Vaccine development for Group B Neisseria meningitidis and Escherichia coli K1

针对GBM脑膜炎的疫苗开发因病原体荚膜多糖(PSA)而变得复杂，PSA是一种α2-8连接的聚唾液酸，与大肠杆菌K1荚膜多糖的表面糖以及宿主结构相同，特别是在胎儿发育期间。尽管有有效的抗生素和支持治疗，但全身感染的死亡率和发病率仍然高得令人无法接受，特别是由GBM和大肠杆菌K1引起的脑膜炎。GBM继续在世界各地引起流行和暴发，而大肠杆菌K1是新生儿脑膜炎和肾脏感染的主要原因。为了最终提供针对这些微生物的疫苗，我们检查了PSA抗体与自身免疫性疾病或对胎儿的影响之间是否存在关联的证据。 脑膜炎双球菌根据其CPS被分为血清组。在报告的13个CP组中，有5个(A、B、C、W135和Y)导致了几乎所有的脑膜炎双球菌疾病。作为基本的毒力因子，五组CP抑制补体的保护作用；此外，它们还起到保护性抗原的作用，事实证明，临界水平的血清Ig G CP抗体特异性地诱导A、C、W135和Y组的补体介导的溶解和对GBM组的吞噬细胞杀伤。A、C、W135和Y组存在有效的基于CP的疫苗，但没有针对GBM或E.ColiK1的疫苗。GBM在婴幼儿中引起的感染比A、C、W135或Y组更多。 虽然PSA抗体在体外与许多胎儿和成人组织结合，但没有证据表明体内结合或相关的病理。已经致力于开发使用非囊膜抗原的疫苗，包括外膜蛋白、脂多糖、铁结合蛋白和通过检查生物体DNA确定的其他抗原。这些抗原中的许多是多态的、异质性的，并且容易受到抗原变异的影响，可能并不代表所有的GBM。此外，没有一种对大肠杆菌K1有用。基于b型流感嗜血杆菌、伤寒沙门氏菌(Vi)、肺炎球菌和C群脑膜炎球菌(GCM)结合疫苗的性能，我们开发了一种PSA结合疫苗，可诱导血清中抗PSA抗体的保护性水平。它生产简单，易于标准化，对所有年龄段的人都应该接近100%有效。它在实验室小鼠和灵长类动物身上的表现已经得到证实。 很少有研究比较脑膜炎双球菌血清组之间的感染严重程度和结局，发表的关于脑膜炎双球菌脑膜炎后遗症的研究没有提到自身免疫性疾病，如格林-巴氏综合征、多发性硬化症等。在缺乏流行病学或临床证据将病理与PSA抗体联系起来的情况下，我们对脑膜炎双球菌患者进行了一项回顾性队列研究，以检查自身免疫的证据。所有丹麦人组成了我们的研究队列，研究对象为1977年至2004年间因自身免疫性疾病而接受跟踪调查的7,467,001人。2984名患者被诊断为GBM脑膜炎，914名GCM脑膜炎患者为对照人群。自身免疫性疾病的发病率比率提供了相对风险的衡量标准。与C组脑膜炎或无脑膜炎球菌性脑膜炎病史的患者相比，患有GBM脑膜炎的患者患自身免疫性疾病的风险没有增加。我们还研究了这个队列是否可能增加患有GBM疾病的妇女早产或死产的风险，以及她们的第一个孩子是否有更高的出生缺陷风险。我们没有发现这样的关联。我们的发现表明，系统性感染GBM与自身免疫性疾病或免疫反应性疾病无关，后者可能会在脑膜炎双球菌疾病后长达31年的时间内影响后代的健康。

Vaccine development against GBM meningitis is complicated by the pathogens capsular polysaccharide (PSA), an alpha 2-8-linked polysialic acid that is identical to the surface saccharide of the E. coli K1 capsular polysaccharide as well as to host structures, especially during fetal development. Despite effective antibiotic and supportive therapy, the mortality and morbidity of systemic infections, especially meningitis caused by GBM and Escherichia coli K1, remain unacceptably high. GBM continues to cause epidemics and outbreaks throughout the world, and E. coli K1 is a major cause of neonatal meningitis and kidney infections. With the goal of eventually providing a vaccine against these organisms, we examined evidence or the lack thereof for an association between PSA antibodies and autoimmune disease or effects on fetuses. Meningococci are classified into serogroups according to their CPs. Of the 13 reported CP groups, 5 (A, B, C, W135, and Y) cause almost all meningococcal disease. As essential virulence factors, the five group CPs inhibit the protective actions of complement; in addition, they function as protective antigens as evidenced by the fact that a critical level of serum IgG CP antibodies specifically induces both complement-mediated lysis of groups A, C, W135, and Y and opsonophagocytic killing of group GBM. Effective CP-based vaccines exist for groups A, C, W135, and Y, but none for GBM or E. coli K1. GBM causes more infections in infants and young children than do groups A, C, W135, or Y. Although PSA antibodies bind to many fetal and adult tissues in vitro, there is no evidence for in vivo binding or associated pathology. Efforts have been directed towards developing vaccines using non-capsular antigens, including outer membrane proteins, lipopolysaccharides, iron-binding proteins, and other antigens identified by examining the organisms DNA. Many of these antigens are polymorphic, heterogeneous, and subject to antigenic variation and may not be representative of all GBM. Furthermore, none will be useful against E. coli K1. Based on the performance of the Haemophilus influenzae type b, Salmonella typhi (Vi), pneumococcal, and group C meningococcal (GCM) conjugate vaccines, we developed a PSA conjugate that induced protective levels of serum IgG antiPSA. It is simple to produce and easy to standardize and should be close to 100 percent effective at all ages. Its performance in laboratory mice and primates has been confirmed. Few studies have compared severity of infection and outcome among meningococcal serogroups, and published studies of sequelae of meningococcal meningitis do not mention autoimmune diseases, such as Guillain-Barr syndrome, multiple sclerosis, etc. In the absence of epidemiological or clinical evidence to associate pathology with PSA antibodies, we conducted a retrospective cohort study of meningococcal patients to examine evidence for autoimmunity. The entire Danish population constituted our study cohort of 7,467,001 individuals followed for autoimmune disease between 1977 and 2004. GBM meningitis was diagnosed in 2,984 individuals, and the control population was 914 patients with GCM meningitis. Ratios of incidence rates of autoimmune diseases provided a measure of relative risk. Patients with GBM meningitis, either in comparison with people with group C meningococcal meningitis or those with no history of meningococcal meningitis, exhibited no increased risk of autoimmune diseases. We also studied this cohort for possible increased risk of preterm or stillbirth to women with previous GBM disease and whether their first-born children were at increased risk for birth defects. We found no such associations. Our findings suggest that systemic infection with GBM is not associated with autoimmune diseases or with immunoreactive diseases that may affect the health of offspring for up to 31 years after meningococcal disease.