Corona research at full speed at the HZI

New projects and funding to combat the coronavirus pandemic

Currently, neither a vaccine nor specific drugs are available against the coronavirus SARS-CoV-2. In view of the global pandemic, the Helmholtz Centre for Infection Research (HZI) in Braunschweig with its other locations is bundling its resources for projects that contribute to a better understanding of the infection and to solutions to contain the virus. "Like all infectious diseases, the current coronavirus pandemic can be combated more effectively the better we understand the pathogen and its effects on humans," says Prof Dirk Heinz, Scientific Director of the HZI. "The HZI is very well prepared for such outbreaks and can quickly adapt its scientific activities to such sudden challenges."

Work in the biological safety level 3 laboratory at the HZI. © HZI / TalayIn addition to the many years of expertise of its scientists in infection research, the HZI has the necessary powerful infrastructure at hand. Examples are the high-throughput testing of potential active substances, laboratories of biological safety level 3, in which it is possible to carry out investigations with intact pathogens, as well as a modern animal facility, which also enables investigations in animal models, especially in mice. "We have now been able to strategically align these units very quickly to SARS-CoV-2 research and the identification of potential active substances," said Heinz.

Like other research institutions, the HZI has been working under reduced conditions in basic operation with home office solutions for science and administration since 20 March 2020, in order to impede the spread of the virus and thus protect employees. Excluded from this regulation are all activities and technology platforms contributing to the fight against Covid-19.

Research at the HZI is currently pursuing a number of different approaches. Epidemiologists at the HZI are developing digital tools specifically targeted at Covid-19, most notably the outbreak and surveillance tool "SORMAS" for disease control and risk assessment. This system, which has been developed over the past five years for endemic areas such as Africa, also includes contact tracing of infected persons. In close cooperation with the Robert Koch Institute, it can now provide support to German health authorities at short notice. A further app-based software development (PIA) from the HZI is currently being introduced in order to record regular self-reports on the health status of important contact persons, such as hospital staff, using mobile phones.

In order to initiate the important antibody detection of already recovered Covid-19 patients, tests for epidemiological studies are currently being developed at the HZI. These tests will allow better tracking of the viral disease and the detection of protective antibodies and thus the possible acquired immunity against the new coronavirus. Among other things, they will help to determine the actual extent of the infection and identify persons for whom restrictions on activities or travel could be relaxed due to their immunity.

In parallel to the development of improved antibody detection, the HZI is conducting large-scale tests using already available diagnostic procedures in several cities in Germany at different points in time. Here, the objective is to determine the proportion of people who have already developed immunity and the mortality rate among those infected. At the same time, these data are very important for estimating the further epidemiological development of the pandemic.

In addition, researchers at all HZI locations are concentrating on the development of active substances and vaccines against the virus and on deciphering the molecular mechanisms of disease development and progression.

To combat the coronavirus pandemic, the European Commission has announced calls for research and innovation projects. In total, around 260 million euros have been made available for Covid-19 research until 16 March 2020.To this end, the researchers are to work on monitoring, test procedures, treatment methods and vaccine development.

The HZI now coordinates the EU project CORESMA ("Covid-19 Outbreak Response combining E-health, Serolomics, Modelling, Artificial Intelligence and Implementation Research") and is involved in the SCORE project (Antiviral Drugs against SARS-CoV-2).

The following is a list of the HZI projects currently underway to research the novel coronavirus:

1. Basic research on the novel coronavirus
   
   Analysis of antiviral strategies against SARS-CoV-2 target proteins
   The scientific work on the structural and functional analysis of coronavirus and host target proteins in Dr Joop van den Heuvel's team contributes to a better understanding of the virus. The research group produces coronavirus proteins that are of particular interest as candidates for diagnostic purposes, therapeutic target proteins and as potential candidates for protein-based vaccines - as a vaccine against SARS-CoV-2, but also for the time after. The researchers will analyse the interaction of drugs and antibodies with the coronavirus proteins using biophysical methods in order to determine affinities and inhibition constants, for example. Structural biological methods such as cryo-electron microscopy or X-ray structure analysis will also be used. The aim is to find the best approaches to have an adequate strategy against SARS-CoV-2 and future viruses to combat and contain their spread.
   
