Evaluation of Anti-endotoxin Vaccine for Human Use

描述（由申请人提供）：革兰氏阴性菌引起的感染 可能并发败血症、多器官衰竭和死亡。以来 死亡率在过去十年中没有改变，新的战略补充 需要常规抗生素治疗和支持性护理。我们开发 一种由来自大肠杆菌0111：B4的解毒脂多糖（LPS）组成的疫苗， 与B组外膜蛋白复合的Rc（J5）化学型 脑膜炎球菌（J5 dLPS/ OMP疫苗）。这种疫苗诱导抗体， 细菌LPS的高度保守区域，其具有保护活性， 被动地在脓毒症的动物模型中。在上一个资助期， 给24个人类实验对象注射了这种疫苗疫苗是安全的，耐受性良好，但 抗体应答低于在兔子和啮齿动物中测量的抗体应答。 因此，在本提案中，我们希望评价安全性、免疫原性和 当与佐剂MF-59一起给予时，该疫苗的功能活性， 在一些实施方案中，所述寡核苷酸是寡核苷酸（CpG），其中每一种都已安全地施用于人类。 早些时候，我们发现疫苗诱导的抗体结合异源LPS， 增强大鼠循环中细菌和内毒素的清除 并中和LPS诱导离体细胞因子的能力， 人嗜中性粒细胞形成超氧化物。我们现在将抗体 具有体内功能活性的疫苗/佐剂免疫后的水平 （清除研究和保护活性）和体外（LPS结合和LPS 中和研究）。这些活动可以作为替代标记， 疫苗效力（具体目标一）。然后我们将进行第一阶段的疫苗研究 和佐剂（Specific Aim II）。J5 LPS抑制结合 疫苗诱导的抗异源LPS抗体。因此，我们将确定， 通过比较J5 LPS的抑制活性， J5 LPS与其他核心LPS种类的完整和亚基结构，并将 用疫苗开发针对该表位的单克隆抗体（特异性目的 III）。补体，巨噬细胞和中性粒细胞在功能性 将定义抗J5 dLPS抗体的活性以及 对细胞的LPS表面受体（toll样受体4和CD 14）的免疫 从动物和人类受试者（具体目标IV）。如果成功，这些 研究将导致II期和III期研究的预防和治疗 败血症

Description(provided by applicant): Infections caused by gram negative bacteria may be complicated by sepsis, multi-organ failure and death. Since the mortality has not changed during the last decade, new strategies to supplement conventional antibiotic therapy and supportive care are required. We developed a vaccine composed of detoxified lipopolysaccharide (LPS) from E coli 0111:B4, Rc (J5) chemotype complexed to the outer membrane protein of group B meningococcus (J5 dLPS/ OMP vaccine). This vaccine induces antibodies to a highly conserved region of bacterial LPS that are protective both actively and passively in animal models of sepsis. In the last grant period we administered this vaccine to 24 human subjects. The vaccine was safe and well-tolerated, but the antibody response was lower than that measured in rabbits and rodents. Consequently, in this proposal we wish evaluate the safety, immunogenicity and functional activity of this vaccine when given with the adjuvants MF-59 and oligonucleotide (CpG), each of which has been safely administered to humans. Earlier, we found that vaccine-induced antibody bound heterologous LPS, enhanced the clearance of bacteria and endotoxin from the circulation of rats and neutralized the ability of LPS to induce cytokines ex vivo and to prime superoxide formation by human neutrophils. We now will correlate antibody levels following vaccine/adjuvant immunization with functional activity in vivo (clearance studies and protective activity) and in vitro (LPS binding and LPS neutralization studies). These activities may serve as surrogate markers for vaccine efficacy. (Specific Aim I). We then will do a phase I study of vaccine and adjuvants in human subjects (Specific Aim II). J5 LPS inhibits the binding of vaccine-induced antibody to heterologous LPS. We therefore will determine if there is a specific J5 LPS epitope by comparing the inhibitory activity of complete and subunit structures of J5 LPS with other core LPS species, and will develop monoclonal antibodies to this epitope with the vaccine (Specific Aim III). The role of complement, macrophages and neutrophils in the functional activity of anti-J5 dLPS antibodies will be defined as well as the effect of immunization on LPS surface receptors (toll-like receptor 4 and CD14) of cells from both animals and human subjects (Specific Aim IV). If successful, these studies will lead to Phase II and III studies for the prevention and treatment of sepsis.