Optimizing the formulation of a protein based smallpox vaccine

优化基于蛋白质的天花疫苗的配方

• 批准号: 7454535
• 负责人: Stuart N. Isaacs
• 金额: $ 53.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454535
• 关键词: Adjuvant; Adverse effects; Africa; Area; Bioterrorism; Collaborations; Development; Discipline; Drug Formulations; Environment; Event; Funding Mechanisms; Future Generations; GPA33 gene; HIV Infections; Homologous Gene; Homologous Protein; Immune response; Immunosuppression; Industry; Kansas; Life; Modeling; Monkeypox; Mus; National Institute of Allergy and Infectious Disease; Numbers; Population; Population Heterogeneity; Process; Protein C; Proteins; Range; Research; Research Institute; Research Personnel; Smallpox; Smallpox Vaccine; Smallpox Viruses; Therapeutic immunosuppression; United States Food and Drug Administration; Vaccine Adjuvant; Vaccines; Vaccinia virus; Viral Proteins; base; biodefense; nonhuman primate; response

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)

描述（由申请人提供）：该提案是针对 RFA AI-07-003 的回应，旨在开发可以安全地对不同人群施用的下一代天花疫苗。我们在适当蛋白质靶标的原理验证选择和基于蛋白质的天花疫苗的初始配方方面取得了巨大进步。然而，为了使疫苗更上一层楼，还需要优化疫苗配方并进一步改进疫苗。为了实现这一目标，我们汇集了具有不同专业领域的研究人员，并发展了来自不同学科的学术研究人员和行业之间的合作。我们的假设是，与目前 FDA 批准的活天花疫苗相比，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，但需要采取许多步骤才能将该方法提升到新的水平。我们之前开发的基于蛋白质的天花疫苗大部分都是使用痘苗病毒蛋白，由于其与天花病毒蛋白的高度同源性，可以提供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天花保护的更好候选者，因此我们将生产 A33、B5 和 L1 的天花病毒同源物。此外，需要优化蛋白质与佐剂的配方。现在需要一个迭代和连续的过程来将疫苗提升到一个新的水平。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/佐剂疫苗配方（美国堪萨斯州） 目标 3. 以“棋盘”方式评估优化的疫苗配方在小鼠中产生免疫反应并防止痘苗病毒攻击的能力 （美国宾夕法尼亚大学）目标 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）