Design and Engineering of Nanoparticulate Universal Vaccines

纳米颗粒通用疫苗的设计和工程

• 批准号: 8978668
• 负责人: Gary Fujii
• 金额: $ 29.03万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978668
• 关键词: Adjuvant; Adverse effects; Agonist; Animals; Antigen Targeting; Aspergillus fumigatus; Biological Assay; Body Weight decreased; Cholesterol; Clinic; Control Groups; Data; Dependence; Development; Disease; Dose; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Goals; Harvest; Immune; Immune response; Immune system; Immunity; Immunization; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Lead; Ligands; Lipid A; Lipids; Liposomes; Literature; Lung; Maleimides; Modeling; Monitor; Mus; Outcome; Pathway interactions; Phase; Production; Public Health; Published Comment; Reporting; Research; Sampling; Serum; Signal Transduction; Site; Small Business Innovation Research Grant; Splenocyte; Testing; Time; Toxic effect; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccines; Vesicle; Viral; Viral Antibodies; Women' s Group; adaptive immunity; base; chemokine; cytokine; design; engineering design; enzyme linked immunospot assay; improved; influenza virus strain; influenzavirus; microbial; mouse model; nanoparticulate; pathogen; protective effect; protective efficacy; public health relevance; receptor; research clinical testing; response; toll-like receptor 4; vaccine trial

 DESCRIPTION (provided by applicant): We have noticed anecdotally that, in several of our vaccination studies, certain of our "negative" animal control groups often showed protective efficacy above what we would have expected to observe. In particular, "negative control" groups of animals that contained an immunostimulatory adjuvant molecule (IAM) without the target antigen provided modest protection against challenge with lethal doses of viral (e.g., influenza virus) or fungal (e.g., Aspergillus fumigatus) pathogens. Further, the protective effect appeared to be enhanced by the presence of the cholesterol maleimide (CMI) moiety that is incorporated into the VesiVax(r) CALV (conjugatable adjuvant lipid vesicles) formulation to facilitate conjugation of the target antigen to the liposomes; in this test group, the target antigen has not been conjugated to the VesiVax(r) CALVs. There also seemed to be a time dependence for the protective effect, i.e., we observed that challenge with the pathogen one week after the last vaccination resulted in more effective protection than challenge three weeks or more after the last vaccination. Based on these observations, we designed and executed a more controlled vaccination study to examine whether or not the protective effect was real and to demonstrate that the addition of the CMI ligand enhances this effect. The most thoroughly studied IAM we have tested in the VesiVax(r) CALV platform is monophosphoryl lipid A (MPL), a Toll-like Receptor (TLR) 4 agonist. We thus used MPL as a model IAM in our preliminary studies. Our results suggest that, indeed, significant protection from pathogen challenge can be achieved without having a target antigen present in the vaccine and that the CMI does improve the protective immune response. We hypothesize that the CMI is facilitating the stimulation of protective immunity via the innate immune response. Thus, we propose in this SBIR Phase I application, to examine the potential commercial utility of this discovery in greater detail with a goal of demonstrating that unconjugated VesiVax(r) CALVs have the potential to be used as a "universal" vaccine against different pathogens. To maximize the impact of these studies, we will test this concept in an outbred mouse model of lethal influenza challenge.

 描述（由适用提供）：我们已经注意到Annectot，在我们的几项疫苗研究中，某些“负”动物对照组通常显示出高于我们期望观察到的受保护的有效性。特别是，没有靶抗原的免疫刺激可调节分子（IAM）的“阴性对照”组提供了适度的保护，以防止致命剂量的病毒（例如流感病毒）或真菌（例如，曲霉菌）病原体。此外，被保护作用似乎通过胆固醇（CMI）部分的存在增强，该部分掺入Vesivax（R）CALV（R）CALV（可连接的可调节脂质蔬菜）的配方中，以促进靶抗原与脂质体的结合；在该测试组中，靶抗原尚未与Vesivax（R）CALV偶联。在上次疫苗后一周的病原体挑战比在最后一次疫苗后三周或更长时间以上的挑战中，对受保护作用的时间似乎也有时间依赖。基于这些观察结果，我们设计并执行了一项更受控的疫苗研究，以检查受保护作用是否真实，并证明添加CMI配体可以增强这种效果。我们在Vesivax（R）CALV平台中测试的最彻底研究的IAM是单磷酸脂质A（MPL），一种Toll样受体（TLR）4激动剂。因此，我们在初步研究中将MPL用作模型IAM。我们的结果表明，实际上，可以在疫苗中存在靶抗原的情况下可以实现病原体挑战的重大保护，并且CMI确实改善了受保护的免疫反应。我们假设CMI通过先天免疫响应促进了受保护的免疫学的刺激。在此SBIR I期应用程序中，我们建议您更详细地研究该发现的潜在商业实用性 证明未结合的Vesivax（R）CALV的目标有可能用作针对不同病原体的“通用”疫苗。为了最大程度地提高这些研究的影响，我们将在致命影响力挑战的杂种小鼠模型中测试这一概念。