The University of Queensland, Australian Institute for Bioengineering and Nanotechnology, Centre for Biomolecular Engineering, St Lucia, QLD 4072, Australia.
Vaccine. 2013 Apr 8;31(15):1950-5. doi: 10.1016/j.vaccine.2013.02.013. Epub 2013 Feb 17.
Group A streptococcus (GAS) causes a wide range of diseases, some of them related to autoimmune diseases triggered by repeated GAS infections. Despite the fact that GAS primarily colonizes the mucosal epithelium of the pharynx, the main mechanism of action of most vaccine candidates is based on development of systemic antibodies that do not cross-react with host tissues, neglecting the induction of mucosal immunity that could potentially block disease transmission. Peptide antigens from GAS M-surface protein can confer protection against infection; however, translation of such peptides into immunogenic mucosal vaccines that can be easily manufactured remains a challenge. In this work, a modular murine polyomavirus (MuPyV) virus-like particle (VLP) was engineered to display a GAS antigenic peptide, J8i. Heterologous modules containing one or two J8i antigen elements were integrated with the MuPyV VLP, and produced using microbial protein expression, standard purification techniques and in vitro VLP assembly. Both modular VLPs, when delivered intranasally to outbred mice without adjuvant, induced significant titers of J8i-specific IgG and IgA antibodies, indicating significant systemic and mucosal responses, respectively. GAS colonization in the throats of mice challenged intranasally was reduced in these immunized mice, and protection against lethal challenge was observed. This study shows that modular MuPyV VLPs prepared using microbial synthesis have potential to facilitate cost-effective vaccine delivery to remote communities through the use of mucosal immunization.
A 组链球菌（GAS）可引起多种疾病，其中一些与 GAS 反复感染引发的自身免疫性疾病有关。尽管 GAS 主要定植于咽腔的黏膜上皮，但大多数候选疫苗的主要作用机制是基于产生不与宿主组织发生交叉反应的系统性抗体，而忽略了诱导可能阻断疾病传播的黏膜免疫。GAS M 表面蛋白的肽抗原可提供抗感染保护；然而，将此类肽翻译为可轻易制造的免疫原性黏膜疫苗仍然是一个挑战。在这项工作中，构建了一种模块化的鼠多瘤病毒（MuPyV）病毒样颗粒（VLP），以展示 GAS 抗原肽 J8i。含有一个或两个 J8i 抗原元件的异源模块与 MuPyV VLP 整合，并使用微生物蛋白表达、标准纯化技术和体外 VLP 组装进行生产。这两种模块化 VLP 在没有佐剂的情况下经鼻腔递送至近交系小鼠时，均诱导产生了显著的 J8i 特异性 IgG 和 IgA 抗体滴度，分别表明存在显著的系统性和黏膜反应。在这些免疫小鼠中，经鼻腔挑战后，其喉咙中的 GAS 定植减少，并观察到对致死性挑战的保护作用。本研究表明，使用微生物合成制备的模块化 MuPyV VLP 具有通过黏膜免疫向偏远社区提供具有成本效益的疫苗接种的潜力。
