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: 7734726
• 负责人: Rachel Schneerson
• 金额: $ 10.18万
• 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/7734726
• 关键词: 4 year old; Acetylglucosamine; Acids; Alaska Native; Amino Sugars; Antibodies; Antigens; Apache Indians; Bacteremia; Bacteriolysis; Brazil; Canada; Cell Wall; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Complement; Conjugate Vaccines; Data; Development; Disease; Dose; Double-Blind Method; Goals; Haemophilus influenzae; Haemophilus influenzae type b bacteria; Herd Immunity; Immunity; Immunization; Incidence; Infant; Infection; Invasive; Laboratories; Lansing Virus; Licensing; Manitoba; Mediating; Medical Surveillance; Meningitis; Methods; Monosaccharides; Mus; Netherlands; Numbers; Persons; Polysaccharides; Population; Property; Proteins; Randomized; Rate; Rattus; Reporting; Resistance; Ribitol; Safety; Serum; Site; South Africa; Structure; Sugar Alcohols; Systemic infection; Testing; Tetanus Toxoid; Time; Vaccination; Vaccines; Virulence; Virulent; Week; anti-IgG; bactericide; base; immunogenicity; pathogen; phosphodiester; programs

Summary The structures of the 6 capsular polysaccharide (CP) types, a, b, c, d, e, and f of Haemophilus influenzae (Hi) have been elucidated. Systemic infections were due mostly to H. influenzae type b (Hib). A critical level of serum IgG anti-Hib CP confers type-specific immunity by complement-mediated bacteriolysis. Herd immunity followed wide spread usage of Hib conjugate vaccine. This near-elimination of Hib led to the speculation that other Hi types may emerge as causes of meningitis. For example, in Brazil, the incidence of Hib meningitis decreased 69% during 1 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 only observed in <4 year-olds. Properties of Hia and Hib CP Hi can be divided into 3 virulence groups of two, related to their CP structures: types a and b; 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 phosphodiester; types d and e have a repeat unit of an N-acetylglucosamine and N-acetylmannosamineuronic acid. Hib and Hia have greater resistance to the bactericidal effects of complement alone than the other four types. Challenge of infant rats showed that the 50% 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 a strains resulted in 55 to 90% bacteremia with type b, and 35% with type a strains. The other types were not invasive. Invasive Diseases Caused By Hia Rates of Hia disease have been constant in the US regardless of Hib vaccination. From 1998 to 2002, The Emerging Infections Program, of CDC conducted active laboratory- and population-based surveillance for Hi disease in data from 9 sites with approximately 35 million people. Seventeen of 1,743 invasive isolates were Hia. Hia is an important cause of meningitis in certain populations such as White Mountain Apache Indian children who have an annual incidence of 254 cases/100,000 children of Hia meningitis. Hammittet al. reported an out break of invasive Hia disease among Native Alaska infants. During a 6-month period in 2 nearby villages, 5 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 cases is too low for a randomized, double-blinded and controlled trial. There is precedence for adding types within a species to a vaccine without evidence for efficacy. Several pneumococcal types, meningococcal groups Y and W135, and poliovirus type 2 were licensed based upon their safety and immunogenicity. The structural, experimental and clinical properties of Hia CP resemble closely that of type b. The increasing number of reports of Hia invasive diseases suggest that development of a 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 antibodies induced in mice by this PS 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 BSA or tetanus toxoid. These conjugates were injected into mice, 3 times 2 weeks a part at 2.5g/mouse and sera obtained a week later. Elisa demonstrated antibodies to both Hia and Hib, with the octamer conjugate being a better immunogen than dodecamer conjugate. Some of these sera tested showed bactericidal activity against both type a and type b, roughly correlated to their Elisa values.

