Microneedle-based immunization against pandemic influenza

描述(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，大流行性流感导致多达5000万人死亡。最近禽流感病毒的传播引发了人们的担忧，即另一场大流行即将到来，可能会导致数百万人死亡。我们应对未来大流行的能力在很大程度上受到迅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，这在每年漫长而低效的流感疫苗接种活动中可见一斑。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，不会产生尖锐的、对生物有害的废物，而且成本低。这样的贴片可以通过药店、消防站甚至美国邮报迅速分发。因为微针贴片的目标是运送到皮肤的树突状细胞，所以应该需要更低的疫苗剂量，这在大流行疫苗供应有限的情况下是至关重要的。为了实现这些目标，该项目有两个具体目标。目标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，以制造微针，这种微针可以容易地插入皮肤，以快速将疫苗运送到目标深度。将使用身体皮肤、活体人体皮肤移植和人体受试者来研究微针设计，以确定微针的机械性能；加工和储存过程中的稳定性；受控剂量靶向和疫苗递送的动力学；以及安全性。这些研究将生产微针，以满足针对大流行性流感的大规模免疫接种的需要。目的2评价微针接种流感疫苗的效果，确定抗原提呈细胞在免疫激活中的作用。针对H5流感病毒株的病毒样颗粒、纯化蛋白和DNA疫苗将使用微针传递给小鼠和无毛豚鼠。微针设计和疫苗接种方案将根据体液免疫反应、细胞免疫反应、记忆B细胞库和针对病毒攻击的保护措施进行优化。将通过鉴定树突状细胞和其他抗原提呈细胞在免疫激活中的作用来评估免疫的细胞途径。这些目标是紧密结合的，以AIM 1微针设计为基础，由AIM 1独特的微针设计推动AIM 2和AIM 2疫苗接种研究中确定的优势和劣势。这一生物工程研究伙伴关系将由一个由五名主要研究人员组成的协作团队执行，其中包括微制造、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。未来的研究预计将向FDA提交IND申请的准备工作，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会拯救生命，因为它使用一种自我管理的、节省剂量的经皮贴片，迅速为数百万人接种疫苗。

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