   Contact: Dr. Joop van den Heuvel, AG Recombinant Gene Expression at the HZI
   
   Cooperation partners: HZI departments and research groups: Prof Wulf Blankenfeldt (SFPR), Prof Ursula Bilitewski (COPS), Prof Carlos Guzman (VAC), Prof Luka Cicin-Sain (IMCI), Dr Monika Strengert (EPID)
   
   Development of a mouse model of infection with SARS-CoV-2
   Researchers are working on the development of a preclinical mouse model of SARS-CoV-2 infection under the direction of Prof Ulrich Kalinke at TWINCORE - Centre for Experimental and Clinical Infection Research in Hanover, a joint institution of the HZI and the Hanover Medical School (MHH). The bred, genetically modified mice are expected to have an increased susceptibility to SARS-CoV-2 infections. This involves mating animals that express the human ACE2 receptor as the virus' entry receptor and animals in which the type I interferon system can be specifically switched off on pneumocytes of the lung. In the course of the infection, similar symptoms and diseases as in humans should develop. An animal model for SARS-CoV-2 is an important prerequisite for developing vaccines and antiviral agents for use in humans.
   
   In cooperation with the Cantonal Hospital in St. Gallen, Switzerland, the researchers are also using a coronavirus model in mice to investigate why many patients lose their sense of smell because of Covid-19 disease.
   
   Contact: Prof Ulrich Kalinke, TWINCORE, Institute for Experimental Infection Research
   
   Cooperation partners:German Primate Center Göttingen, Cantonal Hospital St. Gallen
    
2. Digital tools for infection management
   
   SORMAS: Spread of infection in the population
   The HZI is investigating the dynamics of infection spread of the novel coronavirus in the population. An app for disease control and risk assessment (SORMAS) developed at the HZI is now also available for the current SARS-CoV-2 pandemic. The newly implemented coronavirus module allows the early detection of individual cases of Covid-19 patients even in remote regions, the documentation of clinical details and laboratory confirmations as well as the monitoring of all contact persons. If they also fall ill, quarantine and treatment measures can be initiated at an early stage. Simultaneously, SORMAS generates data in real time for continuous risk assessment at national and international level. SORMAS also offers an app for contact persons to digitalize the daily symptom query in quarantine and thus free up personnel resources at health authorities.
   
   Contact person: Prof Gérard Krause, Department of Epidemiology at the HZI
   
   Cooperation partners: State Health Authorities, Academy for Public Health
   
   PIA: Digital infection monitoring of immunocompromised persons
   An intensified monitoring of immunocompromised patients, for example with previous diseases such as HIV, is to be carried out at the MHH with an application developed by the HZI Department of Epidemiology. In comparison with reference values from the general population, it will be determined whether there is a particular risk with regard to the frequency of infection or the course of the disease. The HZI software PIA (Prospective Monitoring of Acute Infection Application) is currently being used in the NAKO Health Study to investigate acute respiratory diseases: www.info-pia.de
   
   Contact: Dr Stefanie Castell, Department of Epidemiology at the HZI
   
   Cooperation partner: Hannover Medical School (Prof Behrens)
    
3. Diagnostics / Diagnostic tools
   
   Laissez-Passer Serology Detection: SARS-CoV-2 specific antibody test for the detection of protective immunity
   The detection of an immune response mediated by specific antibodies is an essential indicator of whether immune protection against SARS-CoV-2 already exists. Particularly in medical and nursing professions, but also in many other occupational groups, it is crucial to ensure that full care is quickly restored. The project therefore aims at an urgently needed "laissez-passer test proof" based on a positive antibody titer. In practice, the procedure is similar to a yellow fever passport. People with this proof of test would then no longer be subject to travel or activity restrictions. Negative effects of non-pharmaceutical measures such as contact barriers could thus be significantly reduced. Ultimately, such a test will also reduce the fear of infection among an increasing proportion of the population.
   
