P4-IVIG immunotherapy for adjunct treatment of severe respiratory infection

社区获得性肺炎（CAP）是英国感染相关死亡的最常见原因，占重症监护入院人数的6%。尽管使用抗生素和最佳支持治疗，需要重症监护的CAP患者仍有49.4%的住院死亡率。已经研究了类固醇和一些免疫修饰治疗作为严重感染的额外治疗，但是否有任何生存益处的证据存在很大争议。需要新的治疗方法来改善结果，特别是卫生部强调了英国抗生素耐药感染的紧迫威胁。本研究探讨了一种通过改善与感染细菌结合的抗体存在下的吞噬细胞（吞噬并杀死细菌的白细胞）功能来刺激严重肺炎患者肺和血液中免疫反应的策略。肺炎球菌表面粘附素A （PsaA）是肺炎链球菌的表面分子，在细菌粘附中起重要作用。P4是一种由28个氨基酸组成的PsaA肽片段，可激活人吞噬细胞（包括巨噬细胞和中性粒细胞），在实验室实验中导致肺炎球菌、葡萄球菌和革兰氏阴性菌的粘附和内化。此外，P4与静脉注射免疫球蛋白（IVIG）作为抗菌抗体的来源，可增加人肺巨噬细胞对肺炎球菌的摄取和杀伤，同时通过显著减少或清除肺和血液中的细菌，显著提高肺炎和感染动物模型的存活率。该伙伴关系旨在开发增强被动免疫疗法（API）试验，以提高国际电联患者的生存率，特别是重症肺炎患者的生存率。在这个特定的项目中，我们将采取下一步，通过合成少量的P4，筛选其毒性并检查其在已建立的实验室分析中是否有效。我们的当务之急将是P4和P4/IVIG联合的i期研究。

Community-acquired pneumonia (CAP) is the commonest cause of infection-related death in the UK and accounts for 6% of admissions to Intensive Care. Patients with CAP who require Intensive Care still have a hospital mortality of 49.4%, despite antibiotics and optimal supportive care. Steroids and some immune-modifying treatments have been investigated as additional treatment in severe infection, but evidence for any survival benefit is heavily disputed. New therapies are needed to improve outcome, particularly as the Department of Health has highlighted the urgent threat of antibiotic resistant infections in the UK. This proposal investigates a strategy to stimulate immune responses both in the lung and the blood in patients with severe pneumonia by improving phagocyte (white blood cells that ingest and kill bacteria) function in the presence of antibody binding to the infecting bacteria.Pneumococcal surface adhesin A (PsaA) is a surface molecule of Streptococcus pneumoniae with a vital role in bacterial adherence. P4 is a 28-amino acid peptide fragment of PsaA which activates human phagocytes (both macrophages and neutrophils) resulting in adherence and internalization of pneumococci, staphylococci and gram negative bacteria in laboratory experiments. Furthermore, P4 administered with intravenous immunoglobulin (IVIG) as a source of anti-bacterial antibody increases uptake and killing of pneumococci by human lung macrophages, together with dramatically improving survival in animal models of pneumonia and infection by significantly reducing or clearing bacteria in both lungs and blood.This partnership aims to develop Augmented Passive Immunotherapy (API) trials to improve patient survival in the ITU, particularly from severe pneumonia. In this specific project, we will take the next step by synthesising a small quantity of P4, screening this for toxicity and checking that it works in established laboratory assays. Our immediate follow-on priority will be phase 1 study with both P4 and the P4/IVIG combination.