EXPLORATION OF PROTECTIVE IMMUNITY INDUCED BY SALMONELLA COPS: FLIC CONJUGATES

沙门氏菌 COPS 诱导的保护性免疫的探索：FLIC 结合物

• 批准号: 8672915
• 负责人: Raphael Simon
• 金额: $ 37.95万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672915
• 关键词: Accounting; Active Immunization; Address; Adult; Africa South of the Sahara; African; Age; Animal Model; Antibodies; Antibody Formation; Antigens; Area; Avidity; B-Lymphocytes; Bacterial Gastroenteritis; Bacterial Infections; Bacterial Polysaccharides; CD4 Positive T Lymphocytes; Carrier Proteins; Case Fatality Rates; Child; Childhood; Clinical Research; Complication; Conjugate Vaccines; Developed Countries; Disease; Dose; Female; Flagellin; Frequencies; Future; Gastroenteritis; Glycoconjugates; Goals; Haemophilus influenzae type b bacteria; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; Immunization; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunologic Memory; Infant; Infection; Kinetics; Licensing; Life; Link; Longevity; Maternal antibody; Measures; Memory; Memory B-Lymphocyte; Meningitis; Mothers; Multi-Drug Resistance; Mus; Performance; Plasma Cells; Polysaccharides; Proteins; Public Health; Salmonella; Salmonella infections; Sepsis; Serum; Staging; Subunit Vaccines; T-Lymphocyte; Target Populations; Testing; Toddler; Vaccinated; Vaccination; Vaccines; Virulence Factors; anti-IgG; bactericide; cell mediated immune response; design; dosage; immunogenic; immunogenicity; improved; in vitro activity; microbial; mouse model; novel; offspring; pathogen; placental transfer; preclinical study; prevent; protective efficacy; public health relevance; pup; response; tool; vaccination strategy; vaccine candidate; vaccine efficacy; vaccine-induced immunity

DESCRIPTION (provided by applicant): In industrialized countries, non-typhoidal Salmonella (NTS) are important causes of bacterial gastroenteritis that can manifest as invasive disease in infants. In sub-Saharan Africa, multi-drug resistant NTS are a major cause of severe invasive bacterial disease in infants, with a high case fatality rate between 10 - 24 %. Notably, ~ 75-90% of invasive NTS (iNTS) infections in sub-Saharan Africa are accounted for by S. Typhimurium and S. Enteritidis. There are no current or imminent iNTS vaccines for humans. The O polysaccharides (OPS) and flagellin proteins of NTS have been shown to be important virulence factors and protective antigens against fatal iNTS infections in animal models. Bacterial polysaccharides are generally poorly immunogenic in infants and fail to confer immunologic memory at any age. However, these limitations can be overcome by conjugation to proteins. We have developed a novel S. Enteritidis glycoconjugate vaccine using S. Enteritidis flagellin as a carrier protein for chemically linked homologous strain Core and OPS (COPS), and shown improved anti- polysaccharide immune responses and protection against invasive S. Enteritidis infection in adult mice. Infants and toddlers are high priority targets for iNTS vaccines and there is precedent for conjugate vaccines in preventing invasive bacterial infections (e.g. pneumococcal, Hib) in these critical groups. The purpose of this application is to investigate the immunogenicity and protective efficacy of COPS:FliC vaccines in a mouse model of maternal and early life immunization. Immunoprophylactic strategies to protect infants include active immunization initiated during the first 6 months of life and placental transfer of maternal antibodies. The magnitude and quality of immune responses, and the longevity of protection imparted by COPS:FliC vaccines in infants, will determine their potential use as pediatric vaccines. The possible interference of maternally transferred antibodies with COPS:FliC vaccination in infants is also an important point of consideration, as maternal antibodies are known to interfere with the take of several vaccines, including glycoconjugates. This is particularly important for highly endemic areas, where maternal antibodies to NTS antigens are expected due to natural exposure. The use of iNTS conjugate vaccines to prevent disease early in life has never been investigated. In Aim 1, we will evaluate the immunogenicity and protective efficacy of COPS:FliC in infant mice testing a range of dosage levels, intervals for immunization and protective efficacy after single or multiple immunizations. Parallel studies in adult mice will compare vaccine performance at difference life stages. In Aim 2, we will assess the duration of vaccine-induced immunity and anamnestic responses. In Aim 3, we will assess the protective efficacy of COPS:FliC induced maternal antibody for infant pups, and determine whether maternal antibodies elicited through vaccination or natural infection with wild-type African iNTS strains interfere with active vaccination of the offspring. These important studies will elucidate the potential use of COPS:FliC conjugates as pediatric vaccines and will facilitate further study as public health tools to protect human infants.

描述（由申请人提供）：在工业化国家，非伤寒沙门氏菌（NTS）是细菌性胃肠炎的重要原因，可表现为婴儿的侵袭性疾病。在撒哈拉以南非洲，多重耐药NTS是婴儿严重侵袭性细菌性疾病的主要原因，病死率高达10 - 24%。值得注意的是，撒哈拉以南非洲约75-90%的侵袭性NTS（iNTS）感染是由S。鼠伤寒沙门氏菌（S.肠道。目前没有或即将出现的人类iNTS疫苗。NTS的O多糖（OPS）和鞭毛蛋白已被证明是重要的毒力因子，并且在动物模型中是针对致死性iNTS感染的保护性抗原。细菌多糖在婴儿中的免疫原性通常很差，并且在任何年龄都不能赋予免疫记忆。然而，这些限制可以通过与蛋白质缀合来克服。我们开发了一种新的S。使用S.肠杆菌鞭毛蛋白作为化学连接的同源菌株Core和OPS（COPS）的载体蛋白，显示出改善的抗多糖免疫应答和对侵袭性S.成年小鼠的肠道感染。婴儿和幼儿是iNTS疫苗的高度优先目标， 是结合疫苗在预防这些关键群体中侵袭性细菌感染（例如肺炎球菌、Hib）的先例。本申请旨在研究COPS：FliC疫苗在母体和生命早期免疫小鼠模型中的免疫原性和保护效力。保护婴儿的免疫预防策略包括在出生后头6个月开始的主动免疫和母体抗体的胎盘转移。免疫应答的强度和质量以及COPS：FliC疫苗在婴儿中赋予的保护寿命将决定其作为儿科疫苗的潜在用途。母体转移抗体对婴儿COPS：FliC疫苗接种的可能干扰也是一个重要的考虑因素，因为已知母体抗体会干扰几种疫苗（包括糖缀合物）的接种。这对于高度流行的地区尤其重要，在这些地区，由于自然暴露，预计母体会产生针对NTS抗原的抗体。从未研究过使用iNTS结合疫苗预防生命早期疾病。在目标1中，我们将在幼小鼠中评价COPS：FliC的免疫原性和保护效力，测试一系列剂量水平、免疫间隔和单次或多次免疫后的保护效力。成年小鼠的平行研究将 比较疫苗在不同生命阶段的性能。在目标2中，我们将评估疫苗诱导的免疫和记忆应答的持续时间。在目标3中，我们将评估COPS：FliC诱导的母体抗体对幼仔的保护效力，并确定通过接种或野生型非洲iNTS菌株自然感染引起的母体抗体是否干扰后代的主动接种。这些重要的研究将阐明COPS：FliC偶联物作为儿科疫苗的潜在用途，并将促进作为保护人类婴儿的公共卫生工具的进一步研究。