PEPTIDE MIMETICS OF STREPTOCOCCAL CARBOHYDRATE ANTIGENS

描述(改编自申请者摘要)：B组链球菌 (GBS)感染是新生儿发病率和死亡率的主要原因。它 众所周知，母源抗体的存在可以保护人类免受 新生儿感染的发生和GBS疫苗的开发 被认为是重要的公共卫生优先事项。GBS抗原，诱导 在胶囊多糖上发现了保护性抗体。因为 微生物多糖是出了名的糟糕的免疫原，GBS胶囊 碳水化合物已经连接到载体蛋白上，以努力 生产出有效的疫苗。在这一应用中，一种新的方法来实现这一点 提出了问题。模拟GBS抗原结构的多肽有 已被发现并被证明可引发抗GBS抗体。使用这些多肽 模拟B群链球菌(GBS)型的主要保护性表位 III胶囊多糖，这些研究将解决以下假设 模拟保护性碳水化合物表位构象的多肽 将可靠地诱导更大幅度的保护性抗体反应 比基于微生物的免疫原性 碳水化合物。 抗GBS的单抗已被用来选择多肽展示物 噬菌体文库用于鉴定模拟GBS碳水化合物抗原的多肽。 这些多肽与所选择的抗体结合并抑制抗体结合 以特定的方式发送到GBS。用模拟多肽免疫会导致 抗GBS抗体的产生。这里提出的研究将探索 类碳水化合物多肽在增强人免疫原性中的应用 GBS疫苗。提出了以下具体目标：1)一系列 免疫原将使用模拟多肽、载体蛋白、 和GBS壳多糖。2)将对这些共轭项进行比较 它们诱导与GBS结合的抗体的能力和功能 调理细菌。3)偶联物的诱导能力 保护性免疫将在两种动物模型中进行比较：清除GBS 来自免疫成年小鼠和新生挑战模型，其中母鼠 已经接种了疫苗。 这些研究可能会导致开发出更好的母体疫苗 新生儿GBS感染的预防。这里开发的技术可能 也适用于其他微生物多糖类抗原的限制 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.