Candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: Developmental chemistry and investigation of immunological responses following immunization of mice and rabbits
Candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: Developmental chemistry and investigation of immunological responses following immunization of mice and rabbits
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DOI：
10.1016/j.vaccine.2005.06.011
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发表时间：
2005-10-17
期刊：
影响因子：
5.5
通讯作者：
Richards, JC
中科院分区：
文献类型：
--
作者：
Cox, AD;Zou, W;Richards, JC
将免疫原性蛋白载体CRM197与免疫型为L3 galE LPS的脑膜炎奈瑟菌（菌株H44/76）的o -去乙酰化脂多糖（LPS）共价连接制备糖缀合物。该突变株详细阐述了截断的LPS结构，显示76%的B群脑膜炎球菌（NmB）菌株的免疫表位特征。CRM197与o-去酰化LPS的脂质A区还原氨基葡萄糖残基或与o-去酰化LPS的内核区2-酮-3-脱氧辛基酸（Kdo）残基共价连接。在兔和小鼠中，通过脂质a区连接的偶联物对免疫抗原产生了更强的IgG反应。用这些偶联物免疫小鼠血清，测定了它们对几种同源和异源NmB菌株的突变型和野生型LPS的反应性。通过Kdo片段连接载体蛋白的偶联物免疫小鼠的血清只能与来自同源菌株的o -去酰化（但不是完全酰化）LPS发生反应。然而，用偶联物免疫小鼠的血清，其中载体蛋白偶联到脂质A区，主要与含有磷酸乙醇胺的内核表位反应，这些表位位于内核LPS的远端heptose残基（HepII）的相同3位，存在于免疫抗原上。此外，我们观察到用脂质A连接偶联物免疫兔的血清，与小鼠的反应不同，通常对含有磷酸乙醇胺的LPS抗原不像在免疫抗原上一样具有特异性，但表现出更广泛的内核识别，而接受kdo连接偶联物的兔对所有免疫类型只有非常弱的非特异性反应。最后，接受脂质A结合物的6只小鼠中有2只小鼠的血清对L3野生型NmB菌株8047具有杀菌活性，其中1只小鼠在幼鼠模型中能够被动抵抗脑膜炎球菌感染。本研究证明了通过脂质A区与完整磷酸乙醇胺在内核LPS的HepII的O-3位置偶联的Nm内核LPS偶联物的原理证据，有可能引发针对脑膜炎球菌感染的功能性和保护性抗体。(c) 2005 Elsevier Ltd版权所有。
Glycoconjugates were prepared by covalently linking the immunogenic protein carrier CRM197 to O-deacylated lipopolysaccharide (LPS) derived from Neisseria meningitidis (strain H44/76), immunotype L3 galE LPS. This mutant strain elaborates a truncated LPS structure that displays immunological epitopes characteristic of 76% of Group B meningococcal (NmB) strains. CRM197 was covalently linked either to the reducing glucosamine residue of the lipid A region of the O-deacylated LPS or to a 2-keto-3-deoxy-octulosonic acid (Kdo) residue in the inner core region of the O-deacylated LPS. In both rabbits and mice a much stronger IgG response to the immunising antigen was generated in those animals that received conjugates linked via the lipid A region. Sera from mice that were immunized with these conjugates were assayed for their reactivity with LPS, both mutant and wild-type, of several homologous and heterologous NmB strains. Sera obtained from mice immunized with conjugates in which the carrier protein was linked via the Kdo moiety were only able to react with O-deacylated, but not fully acylated (native), LPS from the homologous strain. However, sera obtained from mice that were immunized with conjugates, in which the carrier protein was coupled to the lipid A region, reacted predominately with inner core epitopes that contained phosphoethanolamine at the same 3-position of the distal heptose residue (HepII) of the inner core LPS as was present on the immunising antigen. Additionally it was observed that sera from rabbits immunised with lipid A linked conjugates, unlike the mice responses, were generally not as specific for LPS antigens that contained phosphoethanolamine at the same 3-position as was present on the immunising antigen, but showed a broader inner core recognition, whereas those rabbits that received the Kdo-linked conjugates gave only a very weak non-specific response to all immunotypes. Finally, the sera from two out of six mice that had received lipid A linked conjugates had bactericidal activity against L3 wild-type NmB strain 8047 and one of these was able to passively protect against meningococcal infection in an infant rat model.This study demonstrates evidence towards the proof-in-principle that by using Nm inner core LPS conjugates coupled via the lipid A region with an intact phosphoethanolamine at the O-3 position of the HepII of the inner core LPS, it is possible to elicit functional and protective antibodies against meningococcal infection. (c) 2005 Elsevier Ltd. All rights reserved.