Development of a topical malaria vaccine.

描述(由申请人提供)：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，该疫苗可以产生局部和系统保护，防止疟原虫的红细胞前阶段。通过暴露于受疟疾感染的蚊子叮咬而免疫的人类志愿者能够产生高水平的无菌免疫力，从而支持了经皮肤注射疟疾疫苗的可行性。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式抗原，以确定使用TLR激动剂(S)佐剂进行皮肤划痕所引发的先天和获得性免疫反应，作为经皮疟疾亚单位疫苗可行性的原则证明。预计这些研究结果将直接适用于所有疟原虫物种，因为所有疟原虫CS蛋白的中心重复区域是有效的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联合疫苗，这些抗原也是高水平体液免疫的靶标，例如导致临床疾病的血液阶段和将寄生虫传播到蚊子媒介以继续寄生虫生命周期的性阶段。在拟议的研究中，我们将结合动态和静态显微镜、流式细胞术和细胞因子阵列分析，以确定疟疾多肽和重组蛋白皮肤划痕后发生的先天免疫反应的时空进展(目标1)，单独或联合使用TLR激动剂优化体液和细胞免疫(目标1和2)，以及(目标3)探索使用大型动物模型猪，其皮肤与人类皮肤更具同源性，以推进人类试验。更广泛地说，通过这些研究确定的皮肤结痂传递机制和TLR激动剂佐剂配方也将促进其他媒介传播疾病和皮肤侵袭性寄生虫以及皮肤癌等非传染性疾病的疫苗设计。

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.