Waki Kentarou, Tani Hideki, Kawahara Eigo, Saga Yumiko, Shimada Takahisa, Yamazaki Emiko, Koike Seiichi, Morinaga Yoshitomo, Isobe Masaharu, Kurosawa Nobuyuki
Laboratory of Molecular and Cellular Biology, Graduate School of Science and Engineering for Education, University of Toyama, Toyama, Japan.
Department of Virology, Toyama Institute of Health, Toyama, Japan.
Elife. 2025 May 8;12:RP88387. doi: 10.7554/eLife.88387.
Intranasal vaccination is an attractive strategy for preventing COVID-19 disease as it stimulates the production of multimeric secretory immunoglobulin A (IgA), the predominant antibody isotype in the mucosal immune system, at the target site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. Currently, intranasal vaccine efficacy is evaluated based on the measurement of polyclonal antibody titers in nasal lavage fluid. However, how individual multimeric secretory IgA protects the mucosa from SARS-CoV-2 infection remains to be elucidated. To understand the precise contribution and molecular nature of multimeric secretory IgA induced by intranasal vaccines, we developed 99 monoclonal IgA clones from nasal mucosa and 114 monoclonal IgA or IgG clones from nonmucosal tissues of mice that were intranasally immunized with the SARS-CoV-2 spike protein. The nonmucosal IgA clones exhibited shared origins and common and unique somatic mutations with the related nasal IgA clones, indicating that the antigen-specific plasma cells in the nonmucosal tissues originated from B cells stimulated at the nasal mucosa. Comparing the spike protein binding reactivity, angiotensin-converting enzyme-2-blocking, and in vitro SARS-CoV-2 virus neutralization of monomeric and multimeric secretory IgA pairs recognizing different epitopes showed that even non-neutralizing monomeric IgAs, which represent 70% of the nasal IgA repertoire, can protect against SARS-CoV-2 infection when expressed as multimeric secretory IgAs. We also demonstrated that the intranasal administration of multimeric secretory IgA delivered as prophylaxis in the hamster model reduced infection-induced weight loss. Our investigation is the first to demonstrate the function of nasal IgA at the monoclonal level, showing that nasal immunization can provide effective immunity against SARS-CoV-2 by inducing multimeric secretory IgAs at the target site of the virus infection.
鼻内接种疫苗是预防新冠肺炎的一种有吸引力的策略，因为它能在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）进入的靶位点刺激多聚体分泌型免疫球蛋白A（IgA）的产生，IgA是黏膜免疫系统中的主要抗体亚型。目前，鼻内疫苗的效力是根据鼻灌洗液中多克隆抗体滴度的测量来评估的。然而，个体多聚体分泌型IgA如何保护黏膜免受SARS-CoV-2感染仍有待阐明。为了了解鼻内疫苗诱导的多聚体分泌型IgA的确切作用和分子性质，我们从鼻黏膜中开发了99个单克隆IgA克隆，并从小鼠的非黏膜组织中开发了114个单克隆IgA或IgG克隆，这些小鼠用SARS-CoV-2刺突蛋白进行了鼻内免疫。非黏膜IgA克隆与相关的鼻内IgA克隆表现出共同的起源以及共同和独特的体细胞突变，这表明非黏膜组织中的抗原特异性浆细胞起源于在鼻黏膜处受到刺激的B细胞。比较识别不同表位的单体和多聚体分泌型IgA对的刺突蛋白结合反应性、血管紧张素转换酶2阻断作用以及体外SARS-CoV-2病毒中和作用表明，即使是非中和性的单体IgA（占鼻内IgA库的70%），当以多聚体分泌型IgA形式表达时也能预防SARS-CoV-2感染。我们还证明，在仓鼠模型中预防性给予多聚体分泌型IgA进行鼻内给药可减轻感染引起的体重减轻。我们的研究首次在单克隆水平上证明了鼻内IgA的功能，表明鼻内免疫可通过在病毒感染的靶位点诱导多聚体分泌型IgA来提供针对SARS-CoV-2的有效免疫力。
