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（由申请人提供）：我们注意到，在我们的几项疫苗接种研究中，我们的某些“阴性”动物对照组通常表现出高于我们预期观察到的保护功效，特别是“阴性对照组”。含有免疫刺激佐剂分子（IAM）但不含靶抗原的动物对致命剂量的病毒（例如流感病毒）或真菌（例如烟曲霉）的攻击提供了适度的保护此外，胆固醇马来酰亚胺（CMI）部分的存在似乎增强了VesiVax（r）CALV（可缀合佐剂脂质囊泡）制剂中的存在，以促进靶抗原与脂质体的缀合；在该测试组中，目标抗原尚未与 VesiVax(r) CALV 缀合，保护效果似乎也存在时间依赖性，即，我们观察到，在最后一次疫苗接种后一周用病原体进行攻击比在最后一次疫苗接种后三周或更长时间内进行病原体攻击产生了更有效的保护。基于这些观察，我们设计并执行了一项更加受控的疫苗接种研究，以检查是否具有保护性。效果是真实的，并证明添加 CMI 配体增强了这种效果，我们在 VesiVax(r) CALV 平台中测试的最彻底的 IAM 是单磷酰脂质 A (MPL)，一种 Toll 样受体 (TLR) 4。因此，我们在初步研究中使用 MPL 作为 IAM 模型，结果表明，疫苗中确实可以实现对病原体攻击的显着保护，而 CMI 确实可以改善保护性免疫反应。我们率先提出，CMI 正在通过先天免疫反应促进保护性免疫的刺激，因此，我们建议在此 SBIR 第一阶段应用中，通过更详细的研究来检验这一发现的潜在商业效用。 目的是证明未结合的 VesiVax(r) CALV 有潜力用作针对不同病原体的“通用”疫苗。为了最大限度地发挥这些研究的影响，我们将在致命流感攻击的近交小鼠模型中测试这一概念。