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[FG] Trendelenburg Marten

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Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78

Research Project  | 4 Project Members

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level.

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P5_mobile_sensitive_SARS-CoV-2_test

Research Project  | 3 Project Members

The current pandemic outbreak of the SARS-CoV-2 virus that causes the disease COVID-19 is demonstrating the vulnerability of our globalized society for such threats. 1 Governments around the globe were forced to implement counter measures that put a high burden on public life and our economy in order to prevent the collapse of our healthcare system and the death of thousands of patients. 2 One of the main reasons such measures were needed are the inadequacies of our current disease detection system. State-of-the-art systems, while very accurate, are too slow and too expensive to effectively detect infected subjects and help prevent the spread of a pandemic disease. While the digital remote consulting and assessment of symptomatic patients via phone or video call has been adopted, a remote diagnostic test remains lacking. 3 Thus, our current paradigm to wait until symptoms appear before people are tested in centralized facilities is fundamentally flawed to fight diseases like COVID-19. SARS-CoV-2 can be transmitted by patients long before symptoms appear or even by asymptomatic patients. 4,5 As the incubation period lasts several days, 6 these issues lead to the creation of a blind spot: i.e. many patients that are transmitting the disease are currently not diagnosable. The only way to remedy this blind spot, to contain and further prevent pandemic diseases before a vaccine is available, is a new type of test that is mobile, fast, cheap, lab-independent and accurate. The possibility to test large parts of the population at home, avoiding high costs and high strain for the healthcare system, will significantly contribute to immediate containment of such diseases and prevention of the loss of lives, without the need for counter measures that cause large economic damage such as ones we are currently experiencing. Within this proposed project, the group of Prof. Vörös (ETH Zürich), who is leading this project, will develop a rapid test system based on lateral flow assays, with drastically improved sensitivity, while maintaining the point-of-need principle (i.e. rapid turn-around time and immediate availability of the test result). With this test, a clinical sensitivity of close to 100% for the detection of SARS-CoV-2 from nasopharyngeal or throat swab samples seems likely. Our group will then benchmark this technology with real samples against clinically validated methods. The aim of the planned study is to clinically validate the developed test and determine its performance characteristics compared to the current gold standard [a laboratory-developed, qualitative SARS-CoV-2 real-time polymerase chain reaction (PCR)] and in two scenarios (professional-collected vs. self-collected swabs). Patients with suspicion of COVID-19 presenting to the outpatient clinic of the University Hospital Basel or having been diagnosed with COVID-19 after admission to the hospital will be asked for participation in this validation study if a SARS-CoV-2 test is deemed necessary by the treating physicians. Additionally, patients with confirmed viral upper or lower respiratory tract infections will be included. This proposed new test is a unique tool with a high potential to dramatically impact the spread of infectious diseases such as COVID-19 and to decrease mortality and the high economic burden of pandemic diseases. References: Ghebreyesus, A. T. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Dayrit, M. & Mendoza, R. U. Social Cohesion vs COVID-19. SSRN Electron. J. (2020) doi:10.2139/ssrn.3555152. Greenhalgh, T., Koh, G. C. H. & Car, J. Covid-19: a remote assessment in primary care. BMJ 368 , m1182 (2020). Zou, L. et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N. Engl. J. Med. NEJMc2001737 (2020) doi:10.1056/NEJMc2001737. Corman, V. M. et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Eurosurveillance 25 , 2000045 (2020). Bai, Y. et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA (2020) doi:10.1001/jama.2020.2565

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Complement-dependent pathogenic mechanisms in systemic autoimmunity

Research Project  | 6 Project Members

Systemic Lupus Erythematosus (SLE) is the archetype of an autoimmune disease and can involve any organ system eventually leading to comorbidities that can also be observed independently of underlying SLE. The complex pathogenic mechanisms leading to and being involved in this autoimmune-inflammatory syndrome are not well understood. However, complement C1q, the first component of the classical pathway, seems to play a central role. By analysing the role of C1q as well as it's interaction with autoantibodies targeting C1q (anti-C1q) in SLE, the primary goals of the proposed projects are to elucidate 1) mechanisms being involved in the initiation of autoimmunity, 2) mechanisms of secondary acceleration of inflammation, and 3) processes being associated with comorbidities.With regard to mechanisms being involved in the initiation of SLE, homozygous C1q deficiency is the strongest genetic risk factor for the development of SLE. Vice versa, in SLE patients without primary C1q deficiency, C1q is consumed during disease flares, deposited in affected tissues and becoming a target of autoantibodies (anti-C1q). By the characterisation of structures targeted by anti-C1q we aim to understand mechanisms leading to the development of SLE.Secondly, C1q mediates and modulates the uptake of apoptotic cells, a mechanism that is defective in SLE patients. In the context of a defective clearance, dying cells can become antigenic and trigger the autoimmune response. In previous studies I could show that anti-C1q specifically recognize C1q when being bound to apoptotic cells and that anti-C1q induce a proinflammatory phenotype in macrophages being associated with reduced phagocytic capacity. To explore mechanisms of secondary inflammation, I will further investigate how C1q and anti-C1q interact with other mediators of inflammation.Thirdly, our previous analyses of bone marrow-derived human anti-C1q identified sequence homologies with von Willebrand Factor (vWF). In analogy to anti-C1q, vWF also binds to C1q leading to consecutive platelet rolling and adhesion, thus establishing a novel link between C1q and primary hemostasis. The focus of the third part of our project is to elucidate this link, in particular with regard to comorbidities as observed in SLE. Taken together, the proposed projects will elucidate the role of complement C1q and anti-C1q in interaction with other mediators of inflammation and factors that have been implicated in the pathogenesis of SLE. These data will also improve the understanding of immune-mediated pathology occurring related to but independently of autoimmunity.