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

针对表面唾液酸酶和分泌的 CAMP 因子毒素的痤疮疫苗

基本信息

批准号：
7482001
负责人：
CHUN-MING HUANG
金额：
$ 10万
依托单位：
VAXIN INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7482001
关键词：
Acne Acne Vulgaris Adjuvant Adverse effects Aerobic Affect Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antigens Apoptosis Bacteria Bacterial Drug Resistance Biological Assay Cell Wall Cicatrix Condition Congenital Abnormality Data Development Disease Ear Equilibrium Excision Figs - dietary Genome Genomics Goals Growth Homeostasis Hormones Human Immune Immune response Immunity Immunoglobulin G In Vitro Infection Inflammation Inflammatory Intraperitoneal Injections Isotretinoin Laboratories Lead Lesion Life Measures Medicine Mental Depression Mental disorders Microbe Modality Modeling Mus Neuraminidase Organism Pathogenesis Patients Personal Satisfaction Pharmaceutical Preparations Population Predisposition Pregnant Women Production Propionibacterium acnes Proteins Proteome Proteomics Protocols documentation Public Health Rate Reaction Reporting Resistance Retinoids Risk Risk Management Role Safety Severities Sialic Acids Skin Specificity Staging Staphylococcus aureus Surface Systemic Therapy Therapeutic Thick Tissues Toxin United States Food and Drug Administration Vaccinated Vaccination Vaccines Virulence Virulence Factors Vitamin A base cell injury hormone regulation immunogenicity in vivo keratinocyte killings prevent programs psychologic skin disorder vector-based vaccine

项目摘要

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.

描述（由申请人提供）：痤疮丙酸杆菌（P.acnes）因其在寻常痤疮中的作用而广为人知，寻常痤疮是最常见的皮肤病，影响 85-100% 的人口在其生命中的某个阶段。目前使用异维A酸（13-顺式视黄酸）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的改变。由于异维A酸的副作用，美国食品和药物管理局 (FDA) 宣布加强风险管理计划，以加强异维A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。选择两种痤疮丙酸杆菌蛋白（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，唾液酸酶去除人类皮脂细胞表面的唾液酸会增加其对痤疮丙酸杆菌感染的易感性。此外，在厌氧条件下，痤疮丙酸杆菌中诱导角质形成细胞凋亡的 CAMP 因子上调。因此，与基于灭活痤疮丙酸杆菌的疫苗相比，本提案将创建针对唾液酸酶和 CAMP 因子的痤疮疫苗。我们将构建专门抑制痤疮丙酸杆菌引起的炎症的痤疮疫苗，并最大限度地降低改变常驻皮肤微生物稳态的风险。该提案的具体目标包括 1) 比较各种疫苗接种方式，以最大限度地提高唾液酸酶和 CAMP 因子的免疫原性，2) 通过中和试验和新开发的痤疮动物模型研究痤疮疫苗的体外/体内保护性免疫，以及3）通过检测接种小鼠对各种微生物的敏感性来确定痤疮疫苗的特异性和安全性。该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，以引发强大的抗体 (IgG) 产生； ii) 体内筛选各种痤疮疫苗构建体； iii) 测量痤疮疫苗对细菌生长和炎症的免疫保护作用； iv) 选择一种痤疮丙酸杆菌特异性疫苗，可显着减少痤疮丙酸杆菌引起的炎症 v) 且不破坏皮肤微生物群的平衡。公共卫生相关性美国有超过 5000 万人患有寻常痤疮。痤疮丙酸杆菌（P.acnes）感染与痤疮严重程度之间的关联已有报道。使用抗生素或维生素 A 衍生的类视黄醇进行全身治疗会导致许多副作用，包括激素失衡、精神障碍和致畸性。该提案的目标是开发系统有效的痤疮疫苗，可以特异性抑制痤疮丙酸杆菌引起的皮肤炎症，而不扰乱皮肤菌群的平衡。