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

点击翻译按钮获取中文摘要

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.