Cross Reacting Polysaccharides (H. influenzae types a and b, and B. pumilus)

交叉反应多糖（a 型和 b 型流感嗜血杆菌，以及短小芽孢杆菌）

• 批准号: 8553872
• 负责人: Rachel Schneerson
• 金额: $ 16.7万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553872
• 关键词: 4 year old; Acetylglucosamine; Acids; Alaska Native; Amino Sugars; Antibodies; Antigens; Apache Indians; Bacteremia; Bovine Serum Albumin; Brazil; Canada; Cell Wall; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Complement; Conjugate Vaccines; Data; Development; Disease; Disease Outbreaks; Dose; Double-Blind Method; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Goals; Haemophilus influenzae; Haemophilus influenzae type b bacteria; Herd Immunity; Immunization; Incidence; Infant; Infection; Laboratories; Lansing Virus; Licensing; Link; Manitoba; Meningitis; Methods; Monosaccharides; Mus; Netherlands; Oligosaccharides; Persons; Polysaccharides; Population; Property; Proteins; Randomized; Rattus; Reporting; Research Personnel; Resistance; Ribitol; Safety; Serum; Site; South Africa; Structure; Sugar Alcohols; Testing; Tetanus Toxoid; Time; United States; Vaccination; Vaccines; Virulence; Virulent; bactericide; base; control trial; dimer; immunogenicity; inorganic phosphate; pathogen; phosphodiester; population based; programs; vaccine development

The investigator for this report has retired. There is no report on progress. Following is last year's report. Herd immunity followed widespread use of the Haemophilus influenzae type b (Hib) conjugate vaccine, and the near-elimination of Hib led to speculation that other Haemophilus influenzae (Hi) types may emerge as causes of meningitis. For example, in Brazil, the incidence of Hib meningitis decreased by 69 percent during the first year after initiation of Hib conjugate immunization while the incidence of Hia meningitis increased 8-fold. The Netherlands Reference Laboratory reported that type a was observed only in children younger than 4 years old. Properties of Hia and Hib CP. Hi may be classified into three virulence groups of two, related to their CP structures. Types a and b, which are the most virulent, are composed of a neutral sugar, an alcohol (ribitol), and a phosphodiester; types c and f are composed of an N-acetylated aminosugar, a monosaccharide, and a phosphodiester; and (3) types d and e have a repeat unit of an N-acetylglucosamine and N-acetylmannosamineuronic acid. Compared with the other four types, Hib and Hia are resistant to the bactericidal effects of complement alone. Challenge of infant rats showed that the 50 percent infective dose (ID50) for bacteremia of both Hib and Hia was several logs lower than of the other types. Intranasal challenge of infant rats with type b or type a resulted in 55 to 90 percent bacteremia with type b and 35 percent with type a. The other types were not invasive. Invasive diseases caused by Hia. Rates of Hia disease have remained constant in the United States despite Hib vaccination. From 1998 to 2002, the Emerging Infections Program of the CDC conducted active laboratory- and population-based surveillance for Hi disease in data from nine sites with approximately 35 million people. Seventeen of 1,743 invasive isolates were Hia, which is an important cause of meningitis in certain populations such as White Mountain Apache Indian childrenwith an annual incidence of 254 cases/100,000 children of Hia meningitis. Hammitt et al. (Pediatr Infect Dis J 2005;24:453) reported an outbreak of invasive Hia disease among Native Alaska infants. During a 6-month period in two proximate villages, five Hia cases were documented. In Brazil, an incidence of Hia meningitis of 0.16 cases/100,000 person-years was reported. South Africa and native populations in Manitoba Canada also report Hia meningitis in children. Hia vaccine. The number of Hia cases is too low for a randomized, double-blinded, controlled trial. Yet, precedent exists for adding types within a species to a vaccine without evidence for efficacy. For example, the licensing of several pneumococcal types, including meningococcal groups Y and W135 and poliovirus type 2, was based on their safety and immunogenicity. The structural, experimental, and clinical properties of Hia CP closely resemble those of type b, and the increasing number of reports of Hia-invasive disease suggests that development of an Hia conjugate is warranted. Methods for conjugating type b CP to a protein are applicable to Hia. D-1,5-ribitolphosphate is a constituent of the CPs of Hia and Hib. We reported that the cell wall polysaccharide (PS) of B. pumilus Sh18 contains a poly-1,5-ribitolphosphate as a major component and that antibodies induced in mice by such conjugate cross-reacted with both Hia and Hib. We synthesized polyribitolphosphate chains containing either 8 or 12 repeat units, with the terminal keto groups used for conjugation to aminooxylated bovine serum albumin (BSA or tetanus toxoid. We injected the conjugates into mice, three times at 2-week intervals at 2.5 g/mouse and obtained sera a week later. ELISA demonstrated antibodies to both Hia and Hib, with the octamer conjugate a better immunogen than the dodecamer conjugate. Some of the tested sera showed bactericidal activity against both type a and type b as roughly correlated with their ELISA values. Other constructs and formulations arebeing studied. As an alternative to the native polysaccharide-based vaccine, we are developing a conjugate vaccine against Hia by chemically synthesizing fragments of its capsular material which is built up by glucosyl-ribitol-phosphate repeating units. So far we have synthesized the glucosyl-ribitol unit and were able to assemble a dimer of the repeating unit. Construction of higher-membered phosphodiester-linked oligosaccharides is in progress.

