Optimizing the formulation of a protein based smallpox vaccine

描述（由申请人提供）：作为对RFA AI-07-003的回应，本提案旨在开发可安全用于不同人群的下一代天花疫苗。我们在选择适当的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重大进展。然而，为了使疫苗达到下一个水平，需要优化疫苗配方并进一步改进疫苗。为了实现这一目标，我们汇集了不同专业领域的研究人员，并发展了来自不同学科和行业的学术研究人员之间的合作。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，但是需要采取许多步骤才能使这种方法达到下一个水平。我们先前开发的大多数基于蛋白质的天花疫苗都是基于牛痘病毒蛋白，基于它们与天花病毒蛋白的高度同源性，可以提供对天花的交叉保护。有理论和实验证据表明，天花病毒蛋白最终可能是产生对天花的保护的更好候选者，因此我们将生产A33、B5和L1的天花病毒同源物。此外，佐剂蛋白的配方也需要优化。现在需要一个迭代和连续的过程，以使疫苗达到下一个水平。为实现这一目标，我们将：产生牛痘病毒A33、B5和L1蛋白（C-PERL）的天花病毒蛋白同源物。优化蛋白/佐剂疫苗配方（U. Kansas）评估，以“棋盘”的方式，优化疫苗配方产生免疫反应和保护免受牛痘病毒攻击小鼠的能力（宾夕法尼亚大学）Aim 4。在非人类灵长类动物模型中检查免疫反应和对猴痘攻击的保护（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)