Design and Engineering of Nanoparticulate Universal Vaccines

 描述（由申请方提供）：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”动物对照组经常显示出高于我们预期观察到的保护效力。特别是，含有免疫刺激佐剂分子（IAM）但不含靶抗原的“阴性对照”动物组提供了针对致死剂量病毒（例如，流感病毒）或真菌（例如，烟曲霉）病原体。此外，通过将胆固醇马来酰亚胺（CMI）部分掺入VesiVax（r）CALV（可偶联佐剂脂质囊泡）制剂中以促进靶抗原与脂质体偶联，似乎增强了保护作用;在该试验组中，靶抗原未与VesiVax（r）CALV偶联。保护作用似乎也存在时间依赖性，即，我们观察到，在最后一次接种后一周用病原体攻击比在最后一次接种后三周或更长时间用病原体攻击产生更有效的保护。 基于这些观察结果，我们设计并实施了一项更受控的疫苗接种研究，以检查保护作用是否是真实的，并证明加入CMI配体增强了这种作用。我们在VesiVax（r）CALV平台中测试的研究最彻底的IAM是单磷酰脂质A（MPL），一种Toll样受体（TLR）4激动剂。因此，我们使用MPL作为模型IAM在我们的初步研究。我们的研究结果表明，事实上，显着的保护病原体的挑战，可以实现没有在疫苗中存在的靶抗原和CMI确实提高了保护性免疫应答。我们假设CMI通过先天免疫应答促进保护性免疫的刺激。因此，我们建议在SBIR第一阶段申请中，更详细地研究这一发现的潜在商业用途， 目的是证明未结合的VesiVax（r）CALV有可能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，我们将在致死性流感攻击的远交小鼠模型中测试这一概念。

 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.