   In the course of the project, antigens specific for SARS-CoV-2 will be selected and validated and an optimal test system for the given diagnostic infrastructure will be chosen, e.g. ELISA tests, line assay or lateral flow rapid test. Finally, collaborations for the commercialisation of a selected test system will be established.
   
   Contact: Prof Gérard Krause, Dr Monika Strengert, both Department of Epidemiology at the HZI
   
   Cooperation partners: NMI Natural and Medical Sciences Institute at the University of Tübingen
   
   Antiviral strategies - supporting diagnostics and immunotherapeutics
   The team around Prof Luka Cicin-Sain is experienced in virus-antibody testing and has extensive knowledge in virus genetics. The aim of the research work is to develop a so-called in vitro neutralisation test for SARS-CoV-2. This will support numerous projects on the Braunschweig campus. The test is being developed using clinical isolates. In the next step, the group will establish a more sensitive high-throughput neutralization test for SARS-CoV-2. The test is based on the use of fluorescent protein expressing viruses (GFP) and real-time monitoring and quantification of the fluorescence generated by the virus. In addition, the team will develop a new technology for the production of recombinant viruses carrying, for example, phosphorescence reporter genes. The new technology will support many research activities at the HZI, such as improved serological virus diagnostics, the development of vaccines or the identification of antiviral molecules against SARS-CoV-2. In addition, the research group is working on neutralizing antibodies against SARS-CoV-2 together with industrial partners such as YUMAB.
   
   Contact: Prof. Luka Cicin-Sain, Department of Immune Aging and Chronic Infection at the HZI
   
   Cooperation partners: Technical University of Braunschweig, YUMAB
   
   Diagnostic studies on Covid-19 at HIPS in Saarbrücken
   In the Corsaar study, we will collect and analyze data and blood samples from Covid-19 patients together with partners from Saarland University and the University Hospital Homburg. Our goal is to better understand and predict the course of the disease, identify risk-patients at an early stage, and develop novel means of treatment. Blood samples will be analyzed at HIPS using state of the art mass spectrometry techniques. The HIPS will also take part in coordinating the Corsaar-study.To counteract a shortage in Covid-19 testing capacity, the HIPS currently delegates some of its employees to the University Hospital Homburg. Further, HIPS established its own qPCR-based testing capacities on site to further increase the number of available tests. The HIPS is part of a study analyzing the prevalence of Covid-19 in nursing homes and care facilities. Patient samples are collected and subjected to virus diagnosis. Our aim is an early identification of infected residents, thus preventing a further spread of the virus. Several research projects and proposals regarding novel therapeutic means for the treatment of Covid-19 are currently under preparation.
   
   Contact: Prof Rolf Müller, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
   
   Cooperation partners: Saarland University, University Hospital Homburg
   
   LöwenKIDS study on virus spread in children
   To investigate the susceptibility of children to the coronavirus SARS-CoV-2, scientists are collecting samples from 500 children in the long-term study LöwenKIDS, which was started in 2014. In order to obtain snapshots of the spread of the pathogen, swabs of the test persons analysed at two different points in time. In addition, symptomatic samples will be tested over the next few months. In parallel, detailed information on symptoms and possible contact with coronavirus-infected persons will be collected via health questionnaires. In a later examination, it is also planned to perform antibody test, which indicate whether an infection has been overcome. The results of the investigations will help to determine the role of young children in the spread of the virus.
   
