The extensive alliance project lays the foundation for diverse and comprehensive research on the SARS-CoV-2 coronavirus in Berlin. The participating researchers from Freie Universität Berlin, Humboldt-Universität zu Berlin, Technische Universität Berlin, and Charité – Universitätsmedizin Berlin are investigating, among other things, potential active substances, the development of vaccine approaches, and possible health policy consequences of the coronavirus pandemic.

The pre-exploration project has been funded since July 2020 with approximately 1.8 million euros by the Berlin University Alliance as part of its Grand Challenge Initiative on Global Health.

Rapid and adequate action, as well as sufficient funding for research, are largely responsible for the successful long-term combating of rapidly spreading infectious diseases. For this reason, the Board of Directors of the Berlin University Alliance already decided positively on the funding of the Coronavirus Pre-Exploration Project in spring 2020. The project is dedicated to the study of the SARS coronavirus 2 pandemic from the study of the virus in cell culture to the analysis of the impact of the pandemic on the healthcare system.

The project is divided into six topics, which will be addressed by smaller research teams:

1. Development and testing of antiviral therapies and prevention concepts
2. Two- and three-dimensional human tissue cultures as models for SARS-CoV-2 infections
3. Development of sustainable vaccines
4. Animal and other model systems for SARS-CoV-2 infections
5. Disease progression and prognostic markers
6. Modeling the spread of SARS-CoV-2 infection and its consequences

1. Development and testing of antiviral therapies and prevention concepts

In addition to small-molecule active substances, i.e. those consisting of particularly small chemical compounds, multivalent active substances in particular are especially effective in preventing viral infections, as these larger chemical compounds have not just one but several binding sites for the viral surface. In subproject 1, the researchers are investigating how the binding of SARS-CoV-2 to cell membranes changes upon addition of multivalent virus binding inhibitors. Here, they work with both isolated SARS-CoV-2 spike protein (S protein; it sits on the surface of the virus particle and mediates binding to the cell surface) and inactivated virus particles. Based on recent findings, the infection inhibitors are generated on the interaction between the S protein and its cellular binding sites, heparan sulfate and angiotensin-converting enzyme 2 (ACE2). Another experimental therapeutic approach aims to degrade viral RNA using RNA interference technology. In collaboration with subprojects 2 and 4, the novel antiviral therapy concepts will also be tested on active coronaviruses.

Participating researchers:

• Dr. Sumati Bhatia (Freie Universität Berlin)
• Dr. Stephan Block (Freie Universität Berlin)
• Prof. Dr. Rainer Haag (Freie Universität Berlin)
• Prof. Dr. Christian Hackenberger (Humboldt-Universität zu Berlin und Leibniz-Forschungsinstitut für Molekulare Pharmakologie)
• Prof. Dr. Andreas Herrmann (Humboldt-Universität zu Berlin)
• Prof. Dr. Jens Kurreck, (Technische Universität Berlin)
• Dr. Daniel Lauster (Freie Universität Berlin)

Scientific publications:

• Chuanxiong Nie, Paria Pouyan, Daniel Lauster et al. (2021): Polysulfates block SARS‐CoV‐2 uptake via electrostatic interactions. Angewandte Chemie International Edition.
• Donskyi, I. S., Nie, C., Ludwig, K., Trimpert, J. et al. (2021): Graphene Sheets with Defined Dual Functionalities for the Strong SARS-CoV-2 Interactions. Small.
• Mohammadifar, E. et al. (2021): Graphene-Assisted Synthesis of 2D Polyglycerols as Innovative Platforms for Multivalent Virus Interactions. Adv. Funct. Mater.
• Tolksdorf, B., et al. (2021): Inhibition of SARS‐CoV‐2 replication by a small interfering RNA targeting the leader sequence. Viruses.

• Zhu, H. et al. (2020): Spontaneous binding of potential COVID-19 drugs (Camostat and Nafamostat) to human serine protease TMPRSS2. Comput. Struct. Biotechnol. J.

2. Two- and three-dimensional human tissue cultures as models for SARS-CoV-2 infections

Adequate control of the SARS-CoV-2 pandemic requires a detailed understanding of the factors that determine the infectious nature of SARS-CoV-2, knowledge of the target cells that the virus infects, and the molecular mechanisms involved in immune activation. This is the only way to develop effective and sustainable therapies as quickly as possible. In subproject 2, SARS-CoV-2 infection will be investigated for the aforementioned factors. A human infection model based on human lung tissue is used for this purpose. Tissue cultures from cells of the upper and lower airways are used. These cells are taken from patients and examined in the laboratory. In this way, the various stages of reproduction of the virus can be traced. Tissue from healthy study participants is compared with that from diseased patients. In a complementary approach, a lung model will be generated from different human cell types using 3D bioprinting to study SARS-CoV-2 infection.

In addition, different therapeutic approaches are tested on the human lung models used, for example multivalent inhibitors (see subproject 1) or drugs already approved for other diseases.

Participating researchers:

• Prof. Dr. Christian Drosten (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Andreas Hocke (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Stefan Hippenstiel (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Jens Kurreck, (Technische Universität Berlin)
• Prof. Dr. Marcus Mall (Charité – Universitätsmedizin Berlin)
• PD Dr. Thorsten Wolff (Humboldt-Universität zu Berlin und Robert Koch-Institut)

Scientific publications:

• Michalick, L. et al. (2021): Plasma mediators in patients with severe COVID-19 cause lung endothelial barrier failure. Eur. Respir. J.

