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另辟蹊径:新型 mRNA-纳米制剂用于治疗性 HIV 疫苗接种。

Off the beaten path: Novel mRNA-nanoformulations for therapeutic vaccination against HIV.

机构信息

Neuro-Aging & Viro-Immunotherapy (NAVI), Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Institute for the Biology and Chemistry of Proteins (IBCP), Lyon, France.

出版信息

J Control Release. 2021 Feb 10;330:1016-1033. doi: 10.1016/j.jconrel.2020.11.009. Epub 2020 Nov 10.

Abstract

Over the last few years, immunotherapy for HIV in general and therapeutic vaccination in particular, has received a tremendous boost, both in preclinical research and in clinical applications. This interest is based on the evidence that the immune system plays a crucial role in controlling HIV infection, as shown for long-term non-progressors and elite controllers, and that immune responses can be manipulated towards targeting conserved epitopes. So far, the most successful approach has been vaccination with autologous dendritic cells (DCs) loaded ex vivo with antigens and activation signals. Although this approach offers much promise, it also comes with significant drawbacks such as the requirement of a specialized infrastructure and expertise, as well as major challenges for logistics and storage, making it extremely time consuming and costly. Therefore, methods are being developed to avoid the use of ex vivo generated, autologous DCs. One of these methods is based on mRNA for therapeutic vaccination. mRNA has proven to be a very promising vaccine platform, as the coding information for any desired protein, including antigens and activation signals, can be generated in a very short period of time, showing promise both as an off-the-shelf therapy and as a personalized approach. However, an important drawback of this approach is the short half-life of native mRNA, due to the presence of ambient RNases. In addition, proper immunization requires that the antigens are expressed, processed and presented at the right immunological site (e.g. the lymphoid tissues). An ambivalent aspect of mRNA as a vaccine is its capacity to induce type I interferons, which can have beneficial adjuvant effects, but also deleterious effects on mRNA stability and translation. Thus, proper formulation of the mRNA is crucially important. Many approaches for RNA formulation have already been tested, with mixed success. In this review we discuss the state-of-the-art and future trends for mRNA-nanoparticle formulations for HIV vaccination, both in the prophylactic and in the therapeutic setting.

摘要

在过去的几年中,免疫疗法,特别是治疗性疫苗接种,在临床应用和临床前研究中都取得了巨大的进展。这种兴趣是基于免疫系统在控制 HIV 感染中起着至关重要的作用的证据,正如长期非进展者和精英控制者所显示的那样,并且免疫反应可以被操纵以针对保守表位。到目前为止,最成功的方法是用自体树突状细胞(DC)负载抗原和激活信号进行疫苗接种。尽管这种方法有很大的前景,但也存在着一些显著的缺点,如需要专门的基础设施和专业知识,以及物流和储存方面的重大挑战,使其极其耗时和昂贵。因此,人们正在开发避免使用体外生成的自体 DC 的方法。其中一种方法是基于 mRNA 的治疗性疫苗接种。mRNA 已被证明是一种非常有前途的疫苗平台,因为任何所需蛋白的编码信息,包括抗原和激活信号,可以在很短的时间内产生,作为一种现成的治疗方法和个性化方法都显示出了前景。然而,这种方法的一个重要缺点是由于周围 RNases 的存在,天然 mRNA 的半衰期很短。此外,适当的免疫接种需要抗原在正确的免疫部位(例如淋巴组织)表达、加工和呈递。mRNA 作为疫苗的一个矛盾方面是它能够诱导 I 型干扰素,这可能具有有益的佐剂作用,但也可能对 mRNA 的稳定性和翻译产生有害影响。因此,适当的 mRNA 配方至关重要。已经测试了许多 RNA 配方的方法,取得了不同程度的成功。在这篇综述中,我们讨论了 HIV 疫苗接种中 mRNA-纳米颗粒制剂的最新技术和未来趋势,包括预防性和治疗性疫苗接种。

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