摘要 对流感嗜血杆菌(Hi)的a、b、c、d、e和f 6种衣壳多糖(CP)的结构进行了研究。系统性感染主要由b型流感嗜血杆菌(Hib)引起。临界水平的血清Ig G抗Hib CP可通过补体介导的溶菌作用产生类型特异性免疫。随着Hib结合疫苗的广泛使用，人群免疫也随之增强。这种几乎消除Hib的情况导致了人们的猜测，即其他Hi类型可能会成为脑膜炎的原因。例如，在巴西，在开始进行Hib结合免疫后的一年内，Hib脑膜炎的发病率下降了69%，而Hib脑膜炎的发病率增加了8倍。荷兰参考实验室报告说，a型仅见于4岁的儿童。 Hia和Hib CP的性质 根据其CP结构，HI可分为3个两个毒力组：a和b型；最强的毒力由中性糖、醇(核糖醇)和磷酸二酯组成；c和f型由N-乙酰化氨基糖、单糖和磷酸二酯组成；d和e型具有N-乙酰氨基葡萄糖和N-乙酰甘露糖醛酸的重复单元。Hib和Hia对补体单独杀菌作用的抵抗力比其他四种类型更强。对幼年大鼠的攻击试验表明，对Hib和Hia菌血症的半数感染剂量(ID50)均比其他类型低几个对数。用b型或a型菌株对幼鼠进行鼻腔攻击，可导致55%~90%的b型菌株菌血症和35%的a型菌株菌血症。其他类型均为非侵袭性。 人类免疫缺陷病毒引起的侵袭性疾病 在美国，无论接种Hib疫苗，Hia病的发病率一直保持不变。从1998年到2002年，美国疾病控制与预防中心的新发感染项目在9个地点、约3500万人的数据中进行了积极的实验室和基于人群的Hi疾病监测。1,743株侵袭性分离株中有17株为Hia。HIA是某些人群中脑膜炎的重要原因，例如白山阿帕奇印第安人儿童，每年每100,000名儿童中有254例HIA脑膜炎。Hammittet al.报道了在阿拉斯加土著婴儿中暴发的侵袭性HIA疾病。在附近两个村庄的6个月期间，记录了5例HIA病例。在巴西，据报告出血性脑膜炎发病率为0.16例/100,000人年。南非和加拿大马尼托巴省的当地居民也报告了儿童患有Hia脑膜炎。 HIA疫苗 对于随机、双盲和对照试验来说，病例数量太少了。在没有有效性证据的情况下，将某一物种的类型添加到疫苗中是有先例的。根据安全性和免疫原性，批准了几种肺炎球菌类型，Y和W135脑膜炎球菌组，以及2型脊髓灰质炎病毒。Hia CP的结构、实验和临床特征与b型非常相似。HIA侵袭性疾病的报道越来越多，提示HIA结合物的开发是必要的。B型CP与蛋白质偶联的方法适用于HIA。 D-1，5-核糖醇磷酸是Hia和Hib的CPS的一种成分。我们报道了短小芽孢杆菌Sh18细胞壁多糖(PS)的主要成分是聚-1，5-核糖醇磷酸，用这种PS结合物诱导的小鼠抗体能与Hia和Hib发生交叉反应。我们合成了含有8个或12个重复单元的聚核糖醇磷酸链，末端的酮基用于与氨基氧基化的牛血清白蛋白或破伤风类毒素结合。将这些结合物以2.5g/只的剂量注射到小鼠体内，每次3次，每次2周，一周后获得血清。酶联免疫吸附试验证实了对Hia和Hib的抗体，其中八聚体结合物比十二聚体结合物是更好的免疫原。其中一些被测试的血清对A型和B型都显示出杀菌活性，这与它们的ELISA值大致相关。

项目成果

Vaccination of COPD patients with a pneumococcus type 6B tetanus toxoid conjugate vaccine.

为 COPD 患者接种 6B 型肺炎球菌破伤风类毒素结合疫苗。

• DOI: 10.1183/09031936.02.00289702
• 发表时间: 2002
• 期刊: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology
• 作者: Jonsson,S;Vidarsson,G;Valdimarsson,H;Schiffman,G;Schneerson,R;Jonsdottir,I
• 通讯作者: Jonsdottir,I

Surveillance for bacterial meningitis by means of polymerase chain reaction.

通过聚合酶链反应监测细菌性脑膜炎。

• DOI: 10.1086/426448
• 发表时间: 2005
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Robbins,JohnB;Schneerson,Rachel;Gotschlich,EmilC
• 通讯作者: Gotschlich,EmilC

Clostridium difficile recombinant toxin A repeating units as a carrier protein for conjugate vaccines: studies of pneumococcal type 14, Escherichia coli K1, and Shigella flexneri type 2a polysaccharides in mice.

艰难梭菌重组毒素 A 重复单元作为结合疫苗的载体蛋白：对小鼠 14 型肺炎球菌、大肠杆菌 K1 和福氏志贺氏菌 2a 型多糖的研究。

• DOI: 10.1128/iai.68.4.2161-2166.2000
• 发表时间: 2000
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Pavliakova,D;Moncrief,JS;Lyerly,DM;Schiffman,G;Bryla,DA;Robbins,JB;Schneerson,R
• 通讯作者: Schneerson,R

Similarities between the pathogenesis of and immunity to diphtheria and pertussis: the complex nature of serum antitoxin-induced immunity to these two diseases.

白喉和百日咳的发病机制和免疫之间的相似之处：血清抗毒素诱导的对这两种疾病的免疫的复杂性。

• DOI: 10.1086/515060
• 发表时间: 1999
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Schneerson,R

Antibodies against Haemophilus influenzae type b capsular polysaccharide and tetanus toxoid before and after a booster dose of the carrier protein nine years after primary vaccination with a protein conjugate vaccine.

在初次接种蛋白缀合物疫苗九年后，在载体蛋白加强剂量之前和之后，针对 B 型流感嗜血杆菌荚膜多糖和破伤风类毒素的抗体。

• DOI: 10.1097/01.inf.0000160955.26151.71
• 发表时间: 2005
• 期刊: The Pediatric infectious disease journal
• 作者: Claesson,BoA;Trollfors,Birger;Lagergard,Teresa;Knutsson,Nina;Schneerson,Rachel;Robbins,JohnB
• 通讯作者: Robbins,JohnB