   Contact: Prof Till Strowig, Department Microbial Immune Regulation
   
   Cooperation partner: University Clinic Halle (Prof Mikolajczyk), TWINCORE Hannover (Dr Gerold)
    
4. Vaccine development/drug research/drug screening
   
   Testing of inhibitor applied by inhalation against the novel coronavirus
   Medical researchers around the world are looking for ways to prevent the proliferation of the novel coronavirus with the help of active substances. A team from the University of Lübeck and the HZI has found a promising approach. The basis for this is the analysis of the three-dimensional structure of functional viral proteins. Using the high-intensity X-ray light from the synchrotron source BESSY II at the Helmholtz-Zentrum Berlin (HZB), researchers were able to decipher the three-dimensional architecture of the viral main protease of SARS-CoV-2. This enzyme is involved in the replication of the viruses. Using the crystal structure, the University of Lübeck (Prof Hilgenfeld) was able to transform a previously developed lead compound into a potent inhibitor.
   
   Dr Katharina Rox, DZIF scientist at the HZI in Braunschweig, tested larger amounts of the inhibitor in healthy mice and showed that it is non-toxic. The compound has the best effect when applied under the skin or by inhalation.
   
   Contact: Dr Katharina Rox, Head of Pharmacokinetics/Pharmacodynamics, Department of Chemical Biology at the HZI
   
   Cooperation partners: University of Lübeck, Helmholtz Centre Berlin (HZB)
   
   Original publication: Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Ute Curth, Christian Drosten, Lucie Sauerhering, Stephan Becker, Katharina Rox, Rolf Hilgenfeld, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science 2020, DOI: 2010.1126/science.abb3405
   
   Proof of concept studies of a SARS-CoV-2 vaccine with recombinant spike protein
   Since the beginning of the SARS-CoV-2 outbreak, many research groups have been trying to develop a prophylactic vaccine. The HZI approach is based on a so-called subunit vaccine that can induce protective immunity and has a good safety profile for immunocompromised individuals. Ideally, it is administered via the mucous membranes. It is also comparatively easy to produce in sufficient quantities to meet the needs of the current pandemic. In this respect, the spike (S) protein is a promising vaccine antigen, as it has already been shown for SARS-CoV and MERS-CoV that the stimulation of neutralizing antibodies against the S protein prevents infection. The project aims to provide proof-of-concept for an intranasal S-based vaccine with c-di-AMP as adjuvant. The scientists want to prove that the vaccine stimulates virus-neutralizing humoral immune responses and can protect vaccinated mice against SARS-CoV-2. They will also use silico algorithms to generate synthetic S-variants with optimized sequences that are able to stimulate immune responses against different SARS-CoV variants and possibly also cross-reactively against SARS and MERS. This would potentially lead to a situation where large parts of the population would also be protected against future coronaviruses. The project includes the development of the vaccine candidate and preclinical testing.
   
   Contact:Prof Carlos A. Guzmán, Department of Vaccinology and Applied Microbiology at the HZI
   
   Cooperation partners: Prof Luka Cicin-Sain, Dr Joop van den Heuvel, Prof Alice McHardy, Prof Ulrich Kalinke
   
   Production of SARS-CoV-2 neutralizing monoclonal antibodies from blood samples of recovered Covid-19 patients
   The team around Prof Ulrich Kalinke, Director at TWINCORE and Head of the Institute for Experimental Infection Research, has extensive experience in the analysis of immune cell types in blood and the processing of such information using big data approaches. The researchers are now applying these methods to the analysis of Covid-19 patients, in particular to investigate B-cell responses in these patients. In the short term, the researchers hope to isolate monoclonal antibodies for therapy from the B memory cells of patients who have survived Covid-19 disease. These will be tested for binding and neutralization of the novel coronavirus and promising candidates will be transferred into clinical trials as soon as possible. This goal can probably be better achieved with monoclonal antibodies from B cells than with antibodies isolated from synthetic libraries, because in the human body, primarily antibodies are produced that do not show unexpected cross-reactivities.
   
