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: 9222705
• 负责人: Stuart Michael Levitz
• 金额: $ 64.43万
• 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/9222705
• 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; CD8-Positive T-Lymphocytes; Cell Wall; Cellular Immunity; Characteristics; Chitosan; Clinical; Country; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Defect; Development; Efferent Pathways; Funding; HIV; Human; Immune; Immune system; Immunize; Immunocompetent; Immunocompromised Host; Immunodeficient Mouse; Impairment; Inactivated Vaccines; Infection; Left; Life; Lung; Mediating; Meningoencephalitis; Modeling; Mus; Mycoses; Nature; Neuraxis; Opportunistic Infections; Organ Transplantation; Pathogenicity; Patients; Persons; Populations at Risk; Preventive vaccine; Protocols documentation; Public Health; Resources; Risk; Safety; Serum; Subunit Vaccines; Survivors; T-Lymphocyte; Testing; Toxic effect; Vaccinated; Vaccination; Vaccines; Virulent; adaptive immunity; chemokine; chemotherapy; clinical development; commercialization; cost; cytokine; efficacy study; fungus; killings; mortality; mouse model; mutant; novel vaccines; patient population; pre-clinical; preclinical safety; preclinical study; public health relevance; response; safety study; 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(申请人提供：新生隐球菌属和与之密切相关的加蒂亚氏菌是艾滋病患者中危及生命的机会性感染的主要原因。例如，据估计，在撒哈拉以南非洲，每年约有60万人死于隐球菌病，许多幸存者永久受损。人们在吸入肺部后接触到这种真菌；在免疫系统正常的人中，感染得到了缓解或控制。然而，在细胞免疫缺陷的患者中，特别是艾滋病患者，新生梭菌有生长和传播的倾向，特别是在中枢神经系统，在那里它会导致致命的脑膜脑炎。即使进行了抗真菌治疗，死亡率也徘徊在30%左右。尽管向高危人群提供有效的预防性疫苗将对全球公共卫生产生重大有益影响，但目前还没有用于临床开发的候选疫苗。努力主要集中在亚单位疫苗和保护性抗体上，这些方法即使成功，在资源匮乏的环境中使用也可能过于昂贵。我们已经创造了一种候选的低成本疫苗，由一种高度减毒的三重缺失新生葡萄球菌菌株组成，该菌株缺乏细胞壁壳聚糖。值得注意的是，只接受一次肺部接种这种壳聚糖缺乏菌株的小鼠，可以抵抗一种高度毒力的野生型新生葡萄球菌的强大挑战。重要的是，疫苗毒株可以迅速从免疫严重受损的小鼠的肺部清除，并保持其保护能力，即使在热死的情况下也是如此。在R01的应用中，我们寻求进一步表征壳聚糖缺乏的菌株作为潜在的候选疫苗，探索保护机制，并确定这种保护是否将在模拟晚期艾滋病发展的临床前动物模型中表达。有三个具体目标。在目标1中，我们将进一步确定疫苗接种方案的特点，确定减毒株的保护特性，开发具有更广泛保护作用的疫苗，并检查疫苗的安全性和持久性。在目标2中，我们将探索其在免疫活性小鼠中的保护机制。我们将确定先天免疫、细胞免疫和体液免疫的作用。在目标3中，我们将检查对患有CD4+T细胞缺陷的小鼠的保护作用，以确定疫苗接种是否对感染艾滋病的患者有效。 我们将模拟何时应该接种疫苗，并确定免疫能力和免疫缺陷小鼠之间的保护机制是否不同。我们预计，在资助期结束时，我们将在小鼠身上完成一种新的候选疫苗的鉴定，以预防隐球菌病。如果这些研究成功，正如我们的初步数据显示的那样，下一步将是进一步在其他动物模型上进行临床前安全性和有效性研究，然后商业化以在人类身上进行测试。