Vaccine Strategies for Disseminated Candidiasis

传播性念珠菌病的疫苗策略

• 批准号: 8776669
• 负责人: John E Edwards
• 金额: $ 32.8万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776669
• 关键词: Active Immunization; Adherence; Adjuvant; Affinity; Agreement; Antibodies; Antibody Formation; Antifungal Agents; Antigens; Award; Bacterial Adhesins; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; Candida; Candida albicans; Candidiasis; Caring; Catheters; Cell Surface Proteins; Cell surface; Cells; Clinical; Clinical Trials; Collaborations; Confidentiality; Country; Data; Dedications; Development; Disease; Disseminated candidiasis; Escherichia coli; Foundations; Future; Goals; Healthcare; Healthcare Systems; Human; Human Resources; Immunocompromised Host; Immunology; Immunotherapeutic agent; In Vitro; Individual; Infection; Interferons; Interleukin-17; International; Iron; Life; Medical; Modality; Modeling; Mus; Mycoses; Natural Killer Cells; Outcome; Passive Immunization; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmacologic Substance; Phase; Phase I Clinical Trials; Placebos; Plastics; Population; Production; Protein S; Public Health; Recurrence; Research Design; Resources; Risk; Role; Sampling; Sepsis; Serum; Staphylococcus aureus; Surface Antigens; T-Lymphocyte; Testing; Therapeutic; Time; United States; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Design; Vaccines; Vagina; Virulence; Western Blotting; Work; cell preparation; cost; defined contribution; design; immunogenic; immunogenicity; immunosuppressed; interest; killings; methicillin resistant Staphylococcus aureus; microbial; mortality; novel; pre-clinical; preclinical study; prevent; public health relevance; response; uptake; vaccine candidate; vaccine development; vaccine efficacy; vaginal fluid

DESCRIPTION (provided by applicant): Candida is the most common cause of invasive fungal infections in the United States and in other countries with advanced medical care with $ billions/year in cost to the healthcare of the United States and mortality rates ranging between 30%-40%. Likewise, the significant public health impact of methicillin resistant Staphylococcus aureus (MRSA) infections has evolved extensively in recent years. Although often thought of as an infection confined to immunocompromised hosts, the majority of those who develop potentially life-threatening disseminated candidiasis are not immunosuppressed. Thus, the use of a targeted vaccine to prevent candidiasis is feasible and facilitated by the fact that clinical isk factors for developing candidiasis are well-defined. These risk groups are common to both S. aureus and Candida. We have made the discovery that C. albicans cell surface Als3p, which functions as an adhesin/invasin, is a viable vaccine candidate against infections caused by Candida spp. Importantly, this vaccine (which is composed of a recombinantly produced N-terminus of Als3p [rAls3p-N]) shares 3D structural homology with cell surface proteins of S. aureus. Indeed the rAls3p-N vaccine is protective in murine models of hematogenously disseminated staphylococcemia and SSSI. We formed NovaDigm Therapeutics Inc. to advance the candidate vaccine into clinical trials. Recently, we have successfully completed two Phase I clinical trials and have initiated a national Phase 1b/2a trial in recurrent vulvo-vaginal candidiasis, which includes efficacy analysis. Our preliminary data from serum and PBMCs samples collected during the two Phase 1 clinical trials, show that anti-Als3p antibodies generated by the vaccine are functional with enhanced opsonophagocytosis killing (OPK) of C. albicans and S. aureus. Further, these antibodies reduced C. albicans virulence functions including: adherence, invasion, subsequent damage to host cells, and reduced C. albicans adherence to plastic. Finally, the PBMCs collected from vaccinees had elevated production of interferon-? and IL-17 vs. PBMCs from placebo. We propose to build on these exciting data to further define the basic mechanisms of action of this vaccine in humans, by correlating in vitro functions of antibodies and PBMCs collected from patients vaccinated with rAls3p-N with the efficacy outcome from Phase 1b/2a trial. We will also characterize the antigens on S. aureus that cross react to human sera collected from individuals vaccinated by rAls3p-N. Our goal is to develop and maximize the efficacy of novel active and passive immunization strategies for Candida, and S. aureus infections. These aims will leverage our unique resources from Phase I clinical trials showing that rAls3p-N vaccine was safe and immunogenic, and will further define the potential mechanisms of action of rAls3p-N for the first time in humans, using samples collected from Phase 1b/2a trial. They will create the foundation for development of additional immunotherapeutic modalities targeting Candida and S. aureus infections.

描述（由申请人提供）：念珠菌是侵袭性真菌感染最常见的原因，在美国和其他拥有先进医疗保健的国家，念珠菌每年给美国医疗保健造成数十亿美元的损失，死亡率在30%-40%之间。同样，耐甲氧西林金黄色葡萄球菌（MRSA）感染的重大公共卫生影响近年来已广泛演变。虽然通常被认为是一种局限于免疫功能低下宿主的感染，但大多数发展为可能危及生命的播散性念珠菌病的人并没有免疫抑制。因此，使用靶向疫苗来预防念珠菌病是可行的，而且发展念珠菌病的临床危险因素是明确的，这一事实促进了这种疫苗的使用。这些风险群体对金黄色葡萄球菌和念珠菌都是常见的。我们发现，白色念珠菌细胞表面Als3p作为一种粘附素/入侵素，是一种可行的候选疫苗，可以抵抗念珠菌引起的感染。重要的是，该疫苗（由重组产生的Als3p的n端组成[rAls3p-N]）与金黄色葡萄球菌的细胞表面蛋白具有3D结构同源性。事实上，rAls3p-N疫苗对血源性播散性葡萄球菌血症和SSSI小鼠模型具有保护作用。我们成立了NovaDigm Therapeutics Inc.，以推进候选疫苗进入临床试验。最近，我们已经成功完成了两项I期临床试验，并启动了一项针对复发性外阴-阴道念珠菌病的1b/2a期国家试验，其中包括疗效分析。我们从两项1期临床试验中收集的血清和PBMCs样本中获得的初步数据表明，疫苗产生的抗als3p抗体具有增强白色念珠菌和金黄色葡萄球菌的调理吞噬作用（OPK）的功能。此外，这些抗体降低了白色念珠菌的毒力功能，包括：粘附、入侵、随后对宿主细胞的损伤，并降低了白色念珠菌对塑料的粘附。最后，从疫苗接种者身上收集的pbmc产生的干扰素-？IL-17和安慰剂组的pbmc。我们建议在这些令人兴奋的数据的基础上，通过将从接种rAls3p-N的患者收集的抗体和pbmc的体外功能与1b/2a期试验的疗效结果相关联，进一步确定该疫苗在人体内的基本作用机制。我们还将描述金黄色葡萄球菌上的抗原，这些抗原与从接种过rAls3p-N的个体收集的人血清交叉反应。我们的目标是开发和最大限度地提高对念珠菌和金黄色葡萄球菌感染的新型主动和被动免疫策略的疗效。这些目标将利用我们从I期临床试验中获得的独特资源，这些临床试验表明rAls3p-N疫苗是安全和免疫原性的，并将利用1b/2a期试验收集的样本，首次进一步确定rAls3p-N在人体中的潜在作用机制。它们将为开发针对念珠菌和金黄色葡萄球菌感染的其他免疫治疗方式奠定基础。