Development of a novel PCP Vaccine for AIDS patients

为艾滋病患者开发新型 PCP 疫苗

• 批准号: 8210723
• 负责人: A. Ray Chaudhuri
• 金额: $ 29.87万
• 依托单位: MINIVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210723
• 关键词: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Adenoviruses; Adjuvant; Antibody Formation; Antigens; Attenuated Vaccines; CD4 Positive T Lymphocytes; Chronic Obstructive Airway Disease; Clinical Data; Complication; DNA; Data; Development; Foundations; Future; Goals; HIV; HIV Infections; Human; Immune response; Immunization; Immunocompetent; Immunologic Deficiency Syndromes; Individual; Infection; Lead; Legal patent; Lung; Lung diseases; Macaca; Macaca mulatta; Modeling; Molecular; Mucosal Immunity; Mus; Organ Transplantation; Patients; Peripheral; Pneumocystis; Predisposition; Proteins; Recombinants; Regimen; SIV; Small Business Technology Transfer Research; Solid; TNFSF5 gene; Testing; Transplant Recipients; Vaccination; Vaccines; Validation; aluminum sulfate; base; cohort; comparative efficacy; immunogenicity; kexin; nonhuman primate; novel; novel strategies; novel vaccines; pathogen; pre-clinical; protective efficacy; research study; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): Pulmonary infection with the fungal pathogen, Pneumocystis jirovecii, is a common and often fatal complication of HIV infection/AIDS. Emerging data suggest that Pneumocystis may also complicate lung diseases in non-HIV infected hosts including those with COPD and solid organ transplant recipients. The long-term goal of this project is to develop a vaccine against Pneumocystis. To that end, we have identified a novel vaccine candidate for Pneumocystis termed mini-kexin. We have shown DNA vaccination with mini-kexin followed by mucosal boosting generates robust pulmonary immune responses and provides protective efficacy against Pneumocystis challenge in mice. Furthermore, the use of CD40L as a molecular adjuvant allows for protective antibody responses in CD4+ T cell-deficient mice, a model the closely replicates the immunodeficiency and susceptibility to PCP in AIDS. Based on these data LSUHSC has filed a provisional patent and a PCT on mini-kexin as a PCP vaccine. This STTR under MiniVax will be used to perform further lead optimization and investigate immunogenicity of mini-Kexin in SIV-infected macaques. We hypothesize that prime/boost vaccination with mini-kexin will result in antigen specific antibody responses that are protective against PC challenge on the mouse and that co-administration of CD40L with mini-kexin vaccination will provide effective systemic and mucosal antibody responses in the setting of low peripheral CD4+ T-cells, using a simian model of AIDS. We will first perform lead optimization of the vaccine platform in mice and then conduct an immunogenicity trial in Rhesus macaques rendered immunodeficient by infection with SIV Mac251 to model vaccine efficiency in an HIV-infected cohort. Specific Aim 1 is to perform lead optimization and compare efficacy of systemic versus mucosal immunization in CD4-depleted mice. Specific Aim 2 is to conduct an immunogenicity study in non-human primates. PUBLIC HEALTH RELEVANCE: Pulmonary infection with the fungal pathogen, Pneumocystis jirovecii, is a common and often fatal complication of HIV infection/AIDS. This proposal will perform testing of candidate vaccines for this life-threatening infection.

描述（由申请人提供）：带有真菌病原体的肺部感染，肺炎刺激jirovecii，是HIV感染/艾滋病的常见且通常是致命的并发症。新兴数据表明，肺炎藻还可能使包括患有COPD和固体器官移植受者的非HIV感染宿主中的肺部疾病复杂化。该项目的长期目标是开发针对肺炎胸膜的疫苗。为此，我们已经确定了一种称为迷你性害羞的肺炎藻的新型疫苗候选者。我们已经显示出用微型蛋白的DNA疫苗接种，然后促进粘膜可产生强大的肺免疫反应，并在小鼠中针对肺囊肿挑战提供保护性疗效。此外，将CD40L用作分子佐剂可以在CD4+ T细胞缺陷型小鼠中产生保护性抗体反应，该模型非常重复了AIDS中PCP的免疫缺陷和易感性。基于这些数据，LSUHSC已向迷你风化蛋白作为pcp疫苗提交了临时专利和PCT。在小型乘积下，该STTR将用于进行进一步的铅优化，并研究SIV感染的猕猴中迷你蛋白的免疫原性。我们假设使用微型凯克斯的素数/增强疫苗接种将导致抗原特异性抗体反应，这些抗体反应可抵抗对小鼠的PC挑战，并且CD40L与微型Kexin疫苗的共同给药将在使用Simeian模型的低外围CD4+ T-Cells的设置中提供有效的全身性和粘膜抗体反应。我们将首先在小鼠中对疫苗平台进行铅优化，然后在恒河猕猴中进行免疫原性试验，该试验通过用SIV MAC251感染了免疫缺陷，以模拟感染HIV感染的队列中的疫苗效率。具体目的1是进行铅优化并比较CD4缺失小鼠的全身性和粘膜免疫的功效。具体目的2是在非人类灵长类动物中进行免疫原性研究。 公共卫生相关性：与真菌病原体的肺部感染，肺炎刺激jirovecii，是HIV感染/艾滋病的常见且通常是致命的并发症。该提案将对这种威胁生命的感染进行候选疫苗的测试。