Synthetic microparticle malaria vaccine

合成微粒疟疾疫苗

• 批准号: 8870276
• 负责人: Thomas J Powell
• 金额: $ 132.86万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870276
• 关键词: Adverse event; Agonist; Antibodies; Antibody Response; 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; Health; 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; adaptive immunity; 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; research clinical testing; response; vaccine candidate; vaccine efficacy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该II期项目将开发一种用于疟疾的新型合成微粒疫苗，使用恶性疟原虫（人类疟疾的病原体）环子孢子（CS）蛋白的T1 BT * 表位。疟疾是一种每年在发展中世界造成多达5亿新感染和100万人死亡的疾病，目前还没有批准的疟疾疫苗。临床前和临床研究已经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。保护性免疫包括在感染部位和血流中起作用的寄生虫中和抗体，以及防止红细胞期寄生虫从宿主肝脏释放的特定细胞机制。在成功的I期项目中，我们利用逐层（LbL）制造来生产负载有T1 BT * 的合成微粒，T1 BT * 是一种包含中心重复区（B）的抗体表位和两个T细胞表位的融合肽：与B重叠并在所有恶性疟原虫株中保守的T1表位，和T* 表位，其位于CS的C-末端附近，并且是由多种HLA单倍型识别的通用表位。LbL颗粒由完全合成的原材料（无生物成分）制成，并引发有效的适应性免疫反应，炎症不良事件最少。我们的I期研究表明，携带T1 BT * 的微粒在小鼠中具有强免疫原性，引发寄生虫中和抗体和T细胞，包括对T细胞表位特异性的效应细胞毒性细胞。用T1 BT * 微粒免疫的小鼠被保护免受疟原虫攻击。我们还表明，用先天免疫刺激剂TLR 2配体Pam 3Cys对微粒进行简单修饰，可以增加候选疫苗的效力和功效，而不会引发明显的炎症事件。在当前项目中，我们将通过在小鼠和恒河猴模型中检查负载T1 BT * 或Pam3Cys.T1BT* 的微粒的免疫原性和有效性来选择最终的开发候选物。在恒河猴模型中的有效性将通过用从猴中纯化的IG被动免疫幼稚小鼠，并用疟原虫攻击小鼠来测试。我们将选择激发最高寄生虫中和抗体活性和IFN？+的候选物细胞反应，因为这两种机制似乎负责保护免受疟原虫感染。选定的候选药物将进入临床前开发阶段，包括开发分析放行试验和生产工艺，以及在符合GLP的家兔研究中评估安全性和耐受性。II期开发工作的具体方法和策略将通过与美国食品药品监督管理局（FDA）的讨论来指导，以准备GMP生产和制剂放行，并在随后的III期项目中提交研究性新药（IND）申请。