Targeting the immune system in bacterial meningitis
Bacterial meningitis is a severe infection of the central nervous system. During bacterial meningitis an uncontrolled, massive inflammatory response occurs, causing brain damage and death. InflaRX, the industrial consortium partner, has developed a monoclonal antibody (IFX-1) against complement component 5a (C5a), which is currently the most promising treatment target in bacterial meningitis. This treatment was shown to be safe and effective in inhibiting the complement system in humans. Both applicant and InflaRX aim to work towards a phase-2b clinical trial in bacterial meningitis patients. Before this trial can be initiated questions regarding the underlying mechanisms, safety, and necessary treatment duration need to be answered.
The objective is to confirm the potential of C5a-antibody therapy in bacterial meningitis patients by using human samples both in vitro and in vivo. In work package 1, we will study the dynamics of complement activation in blood and cerebrospinal fluid of acute bacterial meningitis patients to elucidate the duration and mechanisms of complement activation. For this, we will measure complement components and other markers of infection in serial blood samples and cerebrospinal fluid from the diagnostic lumbar puncture in bacterial meningitis patients. In work package 2, we will setup an in vitro whole blood killing assay in which we can study the effect of complement inhibition on bacterial outgrowth and the inflammatory response. This model will allow us to simulate different treatment conditions (e.g. antibiotics and dexamethasone) for the major pathogens causing bacterial meningitis (Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes). This will help to define whether C5a-antibodies can be safely administered to all suspected bacterial meningitis patients irrespective of the causative pathogen. Our project presents an essential step in designing a randomized controlled trial of C5a-antibody treatment in patients with bacterial meningitis.
