Spyros A Kalams, Barbara K Felber, James I Mullins, Hyman M Scott, Mary A Allen, Stephen C De Rosa, Jack Heptinstall, Georgia D Tomaras, Jiani Hu, Allan C deCamp, Margherita Rosati, Jenifer Bear, Michael N Pensiero, John Eldridge, Michael A Egan, Drew Hannaman, M Juliana McElrath, George N Pavlakis
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引用次数: 0
Abstract
Background: An HIV-1 DNA vaccine composed of seven highly conserved, structurally important elements (Conserved Elements, CE) of HIV p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. A CE prime- CE+full-length p55Gag boost DNA vaccine was compared to p55Gag DNA vaccination only.
Methods: Two groups (n=25 each) received 4 DNA vaccinations [2xCE prime- 2xCE+p55Gag boost or 4x p55Gag] by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n=6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses.
Results: Both regimens were safe and generally well-tolerated. The p24CE vaccine was immunogenic (29% CD4+ and 4% CD8+ responders) and was significantly boosted by CE+p55Gag (64% CD4+, p=0.037; 42% CD8+, p=0.004). CE+p55Gag induced CD4+ responses to 5 of 7 CE, compared to only 2 CE by p55Gag DNA alone, with a higher reponse to CE5 in 30% of individuals (p=0.006). CE+p55Gag induced significantly higher mean CD4+ CE Tcell breadth (0.68 vs 0.22 CE; p=0.029) and a strong trend for increased CD4+ and CD8+ T-cell breadth (1.14 vs. 0.52 CE; p=0.051) compared to p55Gag alone. Both groups developed high p55Gag T-cell (91% each) and p24Gag antibody (91% vs. 80%) responses. p24CE vaccine-induced CD4+ CE T-cell responses correlated (p=0.007) with p24Gag antibody responses.
Conclusion: The combination CE/CE+p55Gag DNA vaccine induced T-cell immune responses to conserved regions in p24Gag resulting in significant increases in breadth and epitope recognition throughout p55Gag. Vaccines able to focus immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy.
Trial registration:
Clinical trials: gov NCT03181789 Study URL: https://www.
Clinicaltrials: gov/search?term=NCT03181789 FUNDING. HIV vaccine trial network (HVTN), NIAID/NIH.
背景：一项 I 期随机双盲临床试验（HVTN 119, NCT03181789）在未感染 HIV 的人群中测试了由 HIV p24Gag 的七个高度保守、结构重要的元素（保守元素，CE）组成的 HIV-1 DNA 疫苗。CE基质-CE+全长p55Gag增强DNA疫苗与仅接种p55Gag DNA疫苗进行了比较：两组（每组 25 人）通过肌肉注射/电穿孔接种 4 次 DNA 疫苗[2xCE prime- 2xCE+p55Gag boost 或 4x p55Gag]，包括 IL-12 DNA 佐剂。安慰剂组（n=6）接受生理盐水。对参与者进行安全性和耐受性随访。对T细胞和抗体反应进行免疫原性评估：结果：两种方案均安全且耐受性良好。p24CE疫苗具有免疫原性（29%的CD4+和4%的CD8+应答者），CE+p55Gag可显著增强其免疫原性（64%的CD4+，p=0.037；42%的CD8+，p=0.004）。CE+p55Gag能诱导7个CE中的5个产生CD4+反应，而单独使用p55Gag DNA只能诱导2个CE，其中30%的人对CE5的反应更高（p=0.006）。与单独使用 p55Gag 相比，CE+p55Gag 诱导的 CD4+ CE T 细胞平均广度明显更高（0.68 vs. 0.22 CE；p=0.029），CD4+ 和 CD8+ T 细胞广度也有增加的强烈趋势（1.14 vs. 0.52 CE；p=0.051）。p24CE疫苗诱导的CD4+CE T细胞应答与p24Gag抗体应答相关（p=0.007）：结论：CE/CE+p55Gag DNA联合疫苗可诱导T细胞对p24Gag中的保守区域产生免疫应答，从而显著提高整个p55Gag的广度和表位识别率。能够通过启动对高度保守区域的反应来集中免疫反应的疫苗可以成为全面的艾滋病疫苗策略的一部分：临床试验：gov NCT03181789 研究网址：https://www.Clinicaltrials: gov/search?term=NCT03181789资助。HIV 疫苗试验网络 (HVTN)，NIAID/NIH。
期刊介绍：
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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