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 疟疾仍然是全球公共卫生问题，几乎一半的人口处于危险之中。有效 疟疾疫苗每年可防止近50万人死亡和超过2亿个临床病例，并且 帮助消除该疾病。迄今为止，最有效的实验性疟疾疫苗接种方案是辐射 - 孢子虫（RAS; PFSPZ）和在化学预防基因（CPS）下施用的传染孢子虫。 保护性免疫被认为是由CD8+ T细胞介导的，这些细胞在预寄生虫中攻击了寄生虫 红细胞（PE）感染的实时阶段。但是，这种保护的基础主要抗原在很大程度上是 未知。我们已经开发并应用了全蛋白质组的T细胞筛选方法来识别子集 由全疟原虫寄生虫蛋白质组的T细胞反应靶向的关键抗原。我们 已经表明，通过T细胞优先识别的抗原与抗体靶标不同。在这里，我们 将表征和凭证高度排名的前芽孢杆菌T细胞T细胞抗原来自我们独特的 数据集的重点是被归类为完全T细胞靶标的数据集，因为T细胞针对肝脏 - 阶段抗原被认为是无菌免疫学针对疟疾所需的主要免疫作用 防止疾病并停止传播。我们的选择标准将考虑序列保护的程度 跨疟原虫菌株和物种，靶向供认超越应变和跨物种的疫苗 保护。我们将使用抗原保护能力保护的临床相关选择标准 在已建立的临床前模型中反对有毒的p. yoelii寄生虫挑战，并被召回认可 受保护的人类模型中的疟原虫特异性免疫复杂。我们将使用两种创新疫苗 选定的交付平台，以诱导健壮和持续的T细胞反应的能力，具体关注 针对假定的免疫作用部位的活体特异性居民记忆T细胞（TRM）的诱导。我们的 选定的方案包括完成DNA Prime的“ Prime-Target”，其次是腺病毒增强 静脉注射以靶向肝脏，以及带有掺入激动剂（CA）的脂质体mRNA疫苗平台 激活NKT细胞，并将天生和适应性免疫性史链接；两个平台都可以诱导持续的T细胞响应 并能够保护小鼠免受孢子虫的挑战。我们将分配疫苗的优先级 根据他们的证书开发，评估协同作用的组合，并选择临床的选择 开发具有最大诱导和持续保护的最大可能性的抗原 对人类疟疾的免疫力。通过这种临床前开发定义的最佳疫苗候选者 策略可以直接过渡到临床开发，其最终目的是部署该领域 有效基于理性设计的基于基因组的疫苗，该疫苗将诱导耐用的T细胞介导的保护和 在所有高危人群中改善疾病。