Acne Vaccines Targeting a Surface Sialidase and a Secreted CAMP Factor Toxin

描述（由申请人提供）：痤疮丙酸杆菌（P. acnes）因其在寻常性痤疮（最常见的皮肤病）中的作用而得到最明显的认可，85% -100%的人口在其生命的某个阶段受到影响。目前使用异维甲酸（13-顺式维甲酸）或抗生素治疗寻常痤疮可能会产生许多不良影响，包括抑郁、致畸、激素失衡和皮肤微生物群改变。由于副作用，美国食品和药物管理局（FDA）宣布了一项加强风险管理计划，以加强异维甲酸治疗严重痤疮的安全使用。目前还没有针对寻常痤疮的疫苗。选择两种痤疮P.蛋白（细胞壁锚定唾液酸酶和分泌的CAMP因子毒素）作为开发痤疮疫苗的抗原。我们的数据表明，唾液酸酶去除人皮脂细胞表面的唾液酸增加了他们对痤疮假单胞杆菌感染的易感性。此外，在厌氧条件下，诱导角质形成细胞凋亡的CAMP因子在痤疮假单胞菌中表达上调。因此，在本建议中，针对唾液酸酶和CAMP因子的痤疮疫苗将与灭活的痤疮单胞杆菌疫苗进行比较。我们将构建特异性抑制痤疮P.痤疮引起的炎症的痤疮疫苗，并将改变皮肤微生物稳态的风险降至最低。本课题的具体目的包括：1)比较不同的疫苗接种方式，以最大限度地提高唾液酸酶和CAMP因子的免疫原性；2)通过中和试验和新建立的痤疮动物模型，研究痤疮疫苗的体外/体内保护性免疫；3)通过检测接种小鼠对各种微生物的敏感性，确定痤疮疫苗的特异性和安全性。本提案的定量里程碑将是：i)优化方案，以创建最有效的痤疮疫苗，以激发强大的抗体（IgG）的产生；Ii)在体内筛选各种痘痘疫苗构建体；Iii)测量痤疮疫苗对细菌生长和炎症的免疫保护作用；iv)选择一种痤疮假单胞杆菌特异性疫苗，显著减少痤疮假单胞杆菌引起的炎症v)不破坏皮肤微生物群的平衡。在美国有超过5000万人患有寻常性痤疮。痤疮丙酸杆菌（P. acnes）感染与痤疮严重程度之间的关系已被报道。使用抗生素或维生素a衍生的类维生素a的全身治疗会引起许多副作用，包括激素失衡、精神障碍和致畸性。本建议的目标是开发系统有效的痤疮疫苗，可以特异性地抑制痤疮假单胞杆菌引起的皮肤炎症，而不会扰乱皮肤菌群的平衡。

DESCRIPTION (provided by applicant): Propionibacterium acnes (P. acnes) is most notably recognized for its role in acne vulgaris, the most common skin disease, affecting 85-100% of the population at some point in their lives. Current treatments for vulgaris acne using isotretinoin (13-cis-retinoic acid) or antibiotics can have many undesirable effects, including depression, teratogenicity, hormone imbalance and alteration of skin microflora. Due to the side effects, the Food and Drug Administration (FDA) has announced a strengthened risk management program to enhance safe use of isotretinoin for treating severe acne. Vaccines against acne vulgaris are not yet available. Two P. acnes proteins (a cell-wall anchoring sialidase and a secreted CAMP factor toxin) were selected as antigens for the development of acne vaccines. Our data demonstrated that the removal of sialic acids on the surface of human sebocytes by sialidase increased their susceptibility to P. acnes infection. In addition, CAMP factor, which induced apoptosis in keratinocytes, was up-regulated in P. acnes under anaerobic conditions. Thus, acne vaccines targeting sialidase and CAMP factor will be created in this proposal in comparison with killed P. acnes-based vaccines. We will construct acne vaccines that specifically suppress P. acnes-induced inflammation and minimize the risk of changing the homeostasis of resident skin microbes. The specific aims in this proposal will include 1) comparing various vaccination modalities to maximize the immunogenicities of sialidase and CAMP factor, 2) investigating in vitro/in vivo protective immunity of acne vaccines by neutralization assay and a newly-developed acne animal model, and 3) determining the specificity and safety of acne vaccines by detecting the susceptibility of vaccinated mice to various microbes. The quantitative milestones in this proposal will be to i) optimize a protocol to create the most potent acne vaccine for eliciting robust antibody (IgG) production; ii) screen various acne vaccine constructs in vivo; iii) measure the acne vaccine's immune protection against bacterial growth and inflammation; iv) select a P. acnes specific vaccine that significantly decreases P. acnes-induced inflammation v) without damaging the balance of skin microflora. PUBLIC HEALTH RELEVANCE More than fifty million people in the U.S. suffer from acne vulgaris. The association between Propionibacterium acnes (P. acnes) infection and the acne severity has been reported. Systemic therapies using antibiotics or the vitamin A-derived retinoids cause many side effects including hormone imbalance, mental disorders, and teratogenicity. The goal of this proposal is to develop systemically effective acne vaccines that can specifically suppress P. acnes-induced skin inflammation without disturbing the balance of skin flora.