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

基本信息

批准号：
8385605
负责人：
Mei X Wu
金额：
$ 21.22万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385605
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Brief cutaneous illumination with a safe and noninvasive laser will be employed to facilitate skin-to-liver transportation of live attenuated malarial sporozoite vaccine. Sufficient delivery of the vaccine to the liver will greatly boost the efficacy of the vaccine.

描述（由申请人提供）：该提案的总体目标是证明激光预照射可以增强子孢子（SPZ）从皮肤到肝脏的传递，从而增强基于 SPZ 的疫苗。仍然迫切需要一种有效的、获得许可的抗疟疾疫苗来预防疟原虫感染。迄今为止，疟疾疫苗开发人员的“黄金标准”仍然是通过照射（g）、感染 SPZ 的蚊子叮咬进行免疫。然而，由于通过传染性蚊子叮咬对大量人群进行疫苗接种是不切实际的，并且这种免疫途径不道德，因此将这种方法转化为临床面临着巨大的障碍。对于基于 SPZ 的疫苗，无论 SPZ 是否通过辐射或基因改造减毒，功效都与转运到肝脏的 SPZ 数量相关。虽然静脉 (IV) 注射可能最足以将 SPZ 递送至肝脏，但它并不是临床批准的免疫途径。另一方面，皮内 (ID) 疫苗接种不仅模仿自然感染，而且也是临床上可接受的途径，其效率远低于静脉注射，因为 SPZ 移出皮肤受到真皮中密集网络的限制，这可能会导致皮肤感染。对于冷冻保存的 gSPZ 来说尤其如此，因为它们的运动性降低。我们发现，在 ID 之前对接种部位进行激光预照明可将 gSPZ 的皮肤到肝脏的交通增强至与静脉注射相当的水平。照明短暂地破坏了皮肤致密的微结构，允许 SPZ 相对自由地运动并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 传递，并且当与 SPZ 诱导的免疫佐剂 a-GalCer（α-半乳糖苷神经酰胺）结合使用时，可以进一步增强 SPZ 诱导的疟疾保护。为了验证这一假设，我们将验证激光介导的 SPZ 皮肤至肝脏递送是否是有效的 SPZ 剂量和/或运动依赖性，通过在将不同数量的 SPZ ID 注射到激光照射部位后 40 小时对肝脏中 SPZ 的数量进行量化来实现。然后用新鲜分离或冷冻保存的 gSPZ 或基因减毒 SPZ 测试这种剂量依赖性效应。我们还将在近交和近交小鼠模型中验证，激光照射后进行冷冻保存的 gSPZ 或基因减毒 SPZ 的 ID 接种可提供与静脉注射疫苗类似的针对有毒 SPZ 感染的保护作用，以及激光和 a-GalCer 佐剂对保护性免疫的协同作用。临床前研究如果成功，可能会使基于 SPZ 的疫苗更接近临床应用。公共卫生相关性：将采用安全、无创的激光进行短暂的皮肤照射，以促进减毒活疟疾子孢子疫苗从皮肤到肝脏的运输。将疫苗充分递送至肝脏将大大提高疫苗的功效。