Development of Pre-Erythrocytic Malaria Vaccines

今年的主要发现如下。 1.在肯尼亚完成了在5-12个月婴儿中进行的第二阶段临床试验，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免受自然暴露的保护。目前正在评估免疫反应，以了解为什么疫苗在这个年龄段的保护有限。 2.在疫苗接种和保护对象中分离出抗疟疾特异性蛋白(如CSP)的单抗。在两种不同的小鼠模型中显示了这些抗体在体内具有保护性。在PfCSP上定义了一个新的表位，即中和位点。获得了与PfCSP上特定和唯一的表位结合的人源抗体的晶体结构。这些数据提供了一种抗体，可以用于预防人类疟疾，并定义了PfCSP上一个新的脆弱部位，可以通过基于结构的疫苗设计作为疫苗加以改进。 3.启动了针对CSP结合区的单抗CIS 43的临床开发计划，用于人体试验。 4.确定了一种特异性强、效价较高的新型人源单抗。 5.几种人源抗CSP单抗体内效价的比较分析这些抗体的体内机制主要集中在皮肤和肝脏。

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.