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，大流行性流感造成多达5000万人死亡。最近禽流感病毒的传播引起了人们的担忧，即另一场大流行即将来临，并可能导致数百万人死亡。我们应对未来流行病的能力在很大程度上受到迅速接种疫苗以应对新威胁的方法不足的限制。医务人员皮下注射疫苗极其耗时，这一点从每年流感疫苗接种运动中可以看出。为加快大规模疫苗接种，该项目建议开发可自行接种的微针疫苗贴片；不产生尖锐的、有害生物的废物；而且成本很低。这种贴片可以通过药店、消防站甚至美国邮政迅速分发。由于微针贴片的目标是向皮肤的树突状细胞递送，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，本项目有两个具体目标。目的1旨在设计和表征将流感疫苗输送到皮肤的微针系统。新的微制造技术将被开发出来，以制造易于插入皮肤的微针，从而将疫苗快速输送到目标深度。微针设计将使用尸体皮肤、活体皮肤外植体和人体受试者进行研究，以确定微针的机械性能；加工和储存过程中的稳定性；控制剂量靶向和疫苗递送动力学；和安全。这些研究将生产微针，以满足针对大流行性流感进行大规模免疫的需要。目的2旨在评估使用微针注射流感疫苗的功效，并确定抗原提呈细胞在免疫激活中的作用。针对H5流感毒株的病毒样颗粒、纯化蛋白和DNA疫苗将通过微针注射到小鼠和无毛豚鼠体内。微针的设计和接种方案将基于体液免疫反应、细胞免疫反应、记忆B细胞库和对病毒攻击的保护进行优化。通过确定树突状细胞和其他抗原呈递细胞在免疫激活中的作用，将评估细胞免疫途径。这些目标是紧密结合在一起的，基于Aim 2和Aim 2疫苗接种研究中发现的优势和劣势的Aim 1微针设计，由Aim 1独特的微针设计实现。这一生物工程研究伙伴关系将由五名首席研究员组成的合作小组开展，包括微加工、药物输送、病毒学和免疫学方面的专家，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申请IND，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通过使用自我给药、剂量节约的透皮贴剂迅速对数百万人进行免疫，从而挽救生命

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