原免疫或用 感染性卵感染三次的小鼠混合血清的反应性，选择了 特异性表位。选择了与 免疫血清反应性最强的前 35 个肽，根据构象序列连接构建嵌合抗原。这种嵌合体，称为 ASCVac-1，在 表达系统中作为可溶性重组蛋白产生，并与 MPLA 一起用于免疫小鼠。用 ASCVac-1/MPLA 免疫的小鼠在受到 感染性卵的攻击后，肺部幼虫的产生减少了约 50%，同时炎症和肺组织/功能损伤明显减少。感染肺部寄生虫数量减少和病理学改变与强烈的 Th2 免疫反应有关，表现为血清中抗原特异性 IgG 及其亚类（IgG1、IgG2a 和 IgG3）的高滴度显著增加，肺组织中 IL-4、IL-5 和 IL-13 水平也显著增加。在肺组织中也观察到减少的 IL-33 滴度和刺激的嗜酸性粒细胞，这也可能有助于 ASCVac-1 诱导的保护作用。总之，在小鼠模型中用 ASCVac-1 嵌合体进行的临床前试验证明了其显著的疫苗疗效，与基于 IgG 的强烈 Th2 反应有关，没有 IgE 诱导，从而降低了过敏反应的风险。所有结果表明，基于多表位的 ASCVac-1 嵌合体是一种有前途的抗 感染候选疫苗。
