Optimizing the formulation of a protein based smallpox vaccine

说明(申请人提供)：本提案是对RFA AI-07-003的回应，旨在开发可安全接种给不同人群的下一代天花疫苗。我们在原则证明、选择适当的蛋白质靶标和初步研制以蛋白质为基础的天花疫苗方面取得了很大进展。然而，为了使疫苗更上一层楼，还需要优化疫苗配方，进一步改进疫苗。为了实现这一目标，我们将拥有不同专业领域的研究人员聚集在一起，并在来自不同学科的学术研究人员之间开展合作，并与业界开展合作。我们的假设是，与目前FDA批准的天花活疫苗相比，基于蛋白质的天花疫苗可以更安全地在广泛的接受者中引发保护性反应。虽然我们已经证明了这种方法是可行的，但要将这种方法提升到下一个水平，还需要采取一些步骤。我们之前开发的基于蛋白质的天花疫苗主要是利用痘苗病毒蛋白质，这种蛋白质基于与天花病毒蛋白质的高度同源性，可以提供对天花的交叉保护。有理论和实验证据表明，天花蛋白最终可能是更好的候选蛋白，以产生对天花的保护作用，因此我们将产生A33、B5和L1的天花病毒同源物。此外，含有佐剂的蛋白质的配方还需要优化。现在需要一个迭代和顺序的过程来将疫苗带到下一个水平。为了实现这一目标，我们将：目标1.生产痘苗病毒A33、B5和L1蛋白的天花病毒蛋白同源物(C-Perl)目标2.优化蛋白质/佐剂疫苗配方(U.堪萨斯)目标3.以棋盘式的方式评估优化的疫苗配方在小鼠中产生免疫反应和抵御痘苗病毒攻击的能力(U.Penn)目标4.在非人类灵长类动物模型中检验免疫反应和对猴痘攻击的保护(U.Penn)

DESCRIPTION (provided by applicant): This proposal, in response to RFA AI-07-003, is for the development of a future generation smallpox vaccine that can be safely administered to a diverse population. We have made great strides in the proof-of-principle selection of appropriate protein targets and the initial formulation of a protein-based smallpox vaccine. However, in order to bring the vaccine to the next level, optimization of the vaccine formulation and further improvements of the vaccine are required. To accomplish this, we bring together investigators with different areas of expertise and develop collaborations between academic researchers from different disciplines and with industry. Our hypothesis is that a protein-based smallpox vaccine can more safely elicit a protective response in a broad range of recipients than the current FDA approved live smallpox vaccine. While we have shown that this approach is feasible, there are a number of steps that are needed to bring this approach to the next level. The majority of our prior development of a protein-based smallpox vaccine has been with Vaccinia virus proteins, which based on their high homology to variola virus proteins, could confer cross protection against smallpox. There is theoretical and experimental evidence that variola proteins may ultimately be better candidates to generate protection against smallpox and therefore we will produce the variola virus homologs of A33, B5, and L1. Additionally, the formulation of the proteins with adjuvant needs to be optimized. An iterative and sequential process is now required to bring the vaccine to the next level. To accomplish this we will: Aim 1. Produce the variola virus protein homologs of Vaccinia virus A33, B5, and L1 proteins (C-PERL) Aim 2. Optimize the protein/adjuvant vaccine formulation (U. Kansas) Aim 3. Evaluate, in a "checkerboard" fashion, the ability of the optimized vaccine formulation to generate immune responses and protect from Vaccinia virus challenge in mice (U. Penn) Aim 4. Examine immune responses and protection from monkeypox challenge in a non-human primate model (Southern Research Institute)