A Phase I, double-blind, randomized, vehicle-controlled, dose-finding, safety study of a synthetic nanoparticle-based, T cell priming peptide vaccine against Dengue virus in healthy adults in Switzerland - Switzerland

Abstract
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Background
Vaccines that minimize the risk of vaccine-induced antibody-dependent enhancement and severe dengue are needed to address the global health threat posed by dengue. This study assessed the safety and immunogenicity of a gold nanoparticle (GNP)-based, multi-valent, synthetic peptide dengue vaccine candidate (PepGNP-Dengue), designed to provide protective CD8+ T cell immunity, without inducing antibodies.
Methods
In this randomized, double-blind, vehicle-controlled, phase 1 trial (NCT04935801), healthy naïve individuals aged 18-45 years recruited at the Centre for primary care and public health, Lausanne, Switzerland, were randomly assigned to receive PepGNP-Dengue or comparator (GNP without peptides [vehicle-GNP]). Randomization was stratified into four groups (low dose [LD] and high dose [HD]), allocation was double-blind from participants and investigators. Two doses were administered by intradermal microneedle injection 21 days apart. Primary outcome was safety, secondary outcome immunogenicity. Analysis was by intention-to-treat for safety, intention-to-treat and per protocol for immunogenicity.
Findings
26 participants were enrolled (Aug-Sep 2021) to receive PepGNP-Dengue (LD or HD, n=10 each) or vehicle-GNP (LD or HD, n=3 each). No vaccine-related serious adverse events occurred. Most (90%) related adverse events were mild; injection site pain and transient discoloration were most frequently reported. Injection site erythema occurred in 58% of participants. As expected, PepGNP-Dengue did not elicit anti-DENV antibodies of significance. Significant increases were observed in specific CD8+ T cells and dengue dextramer+ memory cell subsets in the LD PepGNP-Dengue but not in the HD PepGNP-Dengue or Vehicle-GNP groups, specifically PepGNP-activated CD137+CD69+CD8+ T cells (day 90, +0·0318%, 95% CI: 0·0088-0·1723, p= 0·046), differentiated effector memory (TemRA) and central memory (Tcm) CD8+ T cells (day 35, +0·8 /105 CD8+, 95% CI: 0·19-5·13, p= 0·014 and +1·34 /105 CD8+, 95% CI: 0·1-7·34, p= 0·024, respectively).
Interpretation
Results provide proof of concept that a synthetic nanoparticle-based peptide vaccine can successfully induce virus-specific CD8+ T cells. The favourable safety profile and cellular responses observed support further development of PepGNP-Dengue.
Funding
Emergex Vaccines Holding Limited.

Geographic coverage
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Switzerland

Analysis unit
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Individuals. 26 participants were enrolled.

Kind of data
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Clinical data and laboratory data (safety)

摘要
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背景
针对登革热对全球公共卫生构成的威胁，亟需开发出能够降低疫苗诱导的抗体依赖性增强和严重登革热风险的疫苗。本研究旨在评估一种基于金纳米粒子（GNP）的多价合成多肽登革热疫苗候选物（PepGNP-Dengue）的安全性及免疫原性，该疫苗旨在提供保护性CD8+ T细胞免疫，而不诱导抗体产生。
方法
在本项随机、双盲、对照车辆控制的一期临床试验（NCT04935801）中，招募了18至45岁的健康初学者，他们在瑞士洛桑初级护理和公共卫生中心接受随机分配，接受PepGNP-Dengue或对照（不含肽的GNP[车辆-GNP]）。随机化分为四组（低剂量[LD]和高剂量[HD]），分配从参与者到研究人员均为双盲。两次剂量通过皮内微针注射，间隔21天给药。主要结局指标为安全性，次要结局指标为免疫原性。安全性分析按照意向治疗原则进行，免疫原性分析按照意向治疗原则和方案规定进行。
发现
2021年8月至9月，共纳入26名参与者接受PepGNP-Dengue（LD或HD，每组10人）或车辆-GNP（LD或HD，每组3人）。未发生疫苗相关的严重不良事件。大多数（90%）相关不良事件为轻微的；注射部位疼痛和暂时性变色最为常见。58%的参与者出现注射部位红斑。如预期，PepGNP-Dengue未诱导出具有显著性的抗DENV抗体。在LD PepGNP-Dengue组中观察到特异性CD8+ T细胞和登革热二聚体+记忆细胞亚群显著增加，但在HD PepGNP-Dengue组或车辆-GNP组中并未观察到，具体为PepGNP激活的CD137+CD69+CD8+ T细胞（第90天，+0·0318%，95% CI：0·0088-0·1723，p= 0·046），分化效应记忆（TemRA）和中心记忆（Tcm）CD8+ T细胞（第35天，+0·8 /105 CD8+，95% CI：0·19-5·13，p= 0·014和+1·34 /105 CD8+，95% CI：0·1-7·34，p= 0·024，分别）。
解释
研究结果为概念验证提供了证据，表明基于合成纳米粒子的肽疫苗可以成功诱导病毒特异性CD8+ T细胞。观察到的不良反应良好状况和细胞反应支持进一步开发PepGNP-Dengue。
资助
Emergex Vaccines Holding Limited。
地理覆盖范围
瑞士
分析单位
个体。共纳入26名参与者。
数据类型
临床数据和实验室数据（安全性）