Preclinical studies of a Cryptococcus vaccine for AIDS patients

针对艾滋病患者的隐球菌疫苗的临床前研究

• 批准号: 9140479
• 负责人: Stuart Michael Levitz
• 金额: $ 65.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-11 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140479
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Adoptive Transfer; Afferent Pathways; Africa South of the Sahara; Animal Model; Antibodies; Antibody Response; Antifungal Therapy; Attenuated; Breathing; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Wall; Cellular Immunity; Characteristics; Chitosan; Clinical; Country; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Defect; Development; Efferent Pathways; Funding; HIV; Heating; Human; Immune; Immune system; Immunocompetent; Immunocompromised Host; Immunodeficient Mouse; Inactivated Vaccines; Infection; Left; Life; Lung; Mediating; Meningoencephalitis; Modeling; Mus; Mycoses; Nature; Neuraxis; Opportunistic Infections; Organ Transplantation; Patients; Persons; Populations at Risk; Preventive vaccine; Protocols documentation; Public Health; Resources; Risk; Safety; Serum; Staging; Subunit Vaccines; Survivors; T-Lymphocyte; Testing; Toxic effect; Vaccinated; Vaccination; Vaccines; Virulent; adaptive immunity; base; chemokine; chemotherapy; commercialization; cost; cytokine; fungus; killings; mortality; mouse model; mutant; novel vaccines; patient population; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; public health relevance; response; vaccine candidate; vaccine development; vaccine safety

 DESCRIPTION (provided by applicant: Cryptococcus neoformans and the closely related C. gattii are major causes of life-threatening opportunistic infection in persons with AIDS. For example, it has been estimated that in Sub-Saharan Africa, ~600,000 people die annually from cryptococcosis and many survivors are left permanently impaired. People are exposed to the fungus following inhalation into the lungs; in those with normal immune systems, the infection is resolved or contained. However, in patients with defects in cell-mediated immunity, particularly AIDS, C. neoformans has a propensity to grow and disseminate, particularly to the central nervous system where it causes a fatal meningoencephalitis. Even with antifungal therapy, mortality hovers around 30%. Although an effective preventative vaccine given to at risk populations would have a major salutary impact on global public health, there are no candidate vaccines in clinical development. Efforts have mostly focused on subunit vaccines and protective antibodies, approaches that even if successful likely would be too costly to use in resource-poor settings. We have created a candidate low-cost vaccine consisting of a highly attenuated triple deletion C. neoformans strain that lacks cell wall chitosan. Remarkably, mice receiving a single pulmonary inoculation with this chitosan-deficient strain are protected against a robust challenge with a highly virulent strain of wild type C. neoformans. Importantly, the vaccine strain is rapidly cleared from the lungs of severely immunocompromised mice and retains its capacity to protect even when heat-killed. In this R01 application, we seek to further characterize the chitosan-deficient strain as a potential vaccine candidate, to explore the mechanisms of protection, and to determine if the protection will be expressed in preclinical animal models that mimic the development of late stage AIDS. There are three specific aims. In Aim 1, we will further characterize the vaccination protocol, determine the protective characteristics of the attenuated strain, develop a vaccine with broader protection, as well as examine the safety and durability of the vaccine. In Aim 2, we will explore the mechanisms of protection in immunocompetent mice. We will determine the contributions of the innate, cellular and humoral immune defenses. In Aim 3, we will examine the protection in mice with CD4+ T cell deficiencies to determine if the vaccination could be effective in patients that acquire AIDS. We will model when the vaccine should be administered and determine if the mechanisms of protection differ between immunocompetent and immunodeficient mice. We anticipate that by the end of the funding period, we will have completed the characterization in mice of a novel vaccine candidate to protect against cryptococcosis. If these studies are successful, as our preliminary data suggest they will be, the next steps will be further preclinical safety and efficay studies in other animal models and then commercialization to test in humans.

 描述（应用程序提供：Neoformans和密切相关的C. gattii是艾滋病患者威胁生命的机会感染的主要原因。例如，据估计，在撒哈拉以南非洲，每年约有600,000人死亡，遭受了这些习惯的习惯，这些人会遭受永久性的生存。但是，在细胞介导的免疫抑制作用（尤其是艾滋病）中，感染已解决或包含。健康，临床开发中没有候选疫苗。我们创建了一种候选低成本疫苗，该疫苗由缺乏细胞壁壳聚糖的高度减弱三重缺失C. Neoformans菌株。值得注意的是，通过这种缺陷型菌株接收单肺接种的小鼠受到野生型C. Neoformans的高毒性菌株的强大挑战。重要的是，从严重免疫力低下的小鼠的肺中迅速清除了疫苗菌株，即使在热杀死时，也保留其保护能力。在此R01应用中，我们试图进一步将壳聚糖缺陷株作为潜在的疫苗候选者，探索保护机理，并确定在模仿后期艾滋病发展的临床前动物模型中是否会表达保护。有三个特定的目标。在AIM 1中，我们将进一步表征疫苗方案，确定衰减菌株的保护特性，开发具有更广泛保护的疫苗，并检查疫苗的安全性和耐用性。在AIM 2中，我们将探索免疫能力小鼠的保护机制。我们将确定先天，细胞和体液免疫防御的贡献。在AIM 3中，我们将检查CD4+ T细胞缺陷的小鼠的保护，以确定该疫苗是否对获得艾滋病的患者有效。 我们将建模何时应施用疫苗并确定保护机制在免疫能力和免疫缺陷的小鼠之间是否有所不同。我们预计，到资金期结束时，我们将在新型疫苗候选者的小鼠中完成表征，以防止隐孢子蛋白。如果这些研究成功，正如我们的初步数据所表明的那样，下一步将是其他动物模型中的临床前安全性和有效研究，然后是商业化以在人类中进行测试。