Vaccine Strategies for Disseminated Candidiasis

描述(由申请人提供)：念珠菌是美国和其他拥有先进医疗保健的国家最常见的侵袭性真菌感染原因，每年给美国的医疗保健带来数十亿美元的成本，死亡率在30%-40%之间。同样，近年来，耐甲氧西林金黄色葡萄球菌(MRSA)感染对公众健康的重大影响也发生了广泛的变化。虽然通常被认为是一种仅限于免疫受损宿主的感染，但大多数患有潜在威胁生命的播散性念珠菌病的人并没有免疫抑制。因此，使用靶向疫苗预防念珠菌病是可行的，这是因为发生念珠菌病的临床风险因素是明确的。这些风险群在金黄色葡萄球菌和念珠菌中都是常见的。我们发现，白念珠菌细胞表面的Als3p具有粘附素/侵袭素的功能，是预防念珠菌感染的可行疫苗候选。重要的是，这种疫苗(由重组产生的Als3p[rAls3p-N]的N末端组成)与金黄色葡萄球菌细胞表面蛋白有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的小鼠模型具有保护作用。我们成立了NovaDigm治疗公司，以推动候选疫苗进入临床试验。最近，我们成功地完成了两个I期临床试验，并启动了治疗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。我们在两个第一阶段临床试验期间收集的血清和PBMC样本的初步数据表明，疫苗产生的抗Als3p抗体具有增强对白色念珠菌和金黄色葡萄球菌的吞噬细胞杀伤(OPK)的功能。此外，这些抗体降低了白念珠菌的毒力功能，包括：黏附、入侵、随后对宿主细胞的破坏，以及减少白念珠菌对塑料的黏附。最后，从疫苗接种者身上收集的PBMC增加了干扰素的产生。IL-17与来自安慰剂的PBMC的比较。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疫苗的患者收集的抗体和PBMC的体外功能与1b/2a阶段试验的疗效结果相关联，进一步确定该疫苗在人类中的基本作用机制。我们还将确定金黄色葡萄球菌上的抗原与从rAls3p-N疫苗接种的个体收集的人血清发生交叉反应的抗原。我们的目标是开发和最大限度地发挥新的主动和被动免疫策略对念珠菌和金黄色葡萄球菌感染的效果。这些目标将利用我们从第一阶段临床试验中获得的独特资源，表明rAls3p-N疫苗是安全的和免疫原性的，并将使用从1b/2a阶段试验中收集的样本，首次在人类身上进一步确定rAls3p-N的潜在作用机制。他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法奠定基础。

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.