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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

基本信息

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
项目类别：
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

项目摘要

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.