Synthetic Peptide Vaccines for Dental Caries

龋齿合成肽疫苗

基本信息

批准号：
6948655
负责人：
MARTIN A TAUBMAN
金额：
$ 7.27万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2005-06-30
项目状态：
已结题

项目摘要

Our overall aim is to develop immunization constructs, vectors, and strategies which have the best chance of inducing protective immune responses to mutans streptococcal infections in susceptible pediatric populations. We have previously identified several glucosyltransferases (GTF) enzyme sequences which can induce immune response in rodents which will alter GTF activity and reduce subsequent dental caries. To enhance the induction of protective immune responses we will first identify sequences from glucosyltransferase (GTF) enzymes from S. mutans and S. sobrinus associated with potent Class II MHC binding in humans. Peptides based on these and on novel GTF epitopes, recently shown to influence catalytic activity and transitional state stability of the enzyme (activity associated) will be synthesized and evaluated for immunogenicity and protective effect. These epitopes, together with other functionally significant peptides derived from the catalytic and glucans binding domains of GTF previously shown to induce protective responses, well be incorporated into conjugate vaccines with tetanus toxoid (TT). Intranasal routes for mucosal immunization with TT- GTF peptide conjugate vaccine will be investigated for the ability to induce protective levels of immunity in the oral cavity in the well established rodent model of experimental dental caries. Since the intranasal route may be contraindicated in children with upper respiratory conditions such as asthma, the colo-rectal route of administration will also be explored using constructs combined with or without mucosal adjuvants such detoxified mutant E. coli enterotoxin (LT) or unmethylated CpG oligodinucleotides. The protective effect of systemic immunization with TT-GTF peptide conjugate vaccine studies will also be investigated as an approach to minimizing the frequency of visits required for childhood immunizations, since evidence suggests that this route of immunization can induce salivary IgA antibody in young children. Various of the mist effective peptide(s) as determined by TT-GTF peptide conjugate vaccine studies will be expressed recombinantly in attenuated Salmonella typhi vectors which can target these epitopes to appropriate mucosal inductive sites. Caries protection will be evaluated after intranasal immunization with these attenuated Salmonella vectors. Our goal is to design a vaccine that contains a combination of immunologically potent and functionally relevant epitopes, in formats, by routes, and with adjuvants that result in sustained levels of protection from dental caries and that will be acceptable for human use.

我们的总体目标是开发免疫结构、载体和策略，它们最有可能在易感儿科人群中诱导针对变形链球菌感染的保护性免疫反应。我们之前已经鉴定出几种葡萄糖基转移酶（GTF）酶序列，它们可以诱导啮齿动物的免疫反应，从而改变 GTF 活性并减少随后的龋齿。为了增强保护性免疫反应的诱导，我们将首先鉴定来自变形链球菌和远缘链球菌的葡糖基转移酶（GTF）的序列，这些酶与人类中有效的 II 类 MHC 结合相关。基于这些和新的 GTF 表位的肽，最近显示会影响酶的催化活性和过渡态稳定性（活性相关），将被合成并评估其免疫原性和保护作用。这些表位与先前显示可诱导保护性反应的来自 GTF 催化和葡聚糖结合结构域的其他功能上重要的肽一起，可以很好地与破伤风类毒素 (TT) 结合到疫苗中。将研究使用 TT-GTF 肽缀合物疫苗进行鼻内粘膜免疫的途径，以确定其在已建立的实验性龋齿啮齿动物模型中诱导口腔保护性免疫水平的能力。由于鼻内途径可能不适用于患有哮喘等上呼吸道疾病的儿童，因此还将使用联合或不联合粘膜佐剂（如解毒突变型大肠杆菌肠毒素（LT）或未甲基化 CpG 寡二核苷酸）的构建体来探索结肠直肠给药途径。还将研究 TT-GTF 肽结合疫苗全身免疫的保护作用，作为最大限度减少儿童免疫所需就诊频率的方法，因为有证据表明这种免疫途径可以在幼儿中诱导唾液 IgA 抗体。通过 TT-GTF 肽缀合物疫苗研究确定的各种雾有效肽将在减毒伤寒沙门氏菌载体中重组表达，该载体可以将这些表位靶向适当的粘膜诱导位点。使用这些减毒沙门氏菌载体进行鼻内免疫后，将评估龋齿保护作用。我们的目标是设计一种疫苗，其中包含免疫有效和功能相关表位的组合，其形式、途径和佐剂可产生持续水平的龋齿保护，并且可供人类使用。