Multivalent nanocluster universal influenza vaccine given by microneedle patch

微针贴片给予多价纳米簇通用流感疫苗

基本信息

批准号：
10331740
负责人：
Baozhong Wang
金额：
$ 78.13万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-12 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331740
关键词：
Adjuvant Adult Animal Model Antibody titer measurement Antigen Presentation Antigen-Presenting Cells Antigens Avian Influenza Birds Cause of Death Chimeric Proteins Clinical Trials Cold Chains Disease Outbreaks Drug Delivery Systems Encapsulated Epidemic Ferrets Flagellin Formulation Genes Head Hemagglutinin Human Immune Immune response Immunity Immunization Immunologic Tests Infection Infiltration Influenza Influenza A virus Influenza B Virus Influenza vaccination Injections Intramuscular Laboratory Animal Models Lead Longevity Methodology Molecular Mus Mutation Nanotechnology Needles Nucleoproteins Painless Particulate Patch Tests Pathogenesis Phylogenetic Analysis Physiological Proteins Public Health Recombinant Proteins Recombinants Research Research Personnel Risk Role Seasons Self Administration Skin Structure Surface Syringes T-Lymphocyte Epitopes Testing Uncertainty Vaccination Vaccine Design Vaccines Viral Antigens Virus Virus-like particle base cross immunity crosslink design draining lymph node fliC gene product immunogenicity improved influenza epidemic influenza virus vaccine influenzavirus nanocluster nanoparticle novel novel vaccines pandemic disease pandemic influenza particle peptide drug polypeptide prevent protective efficacy response seasonal influenza skin vaccination success synergism thermostability universal influenza vaccine uptake vaccin protein vaccine evaluation vaccine formulation vaccine strategy

项目摘要

SUMMARY Influenza is a major public health risk. Current seasonal influenza vaccines are effective in protecting against closely matched viruses in healthy adults. Because continuous genetic changes occur in influenza, there are major limitations to seasonal influenza vaccines including the need to produce new vaccines every season, uncertainty in selecting vaccin strains, and the inability to prevent novel influenza pandemics. A universal influenza vaccine will overcome these challenges. In our previous and preliminary studies, we have produced double-layered protein nanoclusters by desolvating the conserved ectodomain of the influenza M2 protein (M2e) into nanoparticles as cores and crosslinking influenza A trimeric hemagglutinin (HA) stalk antigens onto the core surfaces. We have also desolvated influenza internal nucleoprotein (NP) into particulate cores and cross linked M2e to generate double-layered nanoclusters. The resulting layered nanoclusters induced cross protection against viruses from both phylogenetic groups of influenza A, including pandemic potential avian strains. Both influenza A and B can cause epidemics. In this proposal, we will develop a multivalent double-layered nanocluster universal influenza vaccine composed of newly designed, conserved, antigenic proteins from both influenza A and B, and a molecular adjuvant. This nanocluster vaccine will induce strong cross immune protection against both influenza A and B in different laboratory animal models. The optimal nanocluster formulation will be encapsulated into dissolvable microneedle (MN) patches to develop a syringe-free, painless, thermostable, and self-administered skin-given universal influenza vaccine. The three specific aims are: Aim 1. Generate constructs of trimeric HA stalk antigen from influenza B and conserved NPs from both influenza A and B, fabricate and characterize nanoclusters from these and previously designed conserved antigenic proteins. We have generated structure-stabilized HA stalk proteins from both phylogenetic groups of influenza A (hrH1 and hrH3) and tetrameric M2e. We will fabricate novel double-layered nanoclusters from previous and new designed conserved influenza antigenic proteins. Aim 2. Test whether the layered nanoclusters or a multivalent optimal combination will induce protection against viruses spanning both influenza A and influenza B in mice. We will optimize a vaccine formulation inducing broadly reactive immune responses and cross protection in mice and further studies in Aim 3. Aim 3. Encapsulate the optimal multivalent nanocluster formulation into dissolvable MN patches and test the breadth of protection of the MN-based skin vaccination in both mice and ferrets. Dissolvable MN patch-based skin influenza vaccination has many advantages over conventional syringe injection including painless, needle-free, self-administration and cold chain-independent distribution. Overall, our research will develop a broadly cross-protective universal influenza vaccine

摘要流感是主要的公共卫生风险。当前的季节性流感疫苗有效预防健康成年人中的紧密匹配的病毒。因为连续的遗传变化发生在流感，季节性流感疫苗包括生产新疫苗在内的季节性流感疫苗有主要限制每个季节，选择疫苗菌株的不确定性以及无法防止新型流感大流感。一个普遍的流感疫苗将克服这些挑战。在我们以前的初步研究中，我们有通过脱溶液的流感M2的保守外体域产生了双层蛋白纳米簇蛋白质（M2E）以核心为核颗粒，并交联的流感A三聚血凝素（HA）茎抗原到核心表面。我们还将流感内部核蛋白（NP）脱脱到颗粒核心和交叉链接的M2E生成双层纳米簇。由此产生的分层纳米簇诱导的交叉从两个流感的系统发育群体中保护病毒，包括大流行潜力禽类菌株。流感和B都可能引起流行病。在此提案中，我们将开发一个多价双层纳米簇通用流感疫苗由两者的新设计，保守的抗原蛋白组成流感A和B，以及分子佐剂。这种纳米簇疫苗将诱导强的交叉免疫在不同的实验室动物模型中，防止流感A和B。最佳纳米群配方将封装成可溶解的微针（MN）斑块中，以形成无注射器，无痛的，可热稳定和自我管理的皮肤传播的通用流感疫苗。三个具体目标是： AIM 1。从流感B产生三聚体HA茎抗原的构建体，并从两者中保守NP 流感和B，制造和表征这些纳米簇，并以前设计保守的抗原蛋白。我们已经从两者中产生了结构稳定的HA茎蛋白流感A（HRH1和HRH3）和四聚体M2E的系统发育群。我们将制造新颖的双层来自以前和新设计的保守流感抗原蛋白的纳米簇。 AIM 2。测试分层的纳米簇或多价最佳组合将诱导保护针对跨越小鼠流感和流感B的病毒。我们将优化疫苗配方在小鼠中引起广泛反应性的免疫反应和交叉保护，并在目标3中进行进一步的研究。 AIM 3。将最佳的多价纳米簇配方封装到可溶解的MN斑块和测试小鼠和雪貂的基于MN的皮肤疫苗接种的保护广度。可溶解的Mn 基于补丁的皮肤流感疫苗接种比常规注射注射器具有许多优势无痛，无针，自我管理和冷链独立的分布。总体而言，我们的研究将开发出广泛的交叉保护普遍流感疫苗