Umemoto Shingo, Nakahashi-Ouchida Rika, Yuki Yoshikazu, Kurokawa Shiho, Machita Tomonori, Uchida Yohei, Mori Hiromi, Yamanoue Tomoyuki, Shibata Takehiko, Sawada Shin-Ichi, Ishige Kazuya, Hirano Takashi, Fujihashi Kohtaro, Akiyoshi Kazunari, Kurashima Yosuke, Tokuhara Daisuke, Ernst Peter B, Suzuki Masashi, Kiyono Hiroshi
Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Otorhinolaryngology & Head and Neck Surgery, Faculty of Medicine, Oita University, Oita, Japan.
NPJ Vaccines. 2023 Jul 24;8(1):106. doi: 10.1038/s41541-023-00700-3.
Respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection, especially in children and the elderly. Various vaccines containing the major transmembrane surface proteins of RSV (proteins F and G) have been tested; however, they have either afforded inadequate protection or are associated with the risk of vaccine-enhanced disease (VED). Recently, F protein-based maternal immunization and vaccines for elderly patients have shown promising results in phase III clinical trials, however, these vaccines have been administered by injection. Here, we examined the potential of using the ectodomain of small hydrophobic protein (SHe), also an RSV transmembrane surface protein, as a nasal vaccine antigen. A vaccine was formulated using our previously developed cationic cholesteryl-group-bearing pullulan nanogel as the delivery system, and SHe was linked in triplicate to pneumococcal surface protein A as a carrier protein. Nasal immunization of mice and cotton rats induced both SHe-specific serum IgG and mucosal IgA antibodies, preventing viral invasion in both the upper and lower respiratory tracts without inducing VED. Moreover, nasal immunization induced greater protective immunity against RSV in the upper respiratory tract than did systemic immunization, suggesting a critical role for mucosal RSV-specific IgA responses in viral elimination at the airway epithelium. Thus, our nasal vaccine induced effective protection against RSV infection in the airway mucosa and is therefore a promising vaccine candidate for further development.
呼吸道合胞病毒（RSV）是引起上、下呼吸道感染的主要原因，尤其是在儿童和老年人中。各种含有RSV主要跨膜表面蛋白（F蛋白和G蛋白）的疫苗已进行了测试；然而，它们要么提供的保护不足，要么与疫苗增强疾病（VED）的风险相关。最近，基于F蛋白的母体免疫和老年患者疫苗在III期临床试验中显示出了有前景的结果，然而，这些疫苗都是通过注射给药的。在此，我们研究了使用小疏水蛋白（SHe）的胞外域（也是一种RSV跨膜表面蛋白）作为鼻用疫苗抗原的潜力。使用我们之前开发的带有阳离子胆固醇基团的支链淀粉纳米凝胶作为递送系统制备了一种疫苗，并且将SHe与肺炎球菌表面蛋白A三联连接作为载体蛋白。对小鼠和棉鼠进行鼻内免疫诱导了SHe特异性血清IgG和粘膜IgA抗体，可预防病毒在上、下呼吸道的侵袭，且不会诱导VED。此外，鼻内免疫比全身免疫在上呼吸道诱导了更强的针对RSV的保护性免疫，这表明粘膜RSV特异性IgA反应在气道上皮细胞消除病毒中起关键作用。因此，我们的鼻用疫苗在气道粘膜中诱导了针对RSV感染的有效保护，因此是一种有前景的可供进一步开发的疫苗候选物。
