Development of small near-infrared laser system capable of improving immune responses to vaccines (laser-based adjuvant)

 描述（由申请人提供）：缺乏安全有效的疫苗佐剂是一个重要的公共卫生问题，也是NIH/NIAID的关键研究重点。目前还没有佐剂被批准用于皮内疫苗。该二期STTR项目的目标是将一种用于皮内接种的新佐剂-小型近红外激光器，其向小面积皮肤发射短暂，无损伤，无痛的光剂量-推向先进的临床前开发。在第一阶段的项目中，我们的团队成功地证明了小型二极管激光系统可以在已建立的小鼠模型中增强对疫苗的免疫反应。第二阶段的项目有三个具体目标：1）设计和构建一个小型的近红外二极管激光装置，适用于皮内疫苗的临床使用。2)在动物模型中表明，这种装置可以增强皮内基孔肯雅病毒疫苗，从而显著降低抗原剂量、剂量数或两者。3)表明激光照射在人体中是可耐受的且无损伤的，同时刺激皮肤免疫信号传导和免疫细胞动员。基于激光的佐剂方法尚未超越学术研究;这个第二阶段项目将有助于将基于激光的佐剂推向临床，届时它可以被许可作为多种疫苗的佐剂。该项目的广泛和长期目标是通过增加可与疫苗抗原一起使用的新佐剂的范围来改进疫苗，并扩大皮内疫苗的应用，这种疫苗可以通过更安全、更少痛苦和更有效的疫苗接种方法提供疾病保护。激光设计将从评估佐剂如何用于临床疫苗接种开始，并将转向迭代原型开发，其中包含这些设计考虑因素并利用我们现有的激光制造资源。最终的原型将进行台架测试，以验证设计要求的一致性，并将建立一个可扩展的，以质量为基础的制造过程。与此同时，三种不同的近红外激光器将在小鼠疫苗模型中进行测试，以确定最能增强基孔肯雅病毒皮内疫苗的特定配置。这些研究将由马萨诸塞州总医院疫苗和免疫治疗中心的Satoshi Kashiwagi博士和格鲁吉亚大学兽医学院的Ted Ross博士进行。它们将证明激光佐剂在减少剂量大小或数量时提供与无佐剂疫苗等效的保护的能力。最后，在这些小鼠研究中效果最好的激光将在人类身上进行测试，以表明它不会伤害或造成任何皮肤损伤，并在小鼠皮肤中产生类似的免疫刺激作用。该激光将在所有肤色的人类受试者中进行测试，以表明皮肤对激光的反应不受色素沉着的影响。本临床研究将由Northeast Dermatology Associates，PA进行。这三个目标将共同为激光佐剂的持续发展做好准备，为临床试验做好准备。

 DESCRIPTION (provided by applicant): The lack of vaccine adjuvants that are both safe and effective is an important public health problem and is a key research priority for the NIH/NIAID. No adjuvants have yet been approved for use with intradermal vaccines. The goal of this phase II STTR project is to move a new adjuvant for intradermal vaccination-small near-infrared lasers that emit brief, non-damaging, non-painful light doses to a small area of skin-to the point of advanced preclinical development. In the phase I project, our team successfully showed that small diode laser systems could augment immune responses to a vaccine in an established mouse model. The phase II project has three specific aims: 1) Design and construct a small near-infrared diode laser device appropriate for clinical use with intradermal vaccines. 2) Show in an animal model that such a device can enhance an intradermal chikungunya virus vaccine, enabling a significant decrease in antigen dose, dose number or both. 3) Show that that laser exposures are tolerable and non-damaging in humans while stimulating skin immune signaling and immune cell mobilization. Laser-based adjuvanting approaches have not been moved beyond academic studies; this phase II project will help move a laser-based adjuvant toward the clinic, at which point it could be licensed as an adjuvant for multiple vaccines. The broad and long-term objectives of this project are to improve vaccines by increasing the range of new adjuvants available for use with vaccine antigens and to expand the application of intradermal vaccines that can offer protection from diseases through safer less painful and more efficient vaccination approaches. Laser design will start with assessment of how the adjuvant would be used in clinical vaccination and will move to iterative prototype development that incorporates these design considerations and leverages our existing laser manufacturing resources. The final prototype will be bench tested to validate consistent achievement of design requirements and a scalable, quality-based manufacturing process will be established. In parallel, three different near infrared lasers will be tested in a mouse vaccine model to determine the specific configuration that best enhances an intradermal vaccine against chikungunya virus. These studies will be conducted by Dr. Satoshi Kashiwagi at the Vaccine and Immunotherapy Center, Massachusetts General Hospital and Dr. Ted Ross at the College of Veterinary Medicine, University of Georgia. They will demonstrate the ability of the laser adjuvant to provide equivalent protection to a non-adjuvanted vaccine at reduced dose size or number. Finally the laser that works best in these mouse studies will be tested in humans to show that it does not hurt or cause any skin damage and produces similar immune stimulating effects in the skin that are seen in mice. This laser will be tested in human subjects of all skin tones to show that skin responses to the laser are not affected by pigmentation. This clinical study will be conducted by Northeast Dermatology Associates, PA. Together these three aims will prepare the laser adjuvant for continued development in preparation for clinical trials.