Immune Response to Cryptococcal Infections

对隐球菌感染的免疫反应

• 批准号: 8963535
• 负责人: Stuart Michael Levitz
• 金额: $ 49.25万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963535
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Adoptive Transfer; Antibodies; Antibody Response; Antigens; Attenuated; Attenuated Vaccines; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Carbohydrates; Carrier Proteins; Cell Wall; Cell physiology; Cells; Combined Vaccines; Conjugate Vaccines; Cryptococcal Meningitis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans infection; Development; Diphtheria Toxoid; Disease; Drug Formulations; Encapsulated; Endemic Diseases; Escherichia coli; Funding; Glucans; Goals; Graft Rejection; HIV; Health Priorities; Hematologic Neoplasms; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Incidence; Infection; Left; Link; Mass Spectrum Analysis; Mediating; Modeling; Mus; Neurologic; Pacific Northwest; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Polysaccharides; Populations at Risk; Preclinical Testing; Proteins; Proteome; Recombinants; Risk Factors; Role; Site; Survivors; T cell response; T-Lymphocyte; TNFRSF10A gene; Testing; Transgenic Mice; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Yeasts; arm; design; disability; fungus; global health; immunoreactivity; immunosuppressed; killings; mortality; novel vaccines; particle; polyglucosan; pre-clinical; prevent; public health relevance; response; vaccine candidate; vaccine development; vaccine evaluation; vaccine response; vaccine-induced immunity

 DESCRIPTION (provided by applicant): Cryptococcal meningitis, due to the encapsulated yeast C. neoformans (Cn), is estimated to kill over 600,000 people annually. Most victims have compromised CD4+ T cell function. A closely related species, C. gattii (Cg), causes endemic disease in persons who generally have mild or no immunocompromise. Development of a vaccine to protect against cryptococcosis is a global health priority. The goal of this project is the preclinical development of candidate vaccines to protect at risk populations from cryptococcosis. We hypothesize such a vaccine will have a subunit formulation and consist of cryptococcal antigens (Ags) delivered with adjuvant(s) that stimulate strong and durable T cell and antibody (Ab) responses. Aim 1 is to synthesize candidate cryptococcal vaccine Ags and test the Ags for immunoreactivity. In preliminary studies, we have obtained 100% protection against lethal cryptococcosis by vaccinating mice with glucan particles (GPs) containing alkaline extracts derived from Cn. The proteome of the protective extract has been defined; however, it is not known which Ags are responsible for protection. In Aim 1A, Ags in the extracts will be recombinantly expressed and tested for their capacity to stimulate ex vivo CD4-biased T cell responses using cells from vaccinated mice and cryptococcosis patients. It is recognized that vaccine-mediated protection can involve arm(s) of the immune system that do not have a predominant role in natural infection. In Aim 1B, GXM, the major capsular component of Cn, will be conjugated to diphtheria toxoid. This is predicted to convert the glycan into a potent immunogen capable of eliciting protective Ab responses. Aim 2 is to formulate candidate cryptococcal vaccines and perform preclinical testing. By the end of Aim 1, we anticipate we will have identified ~10 Cn Ags that stimulate T cell responses and we will have made conjugate vaccines that stimulate Ab responses against GXM. In Aim 2A, we will determine which of these candidate Ags stimulate protective responses in models of cryptococcosis. In Aim 2B, we will optimize Ag combinations and vaccine formulations, including testing GPs and CpG alone and in combination. The durability of protection will be explored. In Aim 2C, we will explore the immune mechanisms of vaccine-induced protection. In Aim 2D, recognizing that AIDS is the major risk factor for cryptococcosis, the effect of CD4-depletion on CD8+ and Ab vaccine responses will be defined. Finally, in Aim 2E, we will test whether vaccine-mediated protection can be achieved against Cg infections. We anticipate that at the end of the funding period, we will have created candidate vaccines capable of eliciting robust and durable Ag-specific Ab and Th1-biased responses that protect mice against challenge with Cn and Cg. The studies address an NIH-identified need for development of cryptococcal vaccines and should establish proofs of principle applicable to other vaccine-preventable diseases, particularly those for which T cell defenses are paramount.