Preclinical development of A CD8 T-Cell Priming Vaccine Against Chikungunya Virus

该项目建议通过临床前开发、cGMP制造和MHRA监管提交在英国进行第一阶段临床试验，推进CD8T细胞启动基孔肯雅病毒(CHIKV)候选疫苗(PepGNP-CHIKV)。该项目的总体目标是在该项目完成后3至6个月内准备进入第一阶段临床试验。CHIKV是一种蚊子传播的甲型病毒，可导致疾病流行，其特征是衰弱的关节痛和关节炎，感染后可持续数月至数年。在过去的十年中，CHIKV已成为一种重新出现的蚊子传播病毒，已传播到欧洲、亚洲、太平洋地区和美洲，流行病造成严重的经济影响。Emergex开发了一种独特的T细胞启动疫苗平台，由两项技术组成：一个是表达的主要组织相容性复合体(MHC)1类限制性病毒特异性多肽库，另一个是自调节金纳米颗粒(GNP)载体系统。Emergex认为，T细胞启动疫苗提供了一种有效的手段来预防疾病和包括基孔肯雅热在内的一系列病原体的传播。T细胞启动疫苗的优势是，由于它们在病毒感染的初始阶段针对人类细胞，它们可以在病毒病原体有机会复制之前清除病毒病原体(称为“流产感染”)。这将防止临床疾病和传播。T细胞初始系统还具有长期保护能力(20年)。利用Emergex平台，两种产品(登革热疫苗和贝塔冠状病毒疫苗)已在瑞士完成了一期试验(NCT04935801和NCT04935801)。这些疫苗被证明是安全的，能够诱导显著的疫苗特异性T细胞效应器和记忆反应。监管部门已批准即将开始的贝塔冠状病毒疫苗1b阶段试验。这些疫苗将在第二阶段试验中取得进展。一种通用流感疫苗将于今年第四季度在美国进入第一阶段试验。这一项目将在上一届竞赛“SBRI-流行病疫苗：为临床开发和监管提交做好准备”的基础上取得进展。在这次比赛中，Emergex达到了所有的里程碑，1)利用免疫蛋白质组学鉴定了基孔肯亚多肽表位文库，2)使用这些表位序列合成了一个实验性候选疫苗，3)展示了候选疫苗的体外效果。根据这些结果，Emergex认为，候选者现在已经准备好进入正式的临床前开发和cGMP生产。

The project proposes to advance a CD8 T-cell priming Chikungunya virus (CHIKV) vaccine candidate (PepGNP-ChikV) through preclinical development, cGMP manufacture and and MHRA regulatory submission for a Phase-1 clinical trial in the UK. The overall aim of this project is be ready to move into a Phase-1 clinical trial within 3 to 6 months of completion of this project.CHIKV is a mosquito-transmitted alphavirus that causes epidemics of illness characterized by debilitating arthralgia and arthritis that can endure for months to years following infection. In the last decade, CHIKV has become a reemerging mosquito-transmitted virus that has spread into Europe, Asia, the Pacific Region, and the Americas, with epidemics causing severe economic impact. No licensed vaccine exists.Emergex has developed a unique T-cell priming vaccine platform comprised of two technologies: a library of expressed major histocompatibility complex (MHC) Class 1-restricted viral specific peptides, and a self-adjuvating gold nanoparticle (GNP) carrier system. Emergex believes that T-cell priming vaccines offer an effective means to prevent disease and transmission for a range of pathogens including Chikungunya. T-cell priming vaccines have the advantage that since they target human cells at the stage of initial viral infection, they can clear the viral pathogen before it has the opportunity to replicate (Termed "abortive infection"). This would prevent both clinical disease and transmission. The T-cell prime system also has the capacity for long term protection (\>20 years).Using the Emergex platform, two products (A Dengue vaccine and a Betacoronavirus vaccine) have completed Phase-1 trials in Switzerland (NCT04935801 and NCT04935801). The vaccines were shown to be safe and capable of inducing significant vaccine specific T-cell effector and memory responses. Regulatory approval has been given for a phase 1b trial for the betacoranavirus vaccine due to begin imminently. These vaccines will be advanced in Phase-2 trials. A universal influenza vaccine is due to enter a Phase-1 trial in the USA in Q4 this year.This project will advance upon outputs from the previous competition "SBRI - Vaccines for epidemic diseases: Readiness for clinical development and regulatory submission". In this competition Emergex met all milestones and 1) identified the Chikungunya peptide epitope library using immunoproteomics 2) synthesized an experimental vaccine candidate using those epitope sequences 3) Showed in vitro efficacy of the candidate. Based on these outputs, Emergex believe the candidate is now in a state of readiness to enter formal preclinical development and cGMP manufacture.