LIPOSOMAL S MUTANS DELIVERY SYSTEM FOR CARIES IMMUNITY

描述(改编自申请人的摘要)：尽管采取了预防措施 已经制定的措施，龋齿仍然是一个主要的 世界性疾病。尽管不是最具破坏性的，但这种传染性 疾病可能也是最流行、最昂贵的疾病。 作为工业化国家。分泌型IgA是第一道防线 对抗侵入口腔的病原体，包括 变形链球菌(与龋齿形成有关的细菌)。 尽管在开发粘膜疫苗方面做出了广泛的努力 微生物病原体(例如，变形链球菌)，这种免疫途径仅 最近被认为是首选路线，而 诱导保护性免疫的常规全身途径。近期 初步的人类免疫研究一直发现唾液 口服脂质体抗原时，S-IgA对变形链球菌的应答； 然而，唾液反应程度低，持续时间短。 为了提高唾液反应的大小和持久性 粘膜脂质体疫苗、免疫佐剂两条新途径 将在这份提案中进行调查。具体地说，拟议的研究 将决定三种含有S。 变形杆菌葡萄糖转移酶(霍乱毒素B亚单位[CTB]-脂质体， 单磷脂A[MPL]-脂质体，常规脂质体)诱导 胃用、鼻用或外用时的口腔粘膜反应 在实验性大鼠龋齿模型中的路线。建议的研究结果 动物研究和以前的临床研究的目的是 为人类协议的设计提供支持证据和理论基础 旨在诱导对变形链球菌疫苗的潜在唾液免疫反应 由FDA进行I期研究。在一项剂量反应研究之后，FDA双盲 II期临床研究(包括100名试验组和对照组 受试者)被提议研究该疫苗的免疫原性和有效性 确定了变形链球菌脂质体疫苗的最佳接种方案和路线。的目标是 这项提议是为了确定一种针对变形链球菌诱导的“候选”疫苗。 龋齿。据认为，这些研究将改善设计 和研制一种龋齿疫苗，以及 用于诱导保护性粘膜的脂质体免疫策略 对各种其他病原体引起的疾病的反应。这是预期的 申请者，在对免疫进行有利的鉴定之前 途径和递送系统--一种预防龋齿的候选粘膜疫苗 将准备好在完成后进行现场试验(FDA第三阶段研究) 这些研究。

DESCRIPTION (Adapted from the Applicant's Abstract): Despite preventive measures that have been developed, dental caries persists as a major worldwide disease. Although not the most devastating, this infectious disease may be the most prevalent and costly disease in developing, as well as industrialized countries. Secretory IgA is a first line of defense against pathogens that invade through the oral cavity, including Streptococcus mutans (the bacterium associated with caries initiation). Despite extensive efforts on the development of a mucosal vaccine against microbial pathogens, (e.g., S. mutans), this route of immunization is only recently being recognized as the preferred route, compared to the conventional systemic route in inducing protective immunity. Recent preliminary human immunization studies have consistently found salivary S-IgA responses to S. mutans when liposomal antigens are given orally; however, the salivary responses were of low magnitude and short duration. In order to improve the magnitude and persistence of salivary responses to the mucosal liposomal vaccine, two new routes of immunization and adjuvants will be investigated in this proposal. Specifically, the proposed studies will determine the effectiveness of three liposome vaccines containing S. mutans glucosyltransferase (Cholera toxin B subunit [CTB]-Liposomes, monophosphoryl lipid A [MPL]-Liposomes, Conventional Liposomes) to induce oral mucosal responses when administered by gastric, nasal, or topical routes in an experimental rat caries model. The results of the proposed animal studies, and those of previous clinical studies, are intended to provide supporting evidence and rationale for the design of human protocols aimed at inducing potential salivary immune responses to S. mutans vaccines by FDA Phase I studies. Following a dose response study, a double blind FDA Phase II clinical study (involving experimental and control groups of 100 subjects) is proposed to study the immunogenicity and efficacy of the identified optimal liposomal S. mutans vaccine and route. The objective of this proposal is to identify a "candidate" vaccine against S. mutans-induced dental caries. It is suggested that these studies will enhance the design and development of a dental caries vaccine, as well as liposomal-immunization strategies for use in inducing protective mucosal responses to various other pathogen-induced diseases. It is anticipated by the applicants that, pending favorable identification of an immunization route and delivery system, a candidate mucosal vaccine against dental caries will be ready for field trials (FDA Phase III studies) upon completion of these studies.