Development of Pre-Erythrocytic Malaria Vaccines

前红细胞疟疾疫苗的开发

• 批准号: 10019257
• 负责人: ROBERT A SEDER
• 金额: $ 168.07万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10019257
• 关键词: Adjuvant; Antibodies; Area; Attenuated; Binding; Blood; Clinical Trials; Crystallization; Data; Development; Development Plans; Drug Kinetics; Epitopes; Erythrocytes; Formulation; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunologic Adjuvants; Infant; Kenya; Liver; Malaria; Malaria Vaccines; Malaria prevention; Modeling; Monoclonal Antibodies; Mus; Phase II Clinical Trials; Preventive; Proteins; Radiation; Route; Safety; Sampling; Site; Skin; Specificity; Sporozoite vaccine; Structure; T-Lymphocyte; Testing; Therapeutic; Vaccinated; Vaccine Design; Vaccines; age group; base; circumsporozoite protein; clinical development; comparative; human monoclonal antibodies; immunogenicity; in vivo; malaria infection; mouse model; neutralizing antibody; neutralizing monoclonal antibodies; novel; prevent; transmission process

The major discovery this year are as follows. 1. Completed a phase II clinical trial in Kenya in 5-12 month infants to assess whether irradiated PfSPZ given by the IV route is safe, and confers durable immunity and protection against natural exposure. Immune responses are currently being assessed to understand why the vaccine had limited protection in this age group. 2. Isolated monoclonal antibodies against malaria specific proteins ( eg CSP) in vaccinated and protected subjects. Showed these antibodies were protective in vivo in two different mouse models. Defined a novel epitope on PfCSP which is the site of neutralization. A crystal structure of a human antibody was obtained binding to a specific and unique epitope on PfCSP. The data provide an antibody that can be advanced for prevention of malaria in humans and defines a novel site of vulnerability on PfCSP that can be advanced as a vaccine using structure based vaccine design. 3. Started a clinical development plan for mAB CIS 43 against the junctional region of CSP for testing in humans. 4. Defined a new human mAb with distinct specificity and increased potency compared to CIS 43. 5. Comparative analysis of the in vivo potency of a number of human mAbs against CSP. Elucidation of the in vivo mechanisms of these antibodies focused in skin and liver.

今年的主要发现如下。 1.在肯尼亚5-12个月的婴儿中完成了第二阶段临床试验，以评估通过静脉注射途径给予经辐照的PfSPZ是否安全，并赋予持久的免疫力和对自然暴露的保护。 目前正在评估免疫反应，以了解为什么疫苗在这个年龄组的保护有限。 2.在接种疫苗和受保护受试者中分离抗疟疾特异性蛋白（例如CSP）的单克隆抗体。显示这些抗体在两种不同的小鼠模型中具有体内保护性。在PfCSP上定义了一个新的表位，这是中和位点。获得了与PfCSP上的特异性和独特表位结合的人抗体的晶体结构。这些数据提供了一种可以用于预防人类疟疾的抗体，并定义了PfCSP上的一个新的脆弱性位点，可以使用基于结构的疫苗设计作为疫苗。 3.启动针对CSP连接区的mAB CIS 43的临床开发计划，用于人体试验。 4.定义了一种新的人mAb，与CIS 43相比具有独特的特异性和更高的效价。 5.许多人单克隆抗体抗CSP的体内效力的比较分析。这些抗体的体内机制的阐明集中在皮肤和肝脏中。