Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis
Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis
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DOI：
10.1016/j.vaccine.2015.10.072
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发表时间：
2015-11-27
期刊：
影响因子：
5.5
通讯作者：
Bajwa, Kanwaldeep K.
中科院分区：
文献类型：
--
作者：
Cross, Alan S.;Greenberg, Nancy;Bajwa, Kanwaldeep K.
背景：革兰氏阴性菌（GNB）是医院感染和败血症的主要原因。多种抗生素耐药性的增加使临床医生的治疗选择更少。 GNB 脂多糖（LPS，或内毒素）抗体可降低感染引起的发病率和死亡率，并且不受细菌针对抗生素的耐药机制的影响。在这项一期研究中，我们注射了一种疫苗，在有或没有 CpG 寡脱氧核苷酸 (ODN) TLR9 激动剂作为佐剂的情况下，可引发针对 LPS 高度保守部分的抗体。 方法：疫苗由来自大肠杆菌 O111:B4（J5 突变体）的解毒 LPS (dLPS) 与 B 组脑膜炎球菌外膜蛋白 (OMP) 非共价复合而成。 20 名健康成年受试者在第 0、29 和 59 天接受三剂抗原（10 μg dLPS），含或不含 CPG 7909（250 或 500 μg）。对受试者的局部和全身不良反应以及实验室检查结果进行评估。通过电化学发光测量抗J5 LPS IgG和IgM抗体水平。由于研究提前终止，并非所有受试者都接受了全部三种剂量。结果：所有疫苗制剂均具有良好的耐受性，没有出现严重程度超过中度的局部或全身事件。单独疫苗组仅在 6 名受试者中的 1 名中实现了 IgG 和 IgM 抗体≥ 4 倍的“应答”反应。相比之下，疫苗加 CPG 7909 组似乎具有更早、更持久的反应（至 180 天）、平均倍数增加更大，以及比基线增加 4 倍以上的“反应者”比例更高。 结论：尽管该研究在所有入组受试者接受所有三剂疫苗之前停止，但无论是否含有 CpG 佐剂，J5dLPS/OMP 疫苗都是安全且耐受性良好的。 CpG 的加入增加了抗体反应≥4 倍的受试者数量，即使在三剂计划剂量中的第二剂之后也很明显。包含 J5dLPS/OMP 抗原和 CpG 佐剂的疫苗值得进一步研究。 (C) 2015 Elsevier Ltd. 保留所有权利。
Background: Gram-negative bacteria (GNB) are a leading cause of nosocomial infection and sepsis. Increasing multi-antibiotic resistance has left clinicians with fewer therapeutic options. Antibodies to GNB lipopolysaccharide (LPS, or endotoxin) have reduced morbidity and mortality as a result of infection and are not subject to the resistance mechanisms deployed by bacteria against antibiotics. In this phase 1 study, we administered a vaccine that elicits antibodies against a highly conserved portion of LPS with and without a CpG oligodeoxynucleotide (ODN) TLR9 agonist as adjuvant.Methods: A vaccine composed of the detoxified LPS (dLPS) from E. coli O111:B4 (J5 mutant) non-covalently complexed to group B meningococcal outer membrane protein (OMP). Twenty healthy adult subjects received three doses at 0, 29 and 59 days of antigen (10 mu g dLPS) with or without CPG 7909 (250 or 500 mu g). Subjects were evaluated for local and systemic adverse effects and laboratory findings. Anti-J5 LPS IgG and IgM antibody levels were measured by electrochemiluminesence. Due to premature study termination, not all subjects received all three doses.Results: All vaccine formulations were well-tolerated with no local or systemic events of greater than moderate severity. The vaccine alone group achieved a >= 4-fold "responder" response in IgG and IgM antibody in only one of 6 subjects. In contrast, the vaccine plus CPG 7909 groups appeared to have earlier and more sustained (to 180 days) responses, greater mean-fold increases, and a higher proportion of "responders" achieving >= 4-fold increases over baseline.Conclusions: Although the study was halted before all enrolled subjects received all three doses, the J5dLPS/OMP vaccine, with or without CpG adjuvant, was safe and well-tolerated. The inclusion of CpG increased the number of subjects with a >= 4-fold antibody response, evident even after the second of three planned doses. A vaccine comprising J5dLPS/OMP antigen with CpG adjuvant merits further investigation. (C) 2015 Elsevier Ltd. All rights reserved.