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：项目总结 疟疾仍然是一个全球性的公共卫生问题，世界上近一半的人口处于危险之中。有效 疟疾疫苗每年可防止近50万人死亡和2亿多临床病例， 帮助根除疾病。迄今为止，最有效的实验性疟疾疫苗接种方案是辐射- 减毒子孢子（RAS; PfSPZ）和在化学预防下施用的感染性子孢子（CPS）。 保护性免疫被认为是由CD 8 + T细胞介导的，所述CD 8 + T细胞在预感染期间攻击寄生虫。 红细胞（PE）肝脏感染阶段。然而，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T细胞亚群。 T细胞反应靶向的关键抗原来自完整的恶性疟原虫寄生虫蛋白质组。我们 已经表明，T细胞优先识别的抗原与抗体靶标不同。这里我们 将表征和认证来自我们独特的红细胞前恶性疟原虫T细胞抗原， 数据集，重点是那些被归类为专门的T细胞靶点，因为T细胞直接针对肝脏- 阶段抗原被认为是抗疟疾的无菌免疫所需的主要免疫效应物， 预防疾病并阻止传播。我们的选择标准将考虑序列保守程度 疟原虫菌株和物种，以靶向疫苗，赋予菌株超越和跨物种 保护我们将使用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抗毒性约氏疟原虫攻毒，并通过召回识别 保护性人类模型中的疟原虫特异性免疫应答。我们将使用两种创新疫苗 选择具有诱导稳健和持续T细胞应答能力的递送平台，特别关注 诱导肝脏特异性驻留记忆T细胞（Trm）靶向假定的免疫作用位点。我们 选定的方案包括“初免-靶向”，其包括DNA初免，随后是腺病毒加强递送 静脉注射以靶向肝脏，以及具有掺入的激动剂（cA）的脂质体mRNA疫苗平台， 激活NKT细胞，连接先天免疫和适应性免疫;两种平台都可以诱导持续的T细胞应答 并且能够保护小鼠免受子孢子攻击。我们会优先考虑疫苗 根据他们的资历开发，评估组合的协同作用，并向下选择临床应用。 开发具有最大可能性诱导稳健和持续的保护性免疫应答的抗原集。 人类对疟疾的免疫力。通过该临床前开发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， 有效的合理设计的基于基因组的疫苗，其将诱导持久的T细胞介导的保护， 改善所有高危人群的疾病。