Development of Pre-Erythrocytic Malaria Vaccines and antibodies

前红细胞疟疾疫苗和抗体的开发

• 批准号: 10683005
• 负责人: ROBERT A SEDER
• 金额: $ 158.46万
• 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/10683005
• 关键词: Adjuvant; Animal Model; Antibodies; Area; Attenuated; Blood; Blood Cells; Child; Clinical Trials; Data; Development; Dose; Drug Kinetics; Epitopes; Erythrocytes; Formulation; Goals; Half-Life; Human; Imaging Techniques; Immune; Immunity; Immunologic Adjuvants; Infant; Infection; Kenya; Liver; Malaria; Malaria Vaccines; Mali; Minor; Modeling; Monoclonal Antibodies; Mus; Mutation; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Prevention; Proteins; Route; Safety; Site; Sporozoites; T-Lymphocyte; Testing; Vaccine Design; Vaccinee; Yeasts; circumsporozoite protein; comparative; efficacy evaluation; efficacy study; human monoclonal antibodies; immunogenicity; improved; in vivo; in vivo Model; in vivo imaging; malaria infection; neutralizing monoclonal antibodies; nonhuman primate; novel vaccines; prevent; safety study; vaccine development; vaccine-induced antibodies

The major discovery this year are as follows. 1. Completed immune and efficacy analysis of 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. 2. Increased the half-life of mAb CIS43 by introducing an LS mutation in the Fc region. CIS43LS was shown to have comparable protection in vivo as CIS43 but have significantly longer half-life in non-human primates. 2. Initiated a Phase I clinical trial for mAB CIS 43LS against the junctional region of PfCSP for safety, pharmacokinetics and protection against controlled human malaria infection. 4. Isolated a new human mAb, L9, which defined a new distinct epitope comprising the minor and major repeats of PfCSP. 5. Comparative analysis of the in vivo potency of L9 against a number of human mAbs against CSP. Elucidated in vivo mechanisms of these antibodies demonstrating that several of them limit infection in the liver. 6. Developed in vivo imaging techniques to model the interaction between antibodies and sporozoites in mice. 7. Completed a Phase 1 safety and efficacy study with L9LS in humans. Data showed high level protection at low doses by SC or IV route. 8. Initiated two Phase 2 clinical trials in Mali and Kenya in infants and children to assess the safety and efficacy of L9LS against seasonal and perennial infection.

今年的主要发现如下。 1.在肯尼亚对5-12个月婴儿进行的第二阶段临床试验完成了免疫和疗效分析，以评估通过静脉注射照射的PfSPZ是否安全，并提供持久的免疫力和对自然暴露的保护。 2.通过在Fc区引入LS突变，延长了单抗Cis43的半衰期。研究表明，在体内，Cis43LS具有与Cis43相当的保护作用，但在非人类灵长类动物中的半衰期要长得多。 2.针对PfCSP的连接区启动了针对PfCSP连接区的单抗CIS 43LS的I期临床试验，用于安全性、药代动力学和对受控的人类疟疾感染的保护作用。 4.分离到一个新的人源单抗L9，它定义了一个新的不同的表位，包括PfCSP的主要和次要重复序列。 5.比较分析L9抗人CSP单抗的体内效价。阐明了这些抗体的体内机制，表明它们中的几个限制了肝脏的感染。 6.开发了体内成像技术来模拟抗体和子孢子之间的相互作用。 7.完成了L9LS在人类身上的第一阶段安全性和有效性研究。数据显示，SC或IV途径在低剂量时具有高水平保护作用。 8.在马里和肯尼亚启动了两项婴儿和儿童第二阶段临床试验，以评估L9LS治疗季节性和常年性感染的安全性和有效性。