PEPTIDE MIMETICS OF STREPTOCOCCAL CARBOHYDRATE ANTIGENS

描述（改编自申请人摘要）：B组链球菌 (GBS)感染是新生儿发病和死亡的主要原因。 它 已知母源抗体的存在可保护免受 新生儿感染的发展和GBS疫苗的开发， 这是一个重要的公共卫生优先事项。 GBS抗原， 在荚膜多糖上发现保护性抗体。 因为 微生物多糖是众所周知的不良免疫原， 碳水化合物已经与载体蛋白结合， 生产有效的疫苗。 在本申请中，提出了一种新的方法， 提出了问题。 模拟GBS抗原结构的肽具有 被鉴定并显示出引发抗GBS抗体。 使用肽 模拟B族链球菌（GBS）型的主要保护性表位 III荚膜多糖，这些研究将解决的假设， 模拟保护性糖表位构象的肽 将可靠地诱导更大幅度的保护性抗体应答， 比基于微生物的免疫原的IgG同种型 糖类。 单克隆抗GBS抗体已被用于选择肽展示 噬菌体文库以鉴定模拟GBS碳水化合物抗原的肽。 这些肽与选择性抗体结合并抑制抗体结合 以特定的方式进行GBS。 用模拟肽免疫导致 抗GBS抗体的产生。 本文提出的研究将探讨 碳水化合物模拟肽增强免疫原性的用途 GBS疫苗。 提出了以下具体目标：1）一系列 免疫原将使用模拟肽，载体蛋白， 和GBS荚膜多糖。 2)将比较这些结合物的 它们诱导与GBS结合的抗体的能力， 调理细菌 3)缀合物诱导 将在两种动物模型中比较保护性免疫：GBS的清除 来自免疫成年小鼠和新生儿攻击模型， 已经免疫了。 这些研究可能会导致更好的孕产妇疫苗的发展， 预防新生儿GBS感染。 这里开发的技术可以 也可应用于其他微生物多糖抗原的限制性 免疫原性

DESCRIPTION (Adapted from applicant's abstract): Group B streptococcal (GBS) infections are a major cause of neonatal morbidity and mortality. It is known that the presence of maternal antibody protects against the development of infection in newborns and the development of a GBS vaccine is considered an important public health priority. GBS antigens that elicit protective antibodies are found on the capsular polysaccharide. Because microbial polysaccharides are notoriously poor immunogens, GBS capsular carbohydrates have been conjugated to carrier proteins in an effort to produce efficacious vaccines. In this application, a novel approach to this problem is proposed. Peptides that mimic the structure of GBS antigens have been identified and shown to elicit anti-GBS antibodies. Using the peptides that mimic the major protective epitope on group B streptococcal (GBS) type III capsular polysaccharide, these studies will address the hypothesis that peptides which simulate the conformation of protective carbohydrate epitopes will reliably induce protective antibody responses of greater magnitude and of the IgG isotype than will immunogens based upon the microbial carbohydrate. Monoclonal anti-GBS antibodies have been used to select a peptide-display phage library to identify peptides that mimic GBS carbohydrate antigens. The peptides bind to the selecting antibodies and inhibit antibody binding to GBS in a specific manner. Immunization with a mimetic peptide results in the production of anti-GBS antibody. Studies proposed here will explore the utility of carbohydrate-mimetic peptides to enhance the immunogenicity of GBS vaccines. The following specific aims are proposed: 1) A series of immunogens will be constructed using mimetic peptides, a carrier protein, and GBS capsular polysaccharide. 2) These conjugates will be compared for their ability to induce antibody that binds to GBS and functionally opsonizes the bacteria. 3) The ability of the conjugates to induce protective immunity will be compared in two animal models: clearance of GBS from immune adult mice and a neonatal challenge model where maternal mice have been immunized. These studies may lead to the development of better maternal vaccines for the prevention of neonatal GBS infection. The techniques developed here may also be applied to other microbial polysaccharide antigens of limited immunogenicity.