Development of a topical malaria vaccine.

描述（由申请方提供）：拟定研究的重点是开发一种有效、安全且易于给药的疟疾疫苗，该疫苗可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了通过暴露于感染疟疾的蚊子的叮咬而免疫的人类志愿者中引发高水平的无菌免疫的能力的支持。更广泛的长期目标是使用定义明确的环子孢子（CS）蛋白作为免疫原和模型抗原，以定义由皮肤划痕引起的先天性和适应性免疫应答，使用TLR激动剂佐剂制剂作为经皮疟疾亚单位疫苗的可行性的原理证明。预期这些研究的结果将直接适用于所有疟原虫物种，因为所有疟原虫CS蛋白的中心重复区是有效子孢子中和抗体的明确靶点。此外，这些研究将支持未来开发含有多种疟疾抗原的组合疫苗，这些抗原也是高水平体液免疫的靶向，例如负责临床疾病的血液阶段和将寄生虫传播给蚊子媒介以继续寄生虫生命周期的性阶段。在本研究中，我们将结合联合收割机动态和静态显微镜、流式细胞术和细胞因子阵列分析来确定用疟疾肽和重组蛋白（Aim 1）划痕皮肤后发生的先天免疫应答的时空进展，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，其皮肤提供与人皮肤更大的同源性，以推进向人试验的转化。更一般地，通过这些研究鉴定的皮肤划痕递送和TLR激动剂佐剂制剂的机制也将推进用于其他媒介传播疾病和皮肤侵入性寄生虫以及非传染性疾病如皮肤癌的疫苗的设计。

DESCRIPTION (provided by applicant): 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 i 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.