P4-IVIG immunotherapy for adjunct treatment of severe respiratory infection

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.

Community-acquired pneumonia (CAP) is the most common cause of sepsis-related death in the UK and accounts for 6% of admissions to Intensive Care. Patients with CAP who require Intensive Care have a hospital mortality of 49.4%, despite antibiotics and optimal supportive care. Steroids and recombinant human activated protein C have been investigated as treatment adjuncts in severe infection, but evidence for any survival benefit is heavily disputed. New therapies are needed to improve outcome, particularly now that the DoH has highlighted the added threat of antibiotic resistant infections. We propose a strategy to potentiate pulmonary and systemic immune responses in severe pneumonia and sepsis by augmenting phagocyte function in the presence of cognate immunoglobulin.

Pneumococcal surface adhesin A (PsaA) is a lipoprotein on the surface of Streptococcus pneumoniae with a vital role in adherence. P4 is a 28-amino acid peptide fragment of PsaA which activates human nasopharyngeal cells, macrophages and neutrophils resulting in adherence and internalization of pneumococci, Staphylococci and gram negative bacteria in vitro. We have shown that P4 administered with intravenous immunoglobulin (IVIG) up-regulates Fc receptors, increases opsonophagocytosis and enhances killing of pneumococci by human lung macrophages. P4 and IVIG together dramatically improve survival in murine models of invasive pneumonia, Gram-positive and negative lethal sepsis by significantly reducing or clearing bacterial loads in both tissue and blood.

This re-application was invited by DPFS. The re-application includes the data requested by the Panel and also includes specific advice from the MHRA that together have substantially reduced (it is now one third of previously) the requested budget. We now request batch synthesis of P4 and pre-clinical commerical toxicology testing. Our follow-on priority will be a phase 1 study with P4 and P4/IVIG.

The impact of this grant will be mainly on the partner Institutions and in the development of a novel treatment.

1. Impact of the collaboration on partner Institutions
a) The Liverpool School of Tropical Medicine (LSTM), University of Liverpool (UoL) and Centres for Disease Control, Atlanta (CDC), share a common purpose in wishing to bring new treatments to license that will reduce the mortality and morbidity of infectious diseases. This project will expand the DPFS portfolio of LSTM and bring a new dimension to the laboratories in the Institute of Infection and Global Health at UoL and Laboratory Science at CDC.
b) The project has a strong exit strategy and will cause the partners - LSTM, UoL and CDC - to further strengthen their existing links with the NHS and in particular with the NIHR funded and MHRA Phase 1 accredited Clinical Trials Unit at the Royal Liverpool University Hospital.
c) The Partners all realise the importance of commercial engagement and share an ambition to develop the fully flexible arrangement with Grifols Inc. In particular, we wish to negotiate a full or gated contribution going forward in to Phase 2.

2. Impact on project staff and students
This project will be the first engagement for several staff with either (a) an international partner (CDC) or (b) a commercial partner. Further, the existing studentships (Mathieu Bangert PhD completed, Suzanne Gore PhD programme year 3 and Ben Morton MD year 1) may be expanded with further leveraged applications.

3. Impact on general public
a) The General Public will gain knowledge that will be disseminated during "Meet the public days" and school visits, which are regular events on both UoL and LSTM. The Department of Health have emphasised the importance of new antimicrobial strategies.
b) The UK government has emphasised the importance of NIHR led development of new treatments both for health and economic benefit. This project, if progressing to Phase 1, will be widely publicised on local and national media.

4. Impact on vulnerable populations
LSTM and UoL have a long track record in global health, particularly in Least Economically Developed Countries (LEDC). The global burden of pneumococcal disease is highest in vulnerable LEDC and while the P4-IVIG strategy is not immediately targeted at HIV infected or other vulnerable groups, there is the potential within the partnership to expand this aspect. P4 has already been tested and confirmed to be effective ex vivo using lung samples from smoke exposed Malawian adults.

5. Impact on antibiotic policy
UK antibiotic policy remains alert to the complication of C.difficile and the addition of P4-IVIG may result in reduced antibiotic duration as well as reduced broad spectrum antibiotic use in future.
b) Prophylactic P4-IVIG is a potential strategy as a pre-operative safety measure which may result in decreased antibiotic use in surgical intervention.