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

基本信息

批准号：
10689691
负责人：
Deborah H. Fuller
金额：
$ 38.42万
依托单位：
NORTHERN ARIZONA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10689691
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 Genetic Geography Goals Health Human Humoral Immunities Immune Immune response Immunity Immunologic Stimulation Incidence Individual Infection Influenza Lead Licensing 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 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 virulence gene

项目摘要

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.

概括球孢子菌病，也称为谷热 (VF)，影响世界干旱地区的居民，包括美国西南部、南美洲和中美洲地区以及墨西哥。每年的发病率总体呈上升趋势据估计，近年来一些地区的增幅超过200%。此外，流行病学研究表明 VF 的地理范围正在扩大，社区获得性肺炎的比例高达 17-29% 这些区域可归因于球孢子菌感染。 VF 对人类构成重大且持续的威胁健康，但迄今为止，还没有安全有效的疫苗获得许可用于治疗 VF。因此，有一个紧迫的未满足的问题需要开发一种可以提供针对该疾病的保护的疫苗。有证据表明有有效的疫苗 VF 应该是可能的。从心室颤动中康复的个体通常具有终生免疫力接触。此外，采用减毒活疫苗策略的早期研究已证明显着尽管存在严重反应原性的风险，但对小鼠和非人类灵长类动物感染模型具有保护作用和基因逆转，人类使用的减毒活疫苗不被认为是可行的方法。核酸疫苗，包括 DNA 和 RNA 疫苗，会导致抗原在细胞内表达，模仿活体感染，包括诱导强大的抗体和 T 细胞反应，但没有与感染相关的风险活感染。 DNA 和 mRNA 疫苗技术的最新进展已将其推向最前沿作为诱导人类保护性免疫力的最有效疫苗策略之一，这一点显而易见目前获得许可的高效 COVID-19 mRNA 疫苗。此外，DNA和RNA疫苗的速度很快而且简单，只需要设计给定抗原的基因序列。施工的简便性和速度生产 DNA 和 RNA 疫苗使其成为快速筛选大量病毒的理想工具识别 VF 疫苗新型免疫原的潜在抗原。在这里，我们建议利用先进的 DNA 华盛顿大学开发的 RNA 疫苗递送技术，用于识别新型免疫原开发 VF 疫苗并研究其在动物模型中的免疫原性和功效。为了这个目标，在与研究项目 1 和 2 以及动物核心合作，我们建议鉴定先导核酸 VF 疫苗的疫苗平台（目标 1），利用该技术研究候选毒力因子并推定的 T 细胞表位作为保护性免疫原，设计可提供最佳效果的先导疫苗组合物在小鼠（目标 2）和非人灵长类动物（目标 3）中的免疫原性、安全性和有效性。如果成功的话，这些研究可能会导致开发出一种新型核酸疫苗，可以提供针对谷热的保护。