Synthetic microparticle malaria vaccine

合成微粒疟疾疫苗

• 批准号: 8647802
• 负责人: Thomas J Powell
• 金额: $ 137.23万
• 依托单位: ARTIFICIAL CELL TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647802
• 关键词: Adverse event; Agonist; Antibodies; Antibody Formation; Biological; Biological Assay; Blood; Blood Circulation; Cessation of life; Clinical Research; Clinical Trials; Cyclic GMP; Development; Disease; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Erythrocytes; Event; Funding; Goals; Haplotypes; Human; Immune; Immune response; Immunity; Infection; Inflammatory; Interferons; Investigational Drugs; Investigational New Drug Application; Ligands; Liver; Macaca mulatta; Malaria; Malaria Vaccines; Measures; Mediating; Methods; Minor; Modeling; Modification; Monitor; Monkeys; Mus; Natural Killer Cells; Oryctolagus cuniculus; Output; Parasites; Peptides; Pharmaceutical Preparations; Phase; Phenotype; Plasmodium; Plasmodium falciparum; Preparation; Process; Process Assessment; Production; Qualifying; Research Contracts; Running; Safety; Site; Source; Sporozoites; Staging; Sterility; Synthetic Vaccines; T-Lymphocyte; T-Lymphocyte Epitopes; TLR2 gene; Technology; Testing; TimeLine; Toxicology; Transgenic Organisms; United States Food and Drug Administration; Vaccines; Validation; Work; base; circumsporozoite; circumsporozoite protein; comparative efficacy; cytokine; design; immune function; immunogenic; immunogenicity; improved; innovation; manufacturing process; meetings; neutralizing antibody; nonhuman primate; novel; particle; pathogen; pre-clinical; pre-clinical research; prevent; public health relevance; research clinical testing; response; vaccine candidate; vaccine efficacy

Abstract This Phase II project will develop a novel synthetic microparticle vaccine for malaria, using the T1BT* epitopes of the circumsporozoite (CS) protein of Plasmodium falciparum, the causative agent of human malaria. There is no approved vaccine for malaria, a disease that causes up to 500 million new infections and 1 million deaths each year in the developing world. Preclinical and clinical research has demonstrated that epitopes of the CS protein of the parasite sporozoite stage can elicit protective immunity. The protective immunity consists of parasite-neutralizing antibodies that act at the site of infection and in the bloodstream, and specific cellular mechanisms which prevent release of erythrocytic stage parasite from the host liver. In the successful Phase I project, we utilized layer-by-layer (LbL) fabrication to produce synthetic microparticles loaded with T1BT*, a fusion peptide comprising the antibody epitope of the central repeat region (B) and two T-cell epitopes: the T1 epitope which overlaps B and is conserved in all strains of P. falciparum, and the T* epitope which is located near the C-terminus of CS and is a universal epitope recognized by multiple HLA haplotypes. LbL particles are made with entirely synthetic raw materials (no biological components) and elicit potent adaptive immune responses with minimal inflammatory adverse events. Our Phase I work showed that microparticles bearing T1BT* were potently immunogenic in mice, eliciting parasite-neutralizing antibodies and T-cells including effector cytotoxic cells specific for the T-cell epitopes. Mice immunized with T1BT* microparticles were protected from Plasmodium challenge. We also showed that a simple modification of the microparticles with an innate immune stimulator, TLR2 ligand Pam3Cys, increased the potency and efficacy of the vaccine candidate without triggering overt inflammatory events. In the current project, we will select the final development candidate by examining immunogenicity and efficacy of microparticles loaded with T1BT* or Pam3Cys.T1BT*, in both the mouse and rhesus macaque models. Efficacy in the rhesus model will be tested by passively-immunizing na¿ve mice with purified Ig from the monkeys, and challenging the mice with Plasmodium. We will select the candidate that elicits the highest parasite-neutralizing antibody activity and IFN¿+ cellular responses, since these two mechanisms appear to be responsible for protection against Plasmodium infection. The selected candidate will be advanced to preclinical development which will include development of analytical release assays and a manufacturing process, and assessment of safety and tolerability in a GLP-compliant rabbit study. The specific methods and strategies of the Phase II development efforts will be guided by discussions with the Food and Drug Administration (FDA) in preparation for GMP manufacturing and release of drug product and submission of an Investigational New Drug (IND) application in a subsequent Phase III project.

摘要 该第二阶段项目将开发一种新型的疟疾合成微粒疫苗，使用T1 BT * 恶性疟原虫的环子孢子（CS）蛋白的表位， 人类疟疾目前还没有批准的疟疾疫苗，这种疾病导致多达5亿新的 感染和100万人死亡。临床前和临床研究 证明寄生虫子孢子阶段的CS蛋白的表位可以引发保护性免疫。 保护性免疫由寄生虫中和抗体组成，这些抗体作用于感染部位和 血液，和特定的细胞机制，防止释放的红细胞阶段寄生虫从 宿主肝脏在成功的第一阶段项目中，我们利用逐层（LbL）制造来生产 负载有T1 BT * 的合成微粒，所述T1 BT * 是包含中心多肽的抗体表位的融合肽， 重复区（B）和两个T细胞表位：T1表位，其与B重叠并且在所有P菌株中是保守的。 T* 表位位于CS的C-末端附近，是一种通用表位 由多种HLA单倍型识别。LbL颗粒是由完全合成的原材料制成的（没有 生物组分）并引发有效的适应性免疫应答， 事件我们的I期研究表明，携带T1 BT * 的微粒在免疫性疾病中具有潜在的免疫原性。 小鼠，引发寄生虫中和抗体和T细胞，包括特异于 T细胞表位用T1 BT * 微粒免疫的小鼠免受疟原虫感染 挑战.我们还表明，用先天免疫刺激剂对微粒进行简单修饰， TLR 2配体Pam 3Cys增加了候选疫苗的效力和功效，而不会引发明显的免疫反应。 炎症事件。在目前的项目中，我们将通过审查， T1 BT * 或Pam3Cys.T1BT* 的微粒的免疫原性和功效，在小鼠和 恒河猴模型。在恒河猴模型中的有效性将通过被动免疫的未处理小鼠进行测试， 从猴中纯化IG，并用疟原虫攻击小鼠。我们将选出 产生最高的寄生虫中和抗体活性和IFN+细胞应答，因为这两个 这些机制似乎负责保护免受疟原虫感染。所选择的候选 将进入临床前开发阶段，其中包括分析释放测定的开发和 生产工艺，并在GLP合规性家兔研究中评估安全性和耐受性。的 第二阶段发展工作的具体方法和战略将由与 美国食品和药物管理局（FDA）在准备GMP生产和释放的药物 产品并在随后的III期中提交研究性新药（IND）申请 项目