Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection
Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection
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DOI：
10.1097/qad.0000000000002026
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发表时间：
2018-11-13
期刊：
影响因子：
3.8
通讯作者：
Garcia, Felipe
中科院分区：
文献类型：
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作者：
Leal, Lorna;Guardo, Alberto C.;Garcia, Felipe
目的：针对HIV-1感染的治疗性疫苗的效果一直是温和的，迫切需要新的惰性物将反应重定向到脆弱位点以改善这些结果。设计：我们进行了首次人体临床试验，使用裸mRNA（IFIIVARNA）结合树突状细胞活化策略（TriMix：CD 40 L + CD 70 + caTLR 4 RNA）与新的HIV免疫原序列方法：在21名接受ART治疗的慢性HIV-1感染患者中进行剂量递增的I期临床试验，这些患者接受了三次结内剂量的mRNA（第0、2和4周），如下：TriMix-100 g、TriMix-300 g、TriMix-300 g与HTI 300 g、TriMix-300 g与HTI-600 g、TriMix-300 g与HTI-900 g。主要终点是安全性和次要探索性终点是免疫原性，在病毒库和transcriptome.Results的变化：总体而言，疫苗是安全的，耐受性良好。有31例1/2级和1例3级不良事件，大多数与疫苗接种无关。接受最高剂量的患者在第8周时显示出跨越HTI序列的T细胞应答中度增加。此外，接受任何剂量HTI的应答者比例从接种后w 0时的31%增加到80%。干预对caHIV-DNA水平没有影响，然而，在最高剂量iHIVARNA的第5周和第6周，cal-IIV-RNA表达和usVL短暂增加，这些变化与HIV-1特异性诱导的免疫应答呈正相关。这项I期剂量递增试验表明，iHIVARNA给药是安全的，耐受性良好，诱导中度HIV特异性T细胞应答，并短暂增加不同的病毒复制读数。这些数据支持在II期研究中进一步探索iHIVARNA。版权所有（C）2018 The Authon（s）.由Wolters Kluwer Health，Inc.出版。
Objective: The efficacy of therapeutic vaccines against HIV-1 infection has been modest, New inerts to redirect responses to vulnerable sites are urgently needed to improve these results.Design: We performed the first-in-human clinical trial with naked mRNA (IFIIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen).Methods: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4) as follow: TriMix-100g, TriMix-300g, TriMix-300g with HTI 300g, TriMix-300 g with HTI-600g, TriMix-300g with HTI-900g. Primary end-point was safety and secondary exploratory end-points were immunogenicity, changes in viral reservoir and transcriptome.Results: Overall, the vaccine was secure and well tolerated. There were 31 grade 1/2 and 1 grade 3 adverse events, mostly unrelated to the vaccination. Patients who received the highest dose showed a moderate increase in T-cell responses spanning HTI sequence at week 8, In addition, the proportion of responders receiving any dose of HTI increased from 31% at w0 to 80% postvaccination. The intervention had no impact on caHIV-DNA levels, however, cal-IIV-RNA expression and usVL were transiently increased at weeks 5 and 6 in the highest dose of iHIVARNA, and these changes were positively correlated with HIV-1-specific-induced immune responses.Conclusion: This phase I dose-escalating trial showed that iHIVARNA administration was safe and well tolerated, induced moderate HIV-specific T-cell responses and transiently increased different viral replication readouts. These data support further exploration of iHIVARNA in a phase II study. Copyright (C) 2018 The Authon(s). Published by Wolters Kluwer Health, Inc.