EXPLORATION OF PROTECTIVE IMMUNITY INDUCED BY SALMONELLA COPS: FLIC CONJUGATES

描述（由申请人提供）：在工业化国家，非伤寒沙门氏菌（NTS）是引起细菌性胃肠炎的重要原因，可在婴儿中表现为侵袭性疾病。在撒哈拉以南非洲，耐多药NTS是造成婴儿严重侵袭性细菌疾病的主要原因，病死率高达10%至24%。值得注意的是，撒哈拉以南非洲约75-90%的侵袭性NTS感染是由鼠伤寒沙门氏菌和肠炎沙门氏菌引起的。目前或即将推出的人类iNTS疫苗还没有。NTS的O多糖（OPS）和鞭毛蛋白在动物模型中已被证明是重要的毒力因子和对致死性iNTS感染的保护性抗原。细菌多糖在婴儿中通常免疫原性差，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结合来克服。本研究以肠炎沙门氏菌鞭毛蛋白为载体蛋白，开发了一种新型肠炎沙门氏菌糖结合疫苗，该疫苗具有较好的抗多糖免疫应答和对成年小鼠肠炎沙门氏菌侵袭性感染的保护作用。婴幼儿是国家免疫系统疫苗的高度优先目标

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.