Development of an anti-endotoxin vaccine for sepsis.
Development of an anti-endotoxin vaccine for sepsis.
复制标题
开发脓毒症抗内毒素疫苗。
DOI：
10.1007/978-90-481-9078-2_13
复制
发表时间：
2010
影响因子：
--
通讯作者：
Cross,AlanS
中科院分区：
文献类型：
--
作者：
Cross,AlanS
革兰氏阴性细菌脂多糖（LPS，内毒素）是脓毒症的重要引发剂，脓毒症是重症监护病房中死亡的主要原因的临床综合征。针对革兰氏阴性菌（GNB）中广泛保守的核心LPS结构的疫苗已被开发用于治疗和/或预防脓毒症。灭活全菌疫苗（E. colio 111：B4，J5 [Rc化学型]突变株和S. minimab，Re化学型）保护小鼠免受实验性脓毒症。在一项大型对照临床试验中，人J5免疫抗血清降低了GNB脓毒症的死亡率;然而，随后的抗内毒素抗体临床研究并未证明脓毒症的保护作用。此后，多项临床研究证明了不同临床环境中LPS核心循环抗体水平与发病率和死亡率之间的相关性。因此，我们通过将解毒的J5 LPS（J5 dLPS）与来自BN组的外膜蛋白（OMP）结合来开发亚单位疫苗。脑膜炎该疫苗在脓毒症实验模型中高度有效，并进展到1期临床试验。虽然耐受性良好，但该疫苗仅诱导抗J5 dLPS抗体增加3-4倍。添加TLR 9激动剂（具有CpG基序的寡脱氧核苷酸）作为疫苗的佐剂增加了小鼠中的抗体水平，并且疫苗/CpG组合将进展到1期人类研究。已经开发了另外的疫苗，其中核心糖脂与载体蛋白缀合或掺入脂质体中，但尚未进展到临床试验。如果一种抗内毒素疫苗成为可能，将需要一种针对不同风险人群的新免疫策略。
Gram-negative bacterial lipopolysaccharide (LPS, endotoxin) is an important initiator of sepsis, a clinical syndrome that is a leading cause of death in intensive care units. Vaccines directed against core LPS structures that are widely conserved among Gram-negative bacteria (GNB) have been developed for the treatment and/or prevention of sepsis. Killed whole bacterial vaccines (E. coliO111:B4, J5 [Rc chemotype] mutant andS. minnesota, Re chemotype) protected mice against experimental sepsis. Human J5 immune antisera reduced the mortality from GNB sepsis in a large controlled clinical trial; however, subsequent clinical studies with antiendotoxin antibodies did not demonstrate protective efficacy in sepsis. Multiple clinical studies have since demonstrated a correlation between the level of circulating antibodies to LPS core and morbidity and mortality in different clinical settings. We therefore developed a subunit vaccine by combining detoxified J5 LPS (J5 dLPS) with the outer membrane protein (OMP) from group BN. meningitidis. This vaccine was highly efficacious in experimental models of sepsis and progressed to phase 1 clinical trial. While well-tolerated, this vaccine induced only 3–4-fold increases in anti-J5 dLPS antibody. Addition of the TLR9 agonist, oligodeoxynucleotide with a CpG motif, as adjuvant to the vaccine increased antibody levels in mice and the vaccine/CpG combination will progress to phase 1 human study. Additional vaccines in which the core glycolipid was either conjugated to carrier protein or incorporated into liposomes have been developed, but have not progressed to clinical trial. Should an antiendotoxin vaccine become available, a new immunization strategy directed towards distinct populations at risk will be required.
登录
查看更多内容
影响因子：
--
作者：
Lukasiewicz, J;Jachymek, W;Lugowski, C
通讯作者：
Lugowski, C
接受同种异体骨髓移植的患者中大肠杆菌粗突变株的抗体滴度对抗移植物抗宿主病的保护作用的证据
DOI：
10.1016/s0140-6736(87)90700-8
发表时间：
1987
期刊：
The Lancet
影响因子：
--
作者：
J. Cohen;S. Hashimi;J. Apperley;R. Moore;L. Jones;V. Aber
通讯作者：
V. Aber
DOI：
10.1177/096805199400100102
发表时间：
1994
期刊：
Journal of Endotoxin Research
影响因子：
--
作者：
I. L. Bennett
通讯作者：
I. L. Bennett
用粗突变型大肠杆菌 J5 免疫人类后产生脂多糖抗体。
DOI：
10.1093/infdis/163.4.769
发表时间：
1991
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
J. Baumgartner;D. Heumann;T. Calandra;M. Glauser
通讯作者：
M. Glauser
革兰氏阴性菌的 R 型脂多糖 (LPS) 作为可能的疫苗抗原。
影响因子：
--
作者：
E. S. Stanislavsky;T. Makarenko;E. V. Kholodkova;C. Lugowski
通讯作者：
C. Lugowski