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

以人为本的数据驱动开发下一代抗疟疾 T 细胞疫苗

• 批准号: 10443906
• 负责人: Denise L. Doolan
• 金额: $ 49.59万
• 依托单位: JAMES COOK UNIVERSITY OF NO QUEENSLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2023-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443906
• 关键词: Address; Adenoviruses; Agonist; Antibodies; Antibody Response; Antigen Targeting; Antigens; Attenuated; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cessation of life; Characteristics; Chemoprophylaxis; Chloroquine; Clinical; Complex; Computational Science; DNA; Data; Data Set; Development; Disease; Erythrocytes; Genome; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunology; In complete remission; Individual; Infection; Intravenous; Lead; Link; Liposomes; Liver; Malaria; Malaria Vaccines; Mediating; Mediator of activation protein; Memory; Messenger RNA; Multiomic Data; Mus; Natural Immunity; Outcome; Parasites; Phase; Plasmodium; Plasmodium falciparum; Populations at Risk; Pre-Clinical Model; Proteins; Proteome; Public Health; RNA vaccine; Radiation; Regimen; Risk; Selection Criteria; Site; Sporozoites; Sterility; T cell response; T memory cell; T-Lymphocyte; Targeted Research; Tissues; Transcend; Vaccination; Vaccine Antigen; Vaccines; Virulent; adaptive immunity; base; clinical development; clinically relevant; combinatorial; data integration; design; human model; immunogenicity; in silico; in vivo; innovation; next generation; novel; novel strategies; pathogen; preclinical development; prevent; rational design; research clinical testing; response; screening; synergism; translational research program; transmission process; vaccination strategy; vaccine candidate; vaccine delivery; vaccine development; vaccine evaluation; vaccine platform; vaccinology

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.

PA-19-077 DOOLAN：项目摘要 疟疾仍然是一个全球公共卫生问题，世界上近一半的人口面临风险。 疟疾疫苗每年可预防近 50 万人死亡和超过 2 亿临床病例， 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（RAS；PfSPZ）和在化学预防（CPS）下施用的传染性子孢子。 保护性免疫被认为是由 CD8+ T 细胞介导的，CD8+ T 细胞在寄生虫感染前攻击寄生​​虫。 然而，这种保护作用的关键抗原很大程度上是感染的红细胞（PE）肝阶段。 我们已经开发并应用了一种全蛋白质组 T 细胞筛选方法来识别该子集。 来自完整的恶性疟原虫寄生虫蛋白质组的 T 细胞反应所针对的关键抗原。 已经表明，T 细胞优先识别的抗原与抗体靶标不同。 将表征并证明来自我们独特的红细胞前恶性疟原虫 T 细胞抗原的高排名 数据集，重点关注那些被归类为专门的 T 细胞靶标，因为 T 细胞针对肝脏 阶段抗原被认为是针对疟疾的无菌免疫所需的主要免疫效应物， 我们的选择标准将考虑序列保守的程度。 跨疟原虫菌株和物种，以疫苗为目标，赋予菌株超越和跨物种 我们将使用由抗原保护能力决定的临床相关选择标准。 在已建立的临床前模型中对抗剧毒约氏疟原虫寄生虫的挑战并通过召回得到认可 我们将使用两种创新疫苗在保护性人体模型中产生疟原虫特异性免疫反应。 选择能够诱导强劲且持续的 T 细胞反应的递送平台，特别关注 诱导针对假定的免疫作用位点的肝脏特异性驻留记忆 T 细胞 (Trm)。 选定的方案包括“Prime-Target”，其中包含 DNA 引发，然后传递腺病毒加强 静脉注射以靶向肝脏，脂质体 mRNA 疫苗平台含有激动剂 (cA) 激活 NKT 细胞并将先天免疫和适应性免疫联系起来；这两个平台都可以诱导持续的 T 细胞反应 并且能够保护小鼠免受子孢子的攻击。我们将分配疫苗的优先顺序。 根据其资历进行开发，评估组合的协同作用，并向下选择临床 开发最有可能诱导强大且持续的保护性的一组抗原 这一临床前开发确定了人类对疟疾的免疫力。 策略可以直接过渡到临床开发，最终目标是在现场部署 有效、合理设计的基于基因组的疫苗，可诱导持久的 T 细胞介导的保护， 改善所有高危人群的疾病。