A novel bacterium-like particles platform displaying antigens by new anchoring proteins induces efficacious immune responses

Lingdi Niu, Mingchun Gao, Hongkun Ren, Xinqi De, Zhigang Jiang, Xinyao Zhou, Runhang Liu, Hai Li, Haoyuan Duan, Chuankun Zhang, Fang Wang, Junwei Ge
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Abstract

Bacterium-like particles (BLP) are the peptidoglycan skeleton particles of lactic acid bacteria, which have high safety, mucosal delivery efficiency, and adjuvant effect. It has been widely used in recent years in the development of vaccines. Existing anchoring proteins for BLP surfaces are few in number, so screening and characterization of new anchoring proteins are necessary. In this research, we created the OACD (C-terminal domain of Escherichia coli outer membrane protein A) to serve as an anchoring protein on the surface of BLP produced by the immunomodulatory bacteria Levilactobacillus brevis 23017. We used red fluorescent protein (RFP) to demonstrate the novel surface display system’s effectiveness, stability, and ability to be adapted to a wide range of lactic acid bacteria. Furthermore, this study employed this surface display method to develop a novel vaccine (called COB17) by using the multi-epitope antigen of Clostridium perfringens as the model antigen. The vaccine can induce more than 50% protection rate against C. perfringens type A challenge in mice immunized with a single dose and has been tested through three routes. The vaccine yields protection rates of 75% for subcutaneous, 50% for intranasal, and 75% for oral immunization. Additionally, it elicits a strong mucosal immune response, markedly increasing levels of specific IgG, high-affinity IgG, specific IgA, and SIgA antibodies. Additionally, we used protein anchors (PA) and OACD simultaneous to show several antigens on the BLP surface. The discovery of novel BLP anchoring proteins may expand the possibilities for creating mucosal immunity subunit vaccines. Additionally, it may work in concert with PA to provide concepts for the creation of multivalent or multiple vaccines that may be used in clinical practice to treat complex illnesses.
通过新的锚定蛋白显示抗原的新型细菌样颗粒平台可诱导有效的免疫反应
类杆菌颗粒(BLP)是乳酸菌的肽聚糖骨架颗粒,具有较高的安全性、粘膜递送效率和佐剂效应。近年来,它已被广泛应用于疫苗的研发。现有的 BLP 表面锚定蛋白数量较少,因此有必要筛选和表征新的锚定蛋白。在这项研究中,我们创建了 OACD(大肠杆菌外膜蛋白 A 的 C 端结构域)作为免疫调节菌 Levilactobacillus brevis 23017 生产的 BLP 表面的锚定蛋白。我们使用红色荧光蛋白(RFP)证明了这种新型表面展示系统的有效性、稳定性和适应多种乳酸菌的能力。此外,本研究还利用这种表面展示方法,以产气荚膜梭菌的多表位抗原为模型抗原,开发了一种新型疫苗(称为 COB17)。该疫苗通过三种途径对小鼠进行了测试,单剂量免疫小鼠对 A 型产气荚膜梭菌挑战的保护率超过 50%。皮下注射、鼻内注射和口服免疫的保护率分别为 75%、50% 和 75%。此外,它还能引起强烈的粘膜免疫反应,显著提高特异性 IgG、高亲和性 IgG、特异性 IgA 和 SIgA 抗体的水平。此外,我们还同时使用了蛋白锚(PA)和 OACD 来显示 BLP 表面的几种抗原。新型 BLP 锚定蛋白的发现可能会扩大粘膜免疫亚单位疫苗的可能性。此外,它还可与 PA 协同作用,为多价或多联疫苗的研制提供概念,这些疫苗可在临床实践中用于治疗复杂的疾病。
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