<br>704/DNA 疫苗利用细胞质 DNA 刺激促进小鼠产生抗 HIV 中和抗体，并促进非人灵长类动物对甲胎蛋白的强烈免疫反应,Molecular Therapy - Nucleic Acids

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704/DNA 疫苗利用细胞质 DNA 刺激促进小鼠产生抗 HIV 中和抗体，并促进非人灵长类动物对甲胎蛋白的强烈免疫反应
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2023-05-04 , DOI: 10.1016/j.omtn.2023.04.029
Thibault Colombani ₁ , Thomas Haudebourg ₁ , Bruno Pitard ₁

Affiliation

基因免疫是一种有吸引力的预防性和治疗性疫苗接种方法，它使用合成载体来递送抗原编码核酸。最近，通过物理方式递送的 DNA 或由四种不同脂质组成的脂质体递送的 RNA 在人体 III 期临床试验中表现出良好的保护作用，并分别获得了印度药品管制局和美国 FDA 的批准，以预防 COVID-19。然而，开发一种允许高效和简单地递送核酸同时改善免疫反应启动的系统有可能释放基因免疫的全部治疗潜力。基于 DNA 的基因疗法和疫苗具有快速发展的潜力，最近批准了 Collategene（一种治疗人类严重肢体缺血的基因疗法）和 ZyCoV（一种由弹簧动力喷射注射器递送的 DNA 疫苗，用于预防 SARS-CoV2 感染）。最近，我们报道了两亲性嵌段共聚物 704 作为一种很有前途的合成载体，可用于各种人类疾病模型中的 DNA 疫苗接种。该载体允许对抗原编码质粒 DNA 进行剂量保留。在这里，我们报道了 704 介导的 HIV 和抗肝细胞癌 DNA 疫苗分别诱导产生针对小鼠 gp120 HIV 包膜蛋白和非人灵长类动物 α-胎蛋白抗原的特异性抗体的能力。对潜在机制的调查表明，704 介导的疫苗接种确实通过以下方式触发了强烈的免疫反应：（1）允许 DNA 直接递送到胞质溶胶中，（2）促进胞浆内 DNA 感应，导致干扰素和 NF-κB 级联刺激，以及（3）诱导肌肉细胞的抗原表达和抗原呈递细胞的呈递，导致诱导强大的适应性反应。总体而言，我们的研究结果表明，704 介导的 DNA 疫苗接种平台是开发预防性和治疗性疫苗的一种有吸引力的方法。

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704/DNA vaccines leverage cytoplasmic DNA stimulation to promote anti-HIV neutralizing antibody production in mice and strong immune response against alpha-fetoprotein in non-human primates

Genetic immunization is an attractive approach for prophylactic and therapeutic vaccination using synthetic vectors to deliver antigen-encoding nucleic acids. Recently, DNA delivered by a physical means or RNA by liposomes consisting of four different lipids demonstrated good protection in human phase III clinical trials and received Drugs Controller General of India and US FDA approval to protect against COVID-19, respectively. However, the development of a system allowing for efficient and simple delivery of nucleic acids while improving immune response priming has the potential to unleash the full therapeutic potential of genetic immunization. DNA-based gene therapies and vaccines have the potential for rapid development, as exemplified by the recent approval of Collategene, a gene therapy to treat human critical limb ischemia, and ZyCoV, a DNA vaccine delivered by spring-powered jet injector to protect against SARS-CoV2 infection. Recently, we reported amphiphilic block copolymer 704 as a promising synthetic vector for DNA vaccination in various models of human diseases. This vector allows dose sparing of antigen-encoding plasmid DNA. Here, we report the capacity of 704-mediated HIV and anti-hepatocellular carcinoma DNA vaccines to induce the production of specific antibodies against gp120 HIV envelope proteins in mice and against alpha-fetoprotein antigen in non-human primates, respectively. An investigation of the underlying mechanisms showed that 704-mediated vaccination did trigger a strong immune response by (1) allowing a direct DNA delivery into the cytosol, (2) promoting an intracytoplasmic DNA sensing leading to both interferon and NF-κB cascade stimulation, and (3) inducing antigen expression by muscle cells and presentation by antigen-presenting cells, leading to the induction of a robust adaptive response. Overall, our findings suggest that the 704-mediated DNA vaccination platform is an attractive method to develop both prophylactic and therapeutic vaccines.

更新日期：2023-05-04

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