Optimizing the formulation of a protein based smallpox vaccine

描述（由申请方提供）：本提案是对RFA AI-07-003的回应，旨在开发可安全用于不同人群的下一代天花疫苗。我们在选择适当蛋白质靶点的原理验证和基于蛋白质的天花疫苗的初步配方方面取得了很大进展。然而，为了使疫苗更上一层楼，需要优化疫苗配方和进一步改进疫苗。为了实现这一目标，我们汇集了具有不同专业领域的研究人员，并在来自不同学科的学术研究人员和行业之间开展合作。我们的假设是，基于蛋白质的天花疫苗可以比目前FDA批准的活天花疫苗更安全地在广泛的接受者中引起保护性反应。虽然我们已经证明这种方法是可行的，但需要采取一些步骤才能使这种方法更上一层楼。我们先前开发的基于蛋白质的天花疫苗的大部分是使用牛痘病毒蛋白，基于其与天花病毒蛋白的高度同源性，牛痘病毒蛋白可以赋予针对天花的交叉保护。有理论和实验证据表明，天花蛋白最终可能是产生对天花的保护的更好的候选者，因此我们将产生A33，B5和L1的天花病毒同源物。此外，需要优化蛋白质与佐剂的制剂。现在需要一个迭代和连续的过程，使疫苗达到下一个水平。为了实现这一目标，我们将：目标1。生产牛痘病毒A33、B5和L1蛋白的天花病毒蛋白同源物（C-PERL）目的2.优化蛋白/佐剂疫苗配方（U。（堪萨斯）目标3.以“棋盘”方式评估优化疫苗制剂在小鼠中产生免疫应答和保护免受牛痘病毒攻击的能力（U.第四章.在非人灵长类动物模型中检查猴痘攻击的免疫应答和保护（南方研究所）

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)