An Avirulent Arthroconidial Vaccine Candidate to Prevent Human Coccidioidomycosis

一种预防人类球孢子菌病的无毒节分孢子疫苗候选物

基本信息

批准号：
9360833
负责人：
JOHN N GALGIANI
金额：
$ 137.12万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-07 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360833
关键词：
Address Animals Antibiotic Resistance Antifungal Therapy Arizona Attenuated Attenuated Vaccines Award Bacterial Vaccines Body part Brain Breathing CYP21A2 gene California Canis familiaris Cessation of life Clinical Distribution Clinical Trials Coccidioides Coccidioides immitis Coccidioides posadasii Coccidioidomycosis Development Development Plans Disease Experimental Models Failure Formulation Future Generations Genes Goals Healthcare Hospital Charges Human Immune system Immunity Immunize Immunologics Industrialization Infection Investments Lead Licensure Life Lymphocyte Subset Mediating Mus Mutation Mycoses Pathogenicity Pneumonia Productivity Reproduction spores Risk Role Running Rupture Safety Solid Structure Surrogate Markers Suspensions Systemic infection Time TimeLine United States Vaccines Viral Vaccines Virulence Work base cost cytokine desert fever efficacy testing experience fungal genetics fungus genetic analysis human disease hygromycin A in vivo mutant pathogen pre-clinical prevent programs resistance gene response success vaccine candidate vaccine development

项目摘要

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.

抽象的球孢子菌病（谷热）是由真菌、粗球孢子菌或 Coccidioides posadasii，是亚利桑那州、加利福尼亚州和美国其他地区的地方病。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），谷热每年平均导致 160 人死亡，并产生 20 亿美元的收入。 2000 年至 2011 年期间的住院费用。目前的治疗方法没有疗效，可能需要继续治疗该提案是对 RFA-AI-16-034 的回应，该提案明确邀请球孢子菌疫苗。我们的候选疫苗看起来 i) 安全，ii) 高效，并且 iii) 商业化生产可行。基于从真菌中删除 CPS1 基因，导致小鼠的毒力完全丧失。当用作实验性鼠球孢子菌病疫苗时，它具有很强的保护作用。候选物（Δcps1）是通过在固体培养基上简单地生长节孢子来“制造”的，因此商品成本可能很低，因此我们建议开发我们的候选疫苗。首先用于预防狗的山谷热，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 的人类 IND 的具体目标是首先使用真菌遗传。分析 CPS1 突变以确定其为何对其毒力至关重要。其次，我们将在真菌中发挥作用，从而更好地评估其作为活疫苗的安全性。第三，我们将开发一种既适用于狗又适用于人类的配方。淋巴细胞亚群及其细胞因子介导的保护作用将有助于理性的研究。最后，我们将开发免疫狗和人类的未来保护替代标记。犬类球孢子菌感染的实验模型，并用它来测试 Δcps1 预防的功效疾病。除了本申请中提出的研究之外，我们还确定了工业合作伙伴 Anivive Lifesciences 已同意与我们合作，并将提供额外的投资和专业知识，以充分我们相信，随着该计划的成功，开发我们疫苗的风险。人类的候选者将大幅减少，以至于需要进一步的投资完成我们工作的最终目标。