Development of a topical malaria vaccine.

项目摘要 拟议的研究重点是开发一种有效、安全和易于管理的疟疾 疫苗，可以产生针对疟原虫红细胞前期阶段的局部和全身保护。 皮肤递送疟疾疫苗的可行性得到以下能力的支持： 通过暴露于感染疟疾的蚊子叮咬而免疫的人类志愿者的免疫力。的 更广泛的长期目标是使用明确的环子孢子（CS）蛋白作为免疫原和免疫抑制剂。 模型抗原，以确定使用TLR通过皮肤划痕引起的先天性和适应性免疫应答 作为经皮疟疾亚单位治疗可行性的原理证明的激动剂佐剂制剂 疫苗。预计这些研究的结果将直接适用于所有疟原虫物种， 由于所有疟原虫CS蛋白的中心重复区是有效子孢子的明确靶点 中和抗体此外，这些研究将支持联合疫苗的未来开发 含有多种疟疾抗原，这些抗原也是高水平体液免疫的目标，如血液 负责临床疾病的阶段和将寄生虫传播给蚊媒的性阶段， 继续寄生虫的生命周期在拟议的研究中，我们将结合联合收割机动态和静态显微镜，流动 流式细胞术和细胞因子阵列分析，以确定先天免疫的时空进展， 在用疟疾肽和重组蛋白进行皮肤划痕后发生的反应（Aim 1）， 使用TLR激动剂单独或组合优化体液和细胞免疫（目的1和2），和（目的3） 探索使用大型动物模型，猪，其皮肤与人类皮肤具有更大的同源性， 将其转化为人体试验。更一般地，皮肤划痕递送和TLR的机制 通过这些研究确定的激动剂佐剂制剂也将推进其他疫苗的设计。 病媒传播疾病和皮肤侵入性寄生虫，以及皮肤癌等非传染性疾病。

PROJECT SUMMARY The proposed studies focus on the development of an efficacious, safe and easily administered malaria vaccine that can generate local and systemic protection against the pre-erythrocytic stages of Plasmodium. The feasibility of skin delivery of malaria vaccine is supported by the ability to elicit high levels of sterile immunity in human volunteers immunized by exposure to the bites of malaria-infected mosquitoes. The broader long-term goal is to use the well-defined circumsporozoite (CS) protein both as an immunogen and a model antigen to define the innate and adaptive immune responses elicited by skin scarification using a TLR agonist(s) adjuvant formulation as a proof-of-principle for the feasibility of transcutaneous malaria subunit vaccines. It is expected that the results of these studies will be directly applicable to all Plasmodium species, since the central repeat region of all Plasmodium CS proteins is a well defined target of potent sporozoite neutralizing antibodies. Moreover, these studies will support future development of combination vaccines containing multiple malaria antigens that are also targeted by high levels of humoral immunity, such as blood stages responsible for clinical disease and sexual stages that transmit the parasite to the mosquito vector to continue the parasite life cycle. In the proposed studies, we will combine dynamic and static microscopy, flow cytometry, and cytokine array analyses to define the spacio-temporal progression of the innate immune response that occur following skin scarification with malaria peptides and recombinant proteins (Aim 1), optimize humoral and cellular immunity using TLR agonists alone or in combination (Aim 1 & 2), and (Aim 3) explore the use of a large animal model, pigs, whose skin provides greater homology to human skin to advance translation towards human trials. More generally, mechanisms of skin scarification delivery and TLR agonist adjuvant formulations identified through these studies will also advance design of vaccines for other vector-borne diseases and skin-invasive parasites, as well as non-infectious diseases such as skin cancer.