Development of a vaccine to prevent Pneumocystis pneumonia

开发预防肺孢子虫肺炎的疫苗

基本信息

批准号：
9906567
负责人：
MICHAEL Robert DOWNES
金额：
$ 27.24万
依托单位：
NXT BIOLOGICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906567
关键词：
Acquired Immunodeficiency Syndrome Address Adverse reactions Aging Amino Acids Antibody titer measurement Antifungal Agents B-Lymphocytes Biology Cancer Patient Chronic Obstructive Airway Disease Clinical Clinical Trials Development Diagnosis Disease Drug resistance Experimental Models Formulation Frequencies Fungal Vaccines Genomics Goals HIV HIV Infections HIV diagnosis Human Immune response Immune system Immunity Immunization Immunocompromised Host Immunoglobulin A Immunoglobulin G Immunoglobulins Immunologic Memory Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Incidence Individual Infection Inflammatory Inflammatory Response Life Lung Macaca Memory Modeling Morbidity - disease rate Obstructive Lung Diseases Opportunistic Infections Organ Transplantation Organism Pathogenesis Persons Phase Plasma Pneumocystis Pneumocystis carinii Pneumocystis carinii Pneumonia Population Populations at Risk Preparation Prevention Primates Production Prophylactic treatment Prospective Studies Protein Subunits Proteins Recombinants Reporting Research Resources Risk SIV Specificity Testing Therapeutic Uses Therapeutic immunosuppression Time Tissues Transplant Recipients Treatment Failure Trimethoprim-Sulfamethoxazole Vaccinated Vaccine Therapy Vaccines Virus Diseases Work antiretroviral therapy base commercialization disorder control experience immunogenicity immunosuppressed lead optimization mortality natural antibodies nonhuman primate novel pathogen patient population prevent prophylactic protective efficacy public health relevance recombinant peptide research clinical testing response seropositive standard care treatment guidelines vaccination strategy vaccine candidate vaccine development vaccine evaluation

项目摘要

Despite the fact that fungal diseases are an increasing clinical burden, particularly among immunocompromised patients, there are no anti-fungal vaccines approved for clinical use. The fungal opportunistic pathogen, Pneumocystis jirovecii is the causative agent of Pneumocystis pneumonia (PCP), which remains a serious AIDS-defining, opportunistic infection and is of increasing concern in persons receiving immunosuppressive therapies, including organ transplant recipients, cancer patients, individuals with inflammatory disease and in persons experiencing natural immunosuppression due to aging, congenital or acquired immunosuppressive states. In addition to causing PCP, several studies have shown an association between Pc colonization and chronic obstructive pulmonary disease (COPD) in both HIV-infected and non-HIV infected populations. Each of these patient populations would benefit from either a prophylactic PCP vaccine administered prior to immunosuppression (for example, prior to a clinical course of immunotherapy) or in populations at risk for HIV infection or individuals at the time of diagnosis of HIV infection. The overall goal of this research is to develop a vaccine for prevention of PCP and related pulmonary sequelae in HIV+ and other immunocompromised populations. Toward this end, we have identified and developed a vaccine candidate based on the Pneumocystis protein, kexin. We have produced a vaccine candidate based on Pneumocystis protein, kexin, and showed that immunization of non-human primates (NHP) prior to simian immunodeficiency virus (SIV) infection induces high level, kexin-specific plasma and lung immunoglobulin titers and protects against Pneumocystis pneumonia. The objective of this Phase I application is to complete lead optimization of the vaccine by testing the immunogenicity of the Pneumocystis jirovecii-derived kexin protein derivative. We will assess the immune response in NHPs following immunization and boost with the P. jiroveciii recombinant peptide in SIV-infected macaques and will evaluate the duration and quality of the specific memory responses in the immunosuppressed state. With the completion of this proof of concept study, we will focus efforts on preparation and evaluation of the vaccine for clinical trial.

尽管事实上真菌病正在日益增加的临床负担，特别是在对于免疫功能低下的患者，目前还没有批准用于临床的抗真菌疫苗。真菌类机会性病原体，耶氏肺孢子虫是肺孢子虫肺炎（PCP）的病原体，它仍然是一种严重的艾滋病定义的机会性感染，并且越来越引起人们的关注接受免疫抑制治疗，包括器官移植受者、癌症患者、患有炎症性疾病以及由于衰老、先天性或先天性疾病而经历自然免疫抑制的人获得性免疫抑制状态。除了导致 PCP 之外，多项研究还表明，与 PCP 存在关联 HIV 感染者和非 HIV 感染者中 PC 定植与慢性阻塞性肺病 (COPD) 之间的关系感染人群。这些患者群体中的每一个都将受益于预防性 PCP 疫苗在免疫抑制之前（例如，在免疫治疗的临床过程之前）或在有 HIV 感染风险的人群或诊断出 HIV 感染时的个人。总体目标为这项研究旨在开发一种疫苗，用于预防 HIV+ 和其他人群的 PCP 和相关肺部后遗症免疫功能低下的人群。为此，我们已经确定并开发了一种候选疫苗基于肺孢子虫蛋白 kexin。我们已经生产了基于肺孢子虫的候选疫苗蛋白质，kexin，并表明在猿猴免疫缺陷之前对非人灵长类动物（NHP）进行免疫病毒 (SIV) 感染可诱导高水平的 Kexin 特异性血浆和肺免疫球蛋白滴度并保护对抗肺孢子菌肺炎。该第一阶段申请的目标是完成先导化合物优化通过测试耶氏肺孢子虫衍生的kexin蛋白衍生物的免疫原性来开发疫苗。我们将评估 NHP 免疫后的免疫反应，并使用 P. jiroveciii 重组体加强免疫感染 SIV 的猕猴中的肽，并将评估特定记忆反应的持续时间和质量处于免疫抑制状态。随着概念验证研究的完成，我们将集中精力临床试验疫苗的制备和评价。