该报告的调查员已退休。没有进度的报告。以下是去年的报告。 在广泛使用B型流感嗜血杆菌（HIB）结合疫苗的情况下，牛群的免疫力以及HIB的近乎灭绝的疫苗，导致人们猜测其他流感嗜血杆菌（HI）类型可能会降低为脑膜炎的原因。例如，在巴西，hib脑膜炎的发生率在启动Hib结合物免疫后的第一年降低了69％，而HIA脑膜炎的发生率增加了8倍。荷兰参考实验室报告说，A型仅在4岁以下的儿童中观察到。 HIA和HIB CP的性质。 HI可以分为与CP结构有关的三个毒力组。最有毒的A型和B型由中性糖，酒精（核糖醇）和磷酸酯组成。 C型和F由N-乙酰化氨基加糖，单糖和磷酸二酯组成。 （3）D型和E具有N-乙酰基葡萄糖和N-乙酰基菜单氨基氨基甲酸的重复单位。与其他四种类型相比，HIB和HIA对单独补体的杀菌作用有抵抗力。婴儿大鼠的挑战表明，HIB和HIA菌血症的50％感染剂量（ID50）比其他类型的几个原木低。婴儿大鼠的鼻内挑战或A型A型导致55％至90％的菌血症，B型和A型35％。其他类型不是侵入性。 HIA引起的侵入性疾病。 尽管疫苗接种了，但在美国，HIA疾病的发生率一直保持不变。从1998年到2002年，CDC的新兴感染计划对来自约3500万人的9个地点的数据进行了活跃的实验室和基于人群的HI疾病监测。 1,743种侵入性分离株中有17个是HIA，这是某些人群中脑膜炎的重要原因，例如白山Apache Indian儿童，年龄为254例/100,000例HIA脑膜炎儿童。 Hammitt等。 （Pediatr Infect Dis J 2005; 24：453）报道了阿拉斯加原住民的侵入性HIA疾病爆发。在两个近端村庄的6个月期间，记录了5例HIA病例。在巴西，报告了HIA脑膜炎的发生率为0.16例/100,000人年。加拿大曼尼托巴省的南非和本地人口也报告儿童脑膜炎。 HIA疫苗。 对于随机，双盲，对照试验而言，HIA病例的数量太低。然而，在没有疗效证据的情况下将物种中的类型添加到疫苗中的先例。例如，几种肺炎球菌类型的许可，包括脑膜炎球菌组Y和W135和2型脊髓灰质炎病毒，是基于它们的安全性和免疫原性。 HIA CP的结构，实验和临床特性与B型的结构性和临床特性以及HIA侵入性疾病的越来越多的报告表明，有必要开发HIA偶联物。将B型CP结合为蛋白质的方法适用于HIA。 D-1,5-核磷酸是HIA和HIB CP的组成部分。我们报道说，B. pumilus SH18的细胞壁多糖（PS）包含聚-1,5-磷酸磷酸盐作为主要成分，并且通过与HIA和HIB相互反应的这种结合诱导的小鼠诱导的抗体。我们合成了包含8或12个重复单位的多义磷酸链链，末端酮类组用于结合用于氨基二氧化牛血清白蛋白（BSA或TETANUS TOXOID）。我们在2.5 g/ever seria seria seria sera and sera and seria sera and. sera and. sera sera and. sera and. sera and. sera and sera sera sera sera and sera sera sera sera sera and sera sera sera sera and. sera sera sera sera and. sera sera and. sera and. sera sera sera and. sera se。 HIB，八聚体偶联物的免疫原比十二聚体缀合物更好。 其他构造和配方正在研究。作为基于天然多糖的天然多糖疫苗的替代方法，我们通过化学合成其囊层材料的化学合成片段开发了针对HIA的偶联疫苗，该材料是由葡萄糖基里比硫醇 - 磷酸重复单元建立的。到目前为止，我们已经合成了葡萄糖基核酸单元，并能够组装重复单元的二聚体。较高元素的磷酸化酯连接寡糖的构建正在进行中。