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

总结 球孢子菌病，也称为山谷热（VF），影响世界干旱地区的居民，包括 美国西南部，南美洲和中美洲以及墨西哥的地区。年发病率总体上升， 估计近年来在一些地区的增长超过200%。此外，流行病学研究 表明VF的地理范围正在扩大， 这些区域可归因于球虫感染。VF对人类构成重大和持续的威胁 然而，到目前为止，还没有安全有效的疫苗被批准用于VF。因此，有一个迫切的未解决问题， 我们需要研制一种疫苗来预防这种疾病。有证据表明一种有效的疫苗 VF应该是可能的。从VF中恢复的个体通常对再感染具有终身免疫力。 exposure.此外，采用减毒活疫苗策略的早期研究已经证明， 尽管存在严重反应原性的风险，但在小鼠和非人灵长类动物感染模型中具有保护作用 和遗传逆转，用于人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，导致抗原的细胞内表达，模拟免疫原性。 活感染，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使它们成为最前沿的技术。 作为诱导人类保护性免疫的最有效的疫苗策略之一， 目前，高效的许可COVID-19 mRNA疫苗。此外，DNA和RNA疫苗快速 并且简单，只需要给定抗原的遗传序列来设计。建造的简易性和速度 生产DNA和RNA疫苗使它们成为快速筛选大量 潜在的抗原，以鉴定VF疫苗的新型免疫原。在这里，我们建议利用先进的DNA 以及华盛顿大学开发的RNA疫苗输送技术，用于识别新型免疫原 并研究其在动物模型中的免疫原性和功效。为了实现这一目标，在 与研究项目1和2以及动物核心合作，我们建议鉴定一种先导核酸， VF疫苗的疫苗平台（目标1），采用该技术研究候选毒力因子， 假定的T细胞表位作为保护性免疫原来设计先导疫苗组合物， 在小鼠（目的2）和非人灵长类动物（目的3）中的免疫原性、安全性和有效性。如果成功，这些研究 可能导致开发一种新的核酸疫苗，可以提供对山谷热的保护。

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.