An Avirulent Arthroconidial Vaccine Candidate to Prevent Human Coccidioidomycosis

摘要 球孢子菌病(谷热)是一种由真菌、球孢子虫或球虫引起的系统性感染。 Posadasii球虫，是亚利桑那州、加利福尼亚州和美国其他地区特有的。疾病 范围从肺炎到危及生命的传播到身体其他部位(播散性感染)， 包括大脑。山谷热平均每年导致160人死亡，并造成20亿美元的 2000-2011年的住院费。目前的治疗方法不能治愈，可能需要继续治疗 生活。这项提议是对明确邀请球虫疫苗的RFA-AI-16-034的响应。 我们的候选疫苗似乎1)安全，2)高效，3)商业生产可行。它是 基于从真菌中删除CPS1基因，导致小鼠完全丧失毒力。 当用作实验小鼠球孢子菌病的疫苗时，它具有很强的保护性。疫苗 候选菌(∆cps 1)是通过在固体培养基上简单地生长节孢子来“制造”的，因此商品成本 可能会很低，这使得商业开发变得可行。我们建议开发我们的候选疫苗 第一个预防狗患谷热病的药物。这将为其安全性和有效性提供临床前信息 大型动物，并进一步支持FDA对人类的IND。具体目标是首先利用真菌基因 分析CPS1突变，以确定为什么它对毒力是必不可少的。对ITS的全面了解 在这种真菌中的作用可以更好地评估其作为活疫苗的安全性。第二，我们将 开发一种既适用于狗也适用于人类的配方。第三，我们将准确地确定哪些 淋巴细胞亚群及其细胞因子介导保护作用。这些信息将对Rational 在免疫狗和人类中鉴定未来的保护替代标志物。最后，我们将发展 犬球虫感染模型的建立及其对∆cps1预防作用的实验研究 疾病。 除了本申请中建议的研究外，我们还确定了一个行业合作伙伴Anivive 生命科学，它已同意与我们合作，并将提供额外的投资和专业知识 研发一种兽医疫苗。我们相信，随着这一计划的成功，开发我们的疫苗的风险 人类的候选者将大幅减少，以至于即将进行进一步的投资 完成我们工作的最终目标。

Abstract Coccidioidomycosis (Valley Fever) is a systemic infection caused by the fungi, Coccidioides immitis or Coccidioides posadasii, which are endemic to Arizona, California and other parts of the United States. Illness ranges from pneumonia to life-threatening spread to other parts of the body (disseminated infection), including the brain. Valley Fever causes an average of 160 deaths annually, and produced $2 billion in hospital charges from 2000 – 2011. Current therapies are not curative and may be need to be continued for life. This proposal responds to RFA-AI-16-034 which explicitly invites vaccines for Coccidioides spp. Our vaccine candidate appears i) safe, ii) highly effective, and iii) feasible to produce commercially. It is based upon a deletion of the CPS1 gene from the fungus, resulting in complete loss of virulence in mice. When used as a vaccine against experimental murine coccidioidomycosis, it is very protective. The vaccine candidate (∆cps1) is “manufactured” by simply growing arthroconidia on solid media and so the cost of goods is likely to be low, making commercial development feasible. We propose to develop our vaccine candidate first to prevent Valley Fever in dogs. This will provide pre-clinical information for its safety and efficacy in a large animal and further support an FDA IND for humans. The specific aims are to first use fungal genetic analysis of the CPS1 mutation to determine why it is essential for virulence. A complete understanding of its role in the fungus could provide a better assessment about its safety as a live vaccine. Second, we will develop a formulation that would be used in both dogs and humans. Third, we will determine exactly which lymphocyte subsets and their cytokines mediate protection. This information will be useful for the rational identification of future surrogate markers of protection in immunized dogs and humans. Finally, we will develop an experimental model of coccidioidal infection in canines and use it to test the efficacy of ∆cps1 to prevent disease. In addition to the studies proposed in this application, we have identified an industrial partner, Anivive Lifesciences, that has agreed to partner with us and will provide additional investment and expertise to fully develop a veterinary vaccine. We believe that with the success of this program, risk of developing our vaccine candidate for humans will be substantially reduced to the point that further investment will be forthcoming to complete the ultimate objective of our work.