Monoclonal antibodies are widely used to treat non-infectious conditions but are costly. Vaccines could offer a cost-effective alternative but have been limited by sub-optimal T-cell stimulation and/or weak vaccine responses in recipients, for example, in elderly patients. We have previously shown that the repetitive structure of virus-like-particles (VLPs) can effectively bypass self-tolerance in therapeutic vaccines. Their efficacy could be increased even further by the incorporation of an epitope stimulating T cell help. However, the self-assembly and stability of VLPs from envelope monomer proteins is sensitive to geometry, rendering the incorporation of foreign epitopes difficult. We here show that it is possible to engineer VLPs derived from a non human-pathogenic plant virus to incorporate a powerful T-cell-stimulatory epitope derived from Tetanus toxoid. These VLPs (termed CMV_TT) retain self-assembly as well as long-term stability. Since Th cell memory to Tetanus is near universal in humans, CMV_TT-based vaccines can deliver robust antibody-responses even under limiting conditions. By way of proof of concept, we tested a range of such vaccines against chronic inflammatory conditions (model: psoriasis, antigen: interleukin-17), neurodegenerative (Alzheimer's, β-amyloid), and allergic disease (cat allergy, Fel-d1), respectively. Vaccine responses were uniformly strong, selective, efficient in vivo, observed even in old mice, and employing low vaccine doses. In addition, randomly ascertained human blood cells were reactive to CMV_TT-VLPs, confirming recognition of the incorporated Tetanus epitope. The CMV_TT-VLP platform is adaptable to almost any antigen and its features and performance are ideally suited for the design of vaccines delivering enhanced responsiveness in aging populations.

中文翻译：

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在银屑病、阿尔茨海默氏症和猫过敏模型中，将破伤风表位掺入病毒样颗粒中，即使在老年接受者中也能实现疫苗反应。


单克隆抗体广泛用于治疗非感染性疾病，但价格昂贵。疫苗可以提供一种具有成本效益的替代方案，但受到接受者（例如老年患者）次优 T 细胞刺激和/或疫苗反应较弱的限制。我们之前已经表明，病毒样颗粒 （VLP） 的重复结构可以有效地绕过治疗性疫苗中的自身耐受性。通过掺入刺激 T 细胞的表位帮助，可以进一步提高它们的疗效。然而，来自包膜单体蛋白的 VLP 的自组装和稳定性对几何形状很敏感，这使得外源表位的掺入变得困难。我们在这里表明，可以设计源自非人类致病植物病毒的 VLP，以整合源自破伤风类毒素的强大 T 细胞刺激表位。这些 VLP（称为 CMV_TT）保持了自组装和长期稳定性。由于 Th 细胞对破伤风的记忆在人类中几乎普遍存在，因此即使在限制条件下，基于 CMV_TT 的疫苗也能提供强大的抗体反应。通过概念验证，我们测试了一系列针对慢性炎症性疾病（模型：银屑病，抗原：白细胞介素 17）、神经退行性疾病（阿尔茨海默病，β-淀粉样蛋白）和过敏性疾病（猫过敏，Fel-d1）的疫苗。疫苗反应始终如一地强烈、选择性、体内有效，即使在老年小鼠中也能观察到，并且采用低疫苗剂量。此外，随机确定的人血细胞对 CMV_TT-VLP 有反应，证实了对掺入的破伤风表位的识别。 CMV_TT-VLP 平台几乎适用于任何抗原，其功能和性能非常适合疫苗设计，为老龄化人群提供增强的响应性。