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）：念珠菌是美国和其他具有先进医疗保健的国家侵袭性真菌感染的最常见原因，美国的医疗保健成本为数十亿美元/年，死亡率为30%-40%。同样，近年来，耐甲氧西林金黄色葡萄球菌（MRSA）感染对公共卫生的重大影响也发生了广泛的变化。 虽然通常被认为是一种局限于免疫功能低下的宿主的感染，但大多数发生可能危及生命的播散性念珠菌病的患者并没有免疫抑制。因此，使用靶向疫苗预防念珠菌病是可行的，并且由于发展念珠菌病的临床风险因素是明确定义的这一事实而得到促进。这些风险群体是共同的两个S。金黄色葡萄球菌和念珠菌。我们发现C.白念珠菌细胞表面Als 3 p作为粘附素/侵袭素发挥作用，是针对念珠菌属引起的感染的可行的疫苗候选物。重要的是，该疫苗（其由重组产生的Als 3 p [rAls 3 p-N]的N-末端组成）与S.金黄色。事实上，rAls 3 p-N疫苗在血源性播散性葡萄球菌血症和SSSI的鼠模型中具有保护性。我们成立了NovaDigm Therapeutics Inc。将候选疫苗推进临床试验最近，我们成功完成了两项I期临床试验，并启动了复发性外阴阴道念珠菌病的国家1b/2a期试验，其中包括疗效分析。我们来自在两个I期临床试验期间收集的血清和PBMC样品的初步数据显示，由疫苗产生的抗Als 3 p抗体具有增强的C.白色念珠菌和S.金黄色。此外，这些抗体减少了C。白念珠菌的毒力功能包括：粘附、侵袭、随后对宿主细胞的损伤和减少C.白色念珠菌粘附在塑料上。最后，从接种者收集的PBMC产生干扰素-？和IL-17相对于来自安慰剂的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rAls 3 p-N的患者中收集的抗体和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中的基本作用机制。我们还将对S.金黄色葡萄球菌，其与从用rAls 3 p-N接种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新的主动和被动免疫策略的念珠菌，和S。金黄色葡萄球菌感染这些目标将利用我们从I期临床试验中获得的独特资源，这些试验表明rAls 3 p-N疫苗是安全的和免疫原性的，并将使用从Ib/IIa期试验中收集的样品，首次进一步确定rAls 3 p-N在人类中的潜在作用机制。他们将为开发针对念珠菌和S.金黄色葡萄球菌感染