Texas Children's Hospital Center for Vaccine Development, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.
Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Front Immunol. 2022 Feb 7;13:800295. doi: 10.3389/fimmu.2022.800295. eCollection 2022.
Trichuriasis is one of the most common neglected tropical diseases of the world's poorest people. A recombinant vaccine composed of WAP49, an immunodominant antigen secreted by adult stichocytes into the mucosa of the cecum to which the parasite attaches, is under development. The prototype is being evaluated in a mouse model of infection, with the ultimate goal of producing a mucosal vaccine through intranasal delivery. Intranasal immunization of mice with WAP49 formulated with the adjuvant OCH, a truncated analog of alpha-GalCer with adjuvanticity to stimulate natural killer T cells (NKT) and mucosal immunity, induced significantly high levels of IgG and its subclasses (IgG1 and IgG2a) in immunized mice. This also resulted in a significant reduction of worm burden after challenge with -infective eggs. The addition of QS-21 adjuvant to this vaccine formulation further reduced worm counts. The improved protection from the dual-adjuvanted vaccine correlated with higher serum antibody responses (IgG, IgG1, IgG2a, IgA) as well as with the induction of antigen-specific IgA in the nasal mucosa. It was also associated with the robust cellular responses including functional subsets of CD4 T cells producing IL-4, and cytotoxic CD8 T cells expressing granzyme B. The worm reduction achieved by mucosal immunization was higher than that induced by subcutaneous immunization. Intranasal immunization also induced a significantly higher nasal mucosa-secreted antigen-specific IgA response, as well as higher functional cellular responses including CD4IL4 (Th1) and CD8GnzB (Th2) T cells, and antigen-specific INFγ-producing T cells in both spleen and MLNs and antibody-producing B cells (CD19B220/B220GL7). Mucosal immunization further induced long-term T lymphocyte memory with increased central (CD62LCD44) and effector (CD62LCD44) memory subsets of both CD4 and CD8 T cells at 60 days after the last immunization. In summary, intranasal immunization with recombinant WAP49 protein induced strong protection versus murine trichuriasis. It represents a promising vaccination approach against intestinal nematodes.
鞭虫病是世界上最贫穷人群中最常见的被忽视热带病之一。一种由 WAP49 组成的重组疫苗正在开发中，WAP49 是一种免疫显性抗原，由成虫的 stichocytes 分泌到寄生虫附着的盲肠粘膜中。该原型正在小鼠感染模型中进行评估，最终目标是通过鼻内给药生产粘膜疫苗。用佐剂 OCH 配制的 WAP49 对小鼠进行鼻内免疫，OCH 是一种具有刺激自然杀伤 T 细胞（NKT）和粘膜免疫的佐剂的 α-GalCer 截断类似物，可诱导免疫小鼠产生显著高水平的 IgG 及其亚类（IgG1 和 IgG2a）。这也导致在用感染性卵攻击后，蠕虫负担显著降低。将 QS-21 佐剂添加到这种疫苗配方中进一步降低了蠕虫计数。双佐剂疫苗的保护作用得到改善，与更高的血清抗体反应（IgG、IgG1、IgG2a、IgA）以及鼻粘膜中抗原特异性 IgA 的诱导相关。它还与强大的细胞反应相关，包括产生 IL-4 的功能性 CD4 T 细胞亚群和表达颗粒酶 B 的细胞毒性 CD8 T 细胞。粘膜免疫诱导的蠕虫减少高于皮下免疫诱导的减少。鼻内免疫还诱导了更高的鼻粘膜分泌的抗原特异性 IgA 反应，以及更高的功能性细胞反应，包括 CD4IL4（Th1）和 CD8GnzB（Th2）T 细胞，以及在脾和 MLN 中产生 IFNγ的抗原特异性 T 细胞和产生抗体的 B 细胞（CD19B220/B220GL7）。粘膜免疫进一步诱导了 T 淋巴细胞的长期记忆，在最后一次免疫后 60 天，增加了 CD4 和 CD8 T 细胞的中央（CD62LCD44）和效应（CD62LCD44）记忆亚群。总之，重组 WAP49 蛋白的鼻内免疫诱导了针对小鼠鞭虫病的强烈保护。它代表了针对肠道线虫的一种有前途的疫苗接种方法。
