P4-IVIG immunotherapy for adjunct treatment of severe respiratory infection

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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.