Microneedle-based immunization against pandemic influenza

描述（由申请人提供）：季节性流感每年在全球造成多达150万人死亡。在上个世纪的三次大流行中，大流行性流感夺去了多达5000万人的生命。最近禽流感病毒的传播引起了人们的担忧，即另一场大流行正在逼近，可能会造成数百万人死亡。我们应对未来大流行病的能力在很大程度上受到快速接种新威胁疫苗的方法不足的限制。医务人员皮下注射疫苗极其耗时，正如每年的流感疫苗接种活动旷日持久且效率低下所示。为了加快大规模疫苗接种，该项目建议开发基于微针的疫苗贴片，这种贴片可以自我管理;不产生尖锐的生物危害废物;并且成本低。这种贴片可以通过药店、消防站甚至美国邮政迅速分发。由于微针贴片靶向递送到皮肤的树突状细胞，因此应该需要低得多的疫苗剂量，这在大流行疫苗供应有限时至关重要。为了实现这些目标，该项目有两个具体目标。目的1寻求设计和表征微针系统以将流感疫苗递送至皮肤。将开发新的微制造技术来制造容易插入皮肤的微针，以将疫苗快速递送到目标深度。将使用尸体皮肤、活体人类皮肤外植体和人类受试者研究微针设计，以确定微针的机械性能;加工和储存期间的稳定性;疫苗递送的受控剂量靶向和动力学;以及安全性。这些研究将生产微针，以满足大规模流感免疫接种的需要。目的2旨在评估使用微针递送的流感疫苗的效力，并确定抗原呈递细胞在免疫活化中的作用。针对H5流感病毒株的病毒样颗粒、纯化蛋白和DNA疫苗将使用微针输送给小鼠和无毛豚鼠。将基于测量体液免疫应答、细胞免疫应答、记忆B细胞库和针对病毒攻击的保护来优化针设计和疫苗接种方案。通过识别树突状细胞和其他抗原呈递细胞在免疫激活中的作用，评价免疫的细胞途径。这些目标是高度整合的，基于目标1微针设计，目标1微针设计由目标2和目标2疫苗接种研究中确定的优势和劣势驱动，目标2和目标2疫苗接种研究由目标1的独特微针设计实现。该生物工程研究伙伴关系将由五名首席研究员组成的合作团队进行，其中包括微细加工，药物输送，病毒学和免疫学专家，并得到科学和行业咨询委员会的指导。未来的研究预计将准备向FDA提交IND申请，并启动I期临床试验。相关性：在流感大流行期间，基于微针的疫苗接种应该通过使用自我施用的、剂量节省的透皮贴剂快速免疫数百万人来挽救生命

DESCRIPTION (provided by applicant): Seasonal influenza causes up to 1.5 million deaths worldwide each year. Pandemic influenza killed up to 50 million people during the three pandemics of the last century. Recent spread of avian influenza viruses has raised concerns that another pandemic is looming and could kill millions more. Our ability to deal with a future pandemic is limited in large part by inadequate methods to rapidly vaccinate against new threats. Hypodermic injection of vaccine by medical personnel is extremely time consuming, as seen during the prolonged and inefficient annual influenza vaccination campaigns. To expedite mass vaccination, this project proposes to develop microneedle-based vaccine patches that can be self-administered; do not produce sharp, biohazardous waste; and are low cost. Such patches could be rapidly distributed through pharmacies, fire stations or even the U.S. mail. Because microneedle patches target delivery to skin's dendritic cells, much lower vaccine doses should be needed, which is vital when pandemic vaccine supplies are limited. To accomplish these goals, this project has two Specific Aims. Aim 1 seeks to design and characterize microneedle systems to deliver influenza vaccines to skin. Novel microfabrication techniques will be developed to make microneedles that easily insert into skin to rapidly deliver vaccine to targeted depths. Microneedle designs will be studied using cadaver skin, living human skin explants, and human subjects to determine microneedle mechanical properties; stability during processing and storage; controlled dose targeting and kinetics of vaccine delivery; and safety. These studies will produce microneedles designed to meet the needs of mass immunization against pandemic influenza. Aim 2 seeks to evaluate the efficacy of influenza vaccines delivered using microneedles and determine the role of antigen presenting cells in immune activation. Virus-like particles, purified protein, and DNA vaccines against the H5 influenza strain will be delivered using microneedles to mice and hairless guinea pigs. Microneedle design and vaccination protocol will be optimized based on measuring humoral immune responses, cellular immune responses, memory B cell repertoire, and protection against virus challenge. Cellular pathways to immunity will be evaluated by identifying the role of dendritic and other antigen-presenting cells in immune activation. These aims are strongly integrated, based on Aim 1 microneedle designs motivated by strengths and weaknesses identified in Aim 2 and Aim 2 vaccination studies enabled by the unique microneedle designs from Aim 1. This Bioengineering Research Partnership will be carried out by a collaborative team of five Lead Investigators, including experts in microfabrication, drug delivery, virology, and immunology, with guidance from scientific and industry advisory boards. Future studies anticipate preparation of an IND application to the FDA and initiation of a Phase I clinical trial. Relevance: During an influenza pandemic, microneedle-based vaccination should save lives by rapidly immunizing millions of people using a self-administered, dose-sparing, transdermal patch