Design and Engineering of Nanoparticulate Universal Vaccines

 描述(申请人提供)：我们从轶事中注意到，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超出我们预期观察的保护效果。特别是，含有免疫刺激佐剂分子(IAM)但不含目标抗原的“阴性对照”组动物对致死剂量的病毒(如流感病毒)或真菌(如烟曲霉菌)的攻击提供了适度的保护。此外，加入VesiVax(R)CALV(可结合佐剂脂泡)配方中的胆固醇马来酰亚胺(CMI)部分似乎增强了保护作用，以促进目标抗原与脂质体的结合；在这一试验组中，目标抗原尚未与VesiVax(R)CALV结合。保护作用似乎也有时间依赖性，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攻击能产生更有效的保护。基于这些观察，我们设计并实施了一项更有控制的疫苗接种研究，以检查保护作用是否真实存在，并证明添加CMI配体增强了这种作用。我们在VesiVax(R)CALV平台上测试的研究最彻底的IAM是Toll样受体(TLR)4激动剂单磷酰脂A(MPL)。因此，我们在初步研究中使用了MPL作为IAM的模型。我们的结果表明，实际上，在疫苗中没有靶抗原的情况下，可以实现对病原体攻击的显著保护，并且CMI确实提高了保护性免疫反应。我们假设CMI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第一阶段应用程序中，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有潜力被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，我们将在致命流感挑战的近交系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.