3. Development of sustainable vaccines

Vaccine development is currently focused primarily on vaccines based on the receptor-binding spike protein (see subproject 1) that enables cell entry of SARS-CoV-2. Such vaccines are likely to be accessible mainly to patients in industrialized nations. The third subproject focuses on producing a series of vaccines that are cost-effective and environmentally safe so that they can be distributed in countries where basic and robust health care is not guaranteed. In addition, such vaccines could be used to stop the spread in animal populations where the virus occurs naturally. So far it is not known which animal species is involved.

Participating researchers:

• Prof. Dr. Christian Drosten (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Klaus Osterrieder (Freie Universität Berlin)
• Prof. Dr. Leif Sander (Charité – Universitätsmedizin Berlin)

Scientific publications:

• Kreye, J. et al. (2020): A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model. Cell.

• Trimpert, J. et al. (2021): Development of safe and highly protective live-attenuated SARS-CoV-2 vaccine candidates by genome recoding. Cell Rep.

4. Animal and other model systems for SARS-CoV-2 infections

Infection research, especially in therapy development, relies on robust model systems to accurately study infection and disease progression. These include animal models. The fourth subproject, in cooperation with the Robert Koch Institute and the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung (BfR)), is concerned with the development of a reliable small animal model for SARS-CoV2 infections.

Participating researchers:

• Prof. Dr. Klaus Osterrieder (Freie Universität Berlin)
• PD Dr. Thorsten Wolff (Humboldt-Universität zu Berlin und Robert Koch-Institut)

Scientific publications:

• Bertzbach, L. D. et al (2021): SARS-CoV-2 infection of Chinese hamsters (Cricetulus griseus) reproduces COVID-19 pneumonia in a well-established small animal model. Transb. Emerg. Dis.
• Trimpert, J. et al. (2020): The Roborovski Dwarf Hamster Is A Highly Susceptible Model for a Rapid and Fatal Course of SARS-CoV-2 Infection. Cell Rep.
• Gruber, A. D. et al. (2020): Standardization of Reporting Criteria for Lung Pathology in SARS-CoV-2-infected Hamsters: What Matters?. Am. J. Respir. Cell Mol. Biol.
• Osterrieder, N. et al. (2020): Age-Dependent Progression of SARS-CoV-2 Infection in Syrian Hamsters. Viruses

5. Disease progression and prognostic markers

Based on a clinical observational trial, subproject 5 will follow the course of the patients to be treated at Charité – Universitätsmedizin Berlin. The fact that the pandemic was detected early provides a unique opportunity to observe the clinical and biological progression of the disease from the early stages through recovery. In this way, prognostic markers can be investigated by which the severity of disease progression can be assessed.

In the observational study, researchers compare two different groups of people (cohorts) during the first wave of Covid-19. The first cohort consists of Charité medical clinic staff, who have an increased risk of infection due to their profession. The second cohort consists of patients from the asthma outpatient clinic of the Charité campus Virchow-Klinikum. Their risk of severe Covid-19 progression is increased due to their asthma history. Using a variety of analytical methods (for example, studies of the elicited immune response to disease or the development of antibodies), both groups are examined at different points in time. The results are expected to help identify prognostic markers and elucidate the evolution of the natural SARS-CoV-2-specific immune response.

Participating researchers:

• Dr. Victor Corman (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Christian Drosten (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Marcus Mall (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Markus Ralser, (Charité – Universitätsmedizin Berlin)
• Prof. Dr. Leif Sander (Charité – Universitätsmedizin Berlin)

Scientific publications:

• Messner, C.B., Demichev, V., Ralser, M., et al. (2021): Ultra-fast proteomics with Scanning SWATH. Nature Biotechnology.
• von Rhein, C. et al. (2021): Comparison of potency assays to assess SARS-CoV-2 neutralizing antibody capacity in COVID-19 convalescent plasma. J. Virol. Methods.
• Schulte-Schrepping, J., Angelov, A. et al. (2020): Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. Cell.
• Kurth, F., Roennefarth, M., Thibeault, C. et al. (2020): Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19). Infection.
• Chua, R.L. et al. (2020): COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis. Nat. Biotechnol.
• Demichev, V. et al. (2021): A time-resolved proteomic and prognostic map of COVID-19. Cell Syst.

6. Modeling the spread of SARS-CoV-2 infection and its consequences

In the sixth subproject, both the spread of the pandemic and the consequences for health care will be analyzed on the basis of mathematical modeling. The study takes a closer look at the care structures (outpatient and inpatient), their utilization (from general practitioner visits to specialists, general inpatient wards to ventilation in intensive care units) as well as treatment outcomes and costs. Thus, the "footprint" of SARS-CoV-2 on the healthcare system (for example, at different incidences, grades of severity, lethality) is calculated in this research team. Here, the German healthcare system as a whole is considered, as well as regions with higher and lower disease incidence and severity.

Participating researchers:

• Prof. Dr. Dirk Brockmann (Humboldt-Universität zu Berlin, Robert Koch-Institut)
• Prof. Dr. Reinhard Busse (Technische Universität Berlin, Charité – Universitätsmedizin Berlin)

Scientific publications:

• Günster, C., Busse, R., Spoden, M., Rombey, T., Schillinger, G., et al. (2021): 6-month mortality and readmissions of hospitalized COVID-19 patients: A nationwide cohort study of 8,679 patients in Germany. PLOS ONE.
• Karagiannidis, C. et al. (2021): Major differences in ICU admissions during the first and second COVID-19 wave in Germany. Lancet Respir. Med.
• Burgess, R. A. et al. (2021): The COVID-19 vaccines rush: participatory community engagement matters more than ever. Lancet
• Gurdasani, D. et al. (2020): The UK needs a sustainable strategy for COVID-19. Lancet