Synthetic Peptide Vaccines for Dental Caries

龋齿合成肽疫苗

基本信息

批准号：
6369849
负责人：
MARTIN A TAUBMAN
金额：
$ 49.78万
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 2006-06-30
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.

我们的总体目的是开发免疫结构，向量和策略，这些策略有最佳机会在易感儿科种群中诱导对突变体链球菌感染的保护性免疫反应。我们先前已经鉴定出几种葡萄糖基转移酶（GTF）酶序列，这些酶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，我们将首先从葡萄糖基转移酶（GTF）酶鉴定出与人类中有效II类MHC相关的葡萄糖和sobrinus酶的序列。基于这些和新型GTF表位的肽，最近显示出酶的催化活性和过渡状态的稳定性（相关活性）将被合成并评估以获得免疫原性和保护作用。这些表位与先前显示的GTF的催化和葡萄糖结合结构域衍生的其他功能显着的肽一起诱导了保护性反应，可以将其纳入与破伤风毒素（TT）的结合疫苗中。将研究用TT-GTF肽缀合物疫苗进行粘膜免疫的鼻内途径，以便在实验性牙齿龋齿的啮齿动物模型中诱导口腔腔中诱导免疫力的能力。由于鼻内途径可能会在具有上呼吸道疾病（例如哮喘）的儿童中禁忌，因此也将使用具有或不具有粘膜佐剂的结合构建体来探索Colo直肠内的给药途径。用TT-GTF肽结合疫苗研究的全身免疫的保护作用也将作为一种方法，是一种方法，是一种方法，以最大程度地减少儿童免疫所需的访问频率，因为证据表明这种免疫途径可以诱导幼儿唾液中的IgA抗体。通过TT-GTF肽结合疫苗研究确定的各种有效肽的各种有效的肽将在潮湿的鼠伤寒沙门氏菌载体中重组表达，这些媒介可以将这些表位定位于适当的粘膜感应部位。这些减毒的沙门氏菌载体后，将评估龋齿保护。我们的目标是设计一种疫苗，该疫苗包含免疫学上有效和功能相关的表位，形式，路线和佐剂，从而可以持续保护龋齿，并且可以接受人类使用。