Preclinical studies of a Cryptococcus vaccine for AIDS patients

 描述（由申请人提供：新型隐球菌和密切相关的隐球菌。格特病是艾滋病患者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，许多幸存者留下永久性损害。人们在吸入肺部后暴露于真菌;在免疫系统正常的人中，感染得到解决或控制。然而，在细胞介导免疫缺陷的患者中，特别是艾滋病，C。新型脑膜炎病毒具有生长和传播的倾向，特别是传播到中枢神经系统，在中枢神经系统中引起致命的脑膜脑炎。即使有抗真菌治疗，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，但临床开发中没有候选疫苗。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，也可能过于昂贵，无法在资源匮乏的环境中使用。我们已经创造了一种候选的低成本疫苗，由高度减毒的三重缺失C组成。缺乏细胞壁壳聚糖的新生菌菌株。值得注意的是，用这种壳聚糖缺陷型菌株接受单次肺部接种的小鼠被保护免受野生型C的高毒性菌株的强烈攻击。新人类重要的是，疫苗株能迅速从严重免疫功能低下小鼠的肺部清除，即使在热灭活时也能保持其保护能力。在这项R 01申请中，我们寻求进一步表征壳聚糖缺陷菌株作为潜在疫苗候选菌株的特征，探索保护机制，并确定这种保护作用是否会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，我们将进一步表征疫苗接种方案，确定减毒株的保护特性，开发具有更广泛保护的疫苗，并检查疫苗的安全性和持久性。在目标2中，我们将探索免疫活性小鼠的保护机制。我们将确定先天、细胞和体液免疫防御的贡献。在目标3中，我们将检查CD 4 + T细胞缺陷小鼠的保护作用，以确定疫苗接种是否对获得艾滋病的患者有效。 我们将建立何时接种疫苗的模型，并确定免疫活性小鼠和免疫缺陷小鼠之间的保护机制是否不同。我们预计，到资助期结束时，我们将完成一种新型疫苗候选物在小鼠中的表征，以保护免受隐球菌病的侵害。如果这些研究成功，正如我们的初步数据所表明的那样，下一步将是在其他动物模型中进行进一步的临床前安全性和有效性研究，然后将其商业化以进行人体测试。

 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.