Early in vivo expressed antigens and their role in virulence, immune response, and vaccines for coccidioidomycosis

早期体内表达的抗原及其在球孢子菌病毒力、免疫反应和疫苗中的作用

• 批准号: 10356630
• 负责人: Deborah H. Fuller
• 金额: $ 44.28万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356630
• 关键词: 2019-nCoV; Animal Model; Animals; Antibodies; Antigen Presentation; Antigens; Area; Attenuated Vaccines; Biotechnology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19; Cellular Immunity; Central America; Clinical; Clinical Research; Clinical Trials; Coccidioides; Coccidioidomycosis; Collaborations; Communicable Diseases; DNA; DNA Vaccines; Development; Disease; Exhibits; Genes; Genetic; Geography; Goals; Health; Human; Humoral Immunities; Immune; Immune response; Immunity; Incidence; Individual; Infection; Influenza; Lead; MHC Class I Genes; Macaca nemestrina; Mexico; Modeling; Mucous Membrane; Mus; Nucleic Acid Vaccines; Nucleic Acids; Pathogenesis; Play; Pneumonia; Pre-Clinical Model; Predisposition; Proteins; RNA; RNA vaccine; Rapid screening; Regimen; Research Project Grants; Risk; Role; Safety; South America; Speed; T cell response; T-Lymphocyte Epitopes; Technology; Universities; Vaccination; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; Washington; base; community acquired pneumonia; desert fever; design; epidemiology study; experimental study; high risk; immunogenic; immunogenicity; in vivo; influenza virus vaccine; lead candidate; mouse model; nonhuman primate; novel; pre-clinical; protective efficacy; success; tool; vaccination outcome; vaccine candidate; vaccine delivery; vaccine development; vaccine platform; vaccine strategy; vaccine trial

SUMMARY Coccidioidomycosis, also known as Valley Fever (VF) impacts residents in arid regions of the world including southwestern US, areas in South and Central America and in Mexico. Annual incidences are rising overall with estimated increases in recent years of more than 200% in some areas. In addition, epidemiological studies indicate that the geographical range of VF is expanding and up to 17-29% of community-acquired pneumonia in these areas can be attributed to Coccidiodes infections. VF poses a significant and ongoing threat to human health, but to date, there is no safe and effective vaccine licensed for VF. As such, there is an urgent unmet need to develop a vaccine that can provide protection from the disease. Evidence suggests an effective vaccine for VF should be possible. Individuals who recover from VF will generally have lifelong immunity against re- exposure. Furthermore, early studies employing live attenuated vaccine strategies have demonstrated significant protection in mouse and nonhuman primate models of infection although due to the risk of severe reactogenicity and genetic reversion, a live attenuated vaccine for human use is not considered a viable approach. Nucleic acid vaccines, including both DNA and RNA vaccines, result in the intracellular expression of antigens, mimicking a live infection including induction of robust antibody and T cell responses, but without the risks associated with a live infection. Recent advances with both DNA and mRNA vaccine technologies have moved them to the forefront as one of the most effective vaccines strategies to induce protective immunity in humans, as evident by the current, highly efficacious licensed COVID-19 mRNA vaccines. In addition, DNA and RNA vaccines are rapid and simple, requiring only the genetic sequence of a given antigen to design. The ease and speed in constructing and producing DNA and RNA vaccines makes them an ideal tool to enable rapid screening of a large number of potential antigens to identify novel immunogens for a VF vaccine. Here, we propose to leverage advanced DNA and RNA vaccine delivery technologies developed at the University of Washington to identify novel immunogens for a VF vaccine and to investigate their immunogenicity and efficacy in animal models. Toward this goal, in collaboration with Research Projects 1 and 2 and the Animal Core, we propose to identify a lead nucleic acid vaccine platform for a VF vaccine (Aim 1), employ that technology to investigate candidate virulence factors and putative T cell epitopes as protective immunogens to design a lead vaccine composition that affords optimum immunogenicity, safety and efficacy in mice (Aim 2) and nonhuman primates (Aim 3). If successful, these studies could lead to development of a novel nucleic acid vaccine that can provide protection from Valley Fever.

概括 球虫菌病，也称为山谷发烧（VF），影响了世界干旱地区的居民 美国西南部，南美洲和中美洲以及墨西哥地区。年度事件的总体上升 近年来，估计在某些领域的增长超过200％。此外，流行病学研究 表明VF的地理范围正在扩大，最多可占社区获得的肺炎的17-29％ 这些区域可以归因于Coccidiodes感染。 VF对人构成了重大且持续的威胁 健康，但迄今为止，尚无对VF许可的安全有效的疫苗。因此，有一个紧急的未安装 需要开发一种可以保护疾病的疫苗。证据表明有效的疫苗 因为VF应该是可能的。从VF中恢复过来的个人通常会终身免疫。 接触。此外，采用活衰减疫苗策略的早期研究表明 尽管有严重的反应性风险 和遗传回归，一种用于人类使用的活疫苗被视为一种可行的方法。核酸 疫苗，包括DNA和RNA疫苗，导致抗原的细胞内表达，模仿A 实时感染包括诱导鲁棒抗体和T细胞反应，但没有与A相关的风险 现场感染。 DNA和mRNA疫苗技术的最新进展已将其移至最前沿 作为诱导人类保护性免疫的最有效的疫苗策略之一， 电流，高效的许可共vid-19 mRNA疫苗。另外，DNA和RNA疫苗很快 简单，仅需要给定抗原设计的遗传序列。构造的易度和速度 并产生DNA和RNA疫苗使其成为快速筛选大量筛查的理想工具 潜在的抗原鉴定VF疫苗的新型免疫原。在这里，我们建议利用先进的DNA 在华盛顿大学开发的RNA疫苗输送技术以识别新型免疫原 用于VF疫苗并研究其在动物模型中的免疫原性和功效。朝着这个目标， 与研究项目1和2和动物核心合作，我们建议识别铅核酸 VF疫苗的疫苗平台（AIM 1）采用该技术来调查候选毒力因素和 推定的T细胞表位为保护性免疫原，以设计提供最佳的铅疫苗成分 小鼠的免疫原性，安全性和功效（AIM 2）和非人类灵长类动物（AIM 3）。如果成功，这些研究 可能导致一种新型核酸疫苗的发展，该核酸疫苗可提供免受山谷热的保护。