Laser-facilitated delivery of malarial sporozoites from the skin to liver

激光促进疟疾子孢子从皮肤输送至肝脏

• 批准号: 8495256
• 负责人: Mei X Wu
• 金额: $ 23.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495256
• 关键词: Address; Adjuvant; Antigens; Antimalarials; Area; Attenuated; Bite; Blood Circulation; Blood Vessels; Blood capillaries; Cessation of life; Clinic; Clinical; Collaborations; Connective Tissue; Culicidae; Cutaneous; Deposition; Dermis; Disease; Dose; Emigrations; Ensure; FDA approved; Face; Fiber; Figs - dietary; Galactosylceramides; Genetic; Gold; Hand; Immunity; Immunization; Immunology; Inbred Mouse; Infection; Intravenous; Lasers; Left; Licensing; Life; Lighting; Liver; Lymphatic vessel; Malaria; Malaria Vaccines; Mediating; Medicine; Modification; Movement; One-Step dentin bonding system; Organ; Parasites; Plasmodium falciparum; Prevention; Recombinant Proteins; Research; Route; Site; Skin; Sporozoite vaccine; Sporozoites; Staging; Testing; Time; Translations; Transportation; Travel; Vaccinated; Vaccination; Vaccines; Virulent; base; capillary; cell motility; clinical application; experience; immunogenicity; intradermal injection; intravenous injection; irradiation; lymph nodes; mouse model; preclinical study; trafficking; vaccine delivery; vaccine efficacy

DESCRIPTION (provided by applicant): The overall objective of this proposal is to demonstrate that laser pre-illumination can enhance skin-to-liver delivery of sporozoites (SPZs), augmenting SPZ-based vaccines. An effective, licensed anti-malarial vaccine remains an urgent need for prevention against plasmodium infection. To date, the "gold standard" for malarial vaccine developers is still immunization by bites of irradiation (g), SPZ-infected mosquitoes. However, translation of this approach into the clinic faces formidable obstacles, due to impracticality of vaccinating a large number of people by bites of infectious mosquitoes and unethic of this route of immunization. For SPZ- based vaccines, irrespective of whether the SPZs are attenuated by irradiation or genetic modification, the efficacy is correlated with the number of SPZs trafficking into the liver. While intravenous (IV) injection may be most sufficient in delivering SPZs to the liver, it is not a clinically approved route of immunization. On the othe hand, intradermal (ID) vaccination, not only mimicking natural infection but also a clinically acceptable route, is much less efficient than IV because emigration of SPZs out of the skin is restricted by the densely packed network in the dermis, which may be particularly true for cryopreserved gSPZs owing to their reduced motility. We found that laser pre-illumination of the inoculation site prior to ID enhanced skin-to-liver traffic of gSPZs to a level comparable to IV injection. The illumination transiently disrupted the dense microarchitecture of the skin, permitting relatively free movement of SPZs and their entry into the capillaries and lymphatic vessels in the dermis. We hypothesize that this laser treatment can augment ID delivery of SPZ-based vaccines and when combined with a-GalCer (a-galactosylceramide), an adjuvant for SPZ-induced immunity, can further boost SPZ-induced protection against malaria. To test this hypothesis, we will verify whether laser-mediated facilitation of skin-to-liver delivery of SPZs is SPZ dose- and/or motility-dependent by quantification of the number of SPZs in the liver 40 hr after ID injection of varying numbers of SPZs into the site of laser illumination. This dose-dependent effect will be then tested with freshly isolated or cryopreserved gSPZs or genetically attenuated SPZs. We will also validate in outbred and inbred mouse models that laser illumination followed by ID inoculation of cryopreserved gSPZs or genetically attenuated SPZs affords similar protection against virulent SPZ infections as IV vaccination and a synergistic effect between laser and a-GalCer adjuvant on the protective immunity. The preclinical study, if successful, can potentially take SPZ-based vaccines one step closer to their clinical application.

描述（由申请人提供）：该提案的总体目标是证明激光预刷子可以增强孢子虫（SPZS）的皮肤至肝脏的递送，增强基于SPZ的疫苗。有效的，有执照的抗疟疾疫苗仍然是防止疟原虫感染的迫切需要。迄今为止，疟疾疫苗开发人员的“黄金标准”仍然是通过辐射（G），SPZ感染的蚊子的叮咬来进行的。然而，由于不切实际地，这种方法将这种方法转化为诊所面临着巨大的障碍，这是通过叮咬传染性蚊子和这种免疫途径不道德的疫苗接种的不切实际。对于基于SPZ的疫苗，无论SPZ是通过辐照还是遗传修饰减弱的，疗效与肝脏中的SPZS数量相关。虽然静脉注射（IV）注射可能足以将SPZ运送到肝脏，但它不是临床批准的免疫途径。在Othe手上，皮内（ID）疫苗接种，不仅模仿自然感染，而且在临床上可接受的途径，效率要比IV高得多，因为SPZ从皮肤中移民的迁移受到了皮肤上的密集包装的网络的限制，这对于造成的动力降低了，这对于冷冻保存的GSPZ可能尤其如此。我们发现，在ID升高GSPZ的皮肤到肝脏流量之前，对接种位点的激光预灌输至与IV注射相当的水平。照明瞬时破坏了皮肤的密集微观结构，允许SPZ相对自由移动及其进入真皮中的毛细血管和淋巴管。我们假设这种激光治疗可以增强基于SPZ的疫苗的ID输送，并且与A-甘油（A-半乳糖基酰胺）结合使用，这是SPZ诱导的免疫力的辅助物，可以进一步增强SPZ诱导的保护抗性疟疾。为了检验这一假设，我们将验证激光介导的SPZ皮肤到肝脏递送的促进是否为 SPZ剂量和/或运动依赖于在ID注入不同数量的SPZ中的肝脏中40小时中SPZ数量的剂量和/或运动性。然后，将使用新鲜分离或冷冻保存的GSPZ或遗传衰减的SPZ对这种剂量依赖性效应进行测试。我们还将验证激光照明的杂种和近交小鼠模型，然后接种冷冻保存的GSPZ或遗传衰减的SPZ，可为激进的SPZ感染与IV疫苗接种，以及激光和A-Galcer对保护性免疫的毒素效应提供类似的保护。临床前研究，如果成功的话，可能会使基于SPZ的疫苗更接近其临床应用。

项目成果

Laser mimicking mosquito bites for skin delivery of malaria sporozoite vaccines.

激光模拟蚊子叮咬，用于皮肤输送疟疾子孢子疫苗。

• DOI: 10.1016/j.jconrel.2015.02.031
• 发表时间: 2015
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Zhou,Chang;Chen,Xinyuan;Zhang,Qi;Wang,Ji;Wu,MeiX
• 通讯作者: Wu,MeiX