   Contact: Prof Ulrich Kalinke, TWINCORE Hannover
   
   Cooperation partners: MHH (Prof Witte, Rheumatology, and Prof Blasczyk, Transfusion Medicine), Memo Therapeutics AG
   
   Repurposing of an active substance against SARS-CoV-2
   Prof Thomas Pietschmann, researcher in the Excellence Cluster RESIST and at TWINCORE Hannover, is heading the German branch of an international research network, which is investigating whether approved drugs are effective against the coronavirus SARS-CoV-2. The "ReFrame" drug collection of Scripps University (USA) contains around 14,000 approved drugs as well as active compounds for which extensive safety data are already available with regard to their use in humans. This so-called repurposing - the use of a proven active compound for new indications - shortens the drug's development phase.
   
   In a first step, the scientists in Hanover use high-throughput processes to search for active ingredients that inhibit the replication of viruses. For these candidates, the mode of action, the effect on lung cells and the optimal dose are analysed. Based on these results, drug candidates from the ReFrame database are to be rapidly transferred into clinical studies.
   
   Contact: Prof Thomas Pietschmann, TWINCORE Hanover
   
   Cooperation partners: MHH (Prof Schulz, Institute of Virology), University of Bern, Scripps University, German Centre for Infection Research (DZIF), HZI Department of Chemical Biology (Prof Brönstrup)
    
5. Modelling
   
   Mathematical modelling provides new insights for risk assessment of the coronavirus pandemic
   Scientists at the HZI and Forschungszentrum Jülich simulated the effect of various conditions on the development of the SARS-CoV-2 epidemic in Germany. Their results suggest that the restrictions on social life are effective and that a further slowing of the spread is possible. The HZI scientists around the physicist Prof Michael Meyer-Hermann described a method to evaluate the effects and the situation on a daily basis, thus providing decision makers in politics with a basis for assessing the situation. A decisive variable in the description of the spread of an infectious pathogen is the reproduction number. The basic reproduction number indicates how many people an infected person infects on average. It is an important indicator of how quickly an epidemic spreads. Daily updated values for the SARS-CoV-2 reproduction number can be found at http://secir.theoretical-biology.de.
   
   The modelling significantly contributed to the Helmholtz position paper on the epidemiological situation from 14 April 2020: https://www.helmholtz-hzi.de/de/aktuelles/news/news-detail/article/complete/helmholtz-positionspapier-zur-epidemiologischen-situation/.
   
   Contact: Prof Michael Meyer-Hermann, HZI Department of Systems Immunology at BRICS (Braunschweig Integrated Centre of Systems Biology)
   
   Cooperation partners: Forschungszentrum Jülich (Prof. Wolfgang Marquardt), Department of Epidemiology at the HZI
    
6. EU Projects
   
   CORESMA - Effective collaboration with Big Data project on Covid-19
   The HZI coordinates the EU project CORESMA (Covid-19 Outbreak Response combining E-health, Serolomics, Modelling, Artificial Intelligence and Implementation Research). This project aims to close existing gaps between clinical, epidemiological and immunological information in order to better respond to the pandemic. European researchers from the Netherlands, Switzerland and Germany, as well as partners from China, Ivory Coast and Nepal are working together to achieve this goal. They are collecting real-time clinical data via the SORMAS app developed by the HZI in 2014, with which outbreak data can be recorded locally and transmitted to health authorities. The focus here is on particularly endangered countries, including Ghana and Nigeria in addition to the Ivory Coast. In addition, existing cross- or partial immunity against SARS-CoV-2 is to be investigated in Germany and Nepal. The data collected will help to better assess the transmission of the virus and evaluate the effectiveness of measures against its spread.
   
   Contact: Prof Gérard Krause, Department of Epidemiology at the HZI
   
   Antiviral drugs against SARS-CoV-2
   The HZI is also involved in the EU project SCORE. SCORE aims to develop antiviral drugs that can be used in the short to medium term for the treatment of patients and to stop the spread of coronaviruses.
   
   Contact: Prof Mark Brönstrup, Department of Chemical Biology at the HZI; Dr Katharina Rox, Head of Pharmacokinetics/Pharmacodynamics, Department of Chemical Biology at the HZI