Human-informed data-driven development of next-generation T cell vaccine against malaria

PA-19-077杜兰：项目总结 疟疾仍然是一个全球公共卫生问题，世界上近一半的人口处于危险之中。卓有成效的 疟疾疫苗每年将防止近50万人死亡和超过2亿临床病例， 帮助根除这种疾病。迄今为止，最有效的实验性疟疾疫苗接种方案是放射治疗- 减毒子孢子组(Ras；PfSPZ)和感染性子孢子组(CPS)。 保护性免疫被认为是由CD8+T细胞介导的，CD8+T细胞在感染前 红细胞(PE)肝-感染期。然而，支持这种保护的关键抗原主要是 未知。我们已经开发并应用了一种蛋白质组范围的T细胞筛选方法来鉴定 恶性疟原虫完整蛋白质组T细胞反应所针对的关键抗原。我们 表明T细胞优先识别的抗原与抗体靶标是不同的。在这里，我们 将表征和认证我们独特的高度排名的前红细胞性恶性疟原虫T细胞抗原 数据集，重点放在那些专门归类为T细胞靶点的数据上，因为T细胞针对肝脏- 阶段抗原被认为是对抗疟疾的无菌免疫所需的主要免疫效应器 预防疾病，阻止传播。我们的选择标准将考虑序列保守的程度 跨疟原虫品系和物种，靶向疫苗，使品系超越和跨物种 保护。我们将使用与临床相关的选择标准，由抗原的保护能力决定。 在已建立的临床前模型中对抗毒力强的约氏疟原虫挑战，并通过Recall识别 保护性人体模型中的疟原虫特异性免疫反应。我们将使用两种创新的疫苗 根据诱导强大和持续的T细胞反应的能力选择递送平台，并特别关注 针对假定的免疫作用部位诱导肝脏特异性驻留记忆T细胞(Trm)。我们的 选定的治疗方案包括“Prime-Target”，包括DNA片段，随后是腺病毒增强注射 以肝脏为靶点的静脉注射，以及具有掺入激动剂(CA)的脂质体mRNA疫苗平台 激活NKT细胞并将先天免疫和获得性免疫联系起来；这两个平台都可以诱导持续的T细胞反应 并能保护小鼠不受子孢子的攻击。我们将为疫苗分配优先事项 根据他们的资历进行开发，评估组合的协同作用，并向下选择用于临床 发展一组最有可能诱导强健和持续保护的抗原 人类对疟疾的免疫力。根据这项临床前研究确定的最佳候选疫苗 战略可以直接过渡到临床开发，最终目标是在现场部署和 有效的合理设计的基于基因组的疫苗，将诱导持久的T细胞介导的保护和 改善所有高危人群的疾病。

PA-19-077 DOOLAN: PROJECT SUMMARY Malaria remains a global public health problem with nearly half of the world's population at risk. An effective malaria vaccine would prevent almost half a million deaths and over 200 million clinical cases each year and help eradicate the disease. The most effective experimental malaria vaccination regimens to date are radiation- attenuated sporozoites (RAS; PfSPZ) and infectious sporozoites administered under chemoprophylaxis (CPS). Protective immunity is believed to be mediated by CD8+ T cells which attack the parasite during the pre- erythrocytic (PE) liver-stage of infection. However, the key antigens underlying this protection are largely unknown. We have developed and applied a proteome-wide T cell screening approach to identify the subset of key antigens targeted by T cell responses from the complete Plasmodium falciparum parasite proteome. We have shown that the antigens preferentially recognized by T cells are distinct from antibody targets. Here, we will characterize and credential highly ranked pre-erythrocytic P. falciparum T cell antigens from our unique dataset, focusing on those that are categorized as exclusively T cell targets, since T cells directed against liver- stage antigens are considered the primary immune effectors required for sterile immunity against malaria which prevents disease and stops transmission. Our selection criteria will consider extent of sequence conservation across Plasmodium strains and species, to target a vaccine that confers strain transcending and cross-species protection. We will use clinically relevant selection criteria governed by the capacity of the antigen to protect against virulent P. yoelii parasite challenge in established preclinical models and to be recognized by recall Plasmodium-specific immune responses in protective human models. We will use two innovative vaccine delivery platforms selected for capacity to induce robust and sustained T cell responses, with a specific focus on the induction of liver-specific resident memory T cells (Trm) targeting the putative site of immune action. Our selected regimens include “Prime-Target” comprising a DNA prime followed by adenovirus boost delivered intravenously to target the liver, and a liposomal mRNA vaccine platform with an incorporated agonist (cA) to activate NKT cells and link innate and adaptive immunity; both platforms can induce sustained T cell responses and are capable of protecting mice against sporozoite challenge. We will assign priorities for vaccine development according to their credentials, evaluate combinations for synergy, and down-select for clinical development the set of antigens that have a maximum likelihood of inducing robust and sustained protective immunity against malaria in humans. The optimal vaccine candidate defined with this preclinical development strategy could be transitioned directly to clinical development with the ultimate goal of deploying in the field an effective rationally-designed genome-based vaccine that would induce durable T-cell mediated protection and ameliorate disease in all at-risk individuals.