Research

Developing a vaccine / researching active substances / screening active substances

Helmholtz has powerful, cutting-edge infrastructure in the field of biomedicine. Examples include drug screening capabilities as well as big data and AI applications that analyze molecular processes at the cellular level. We are using many of these structures to research SARS-CoV-2 and identify potential active substances.

Researchers at the Helmholtz Centre for Infection Research (HZI) are focusing on developing medications and vaccines to fight the virus and are working to unravel the mechanisms behind the pathogenesis and progression of the disease. For example, broad-spectrum active substances against SARS-CoV-2 are sought through screening. The HZI is establishing corresponding preclinical infection models for this purpose. Researchers at the HZI also use time-resolved single-cell RNA sequence analysis of patient samples to investigate virus-host interactions at different points in time of infection.

The German Cancer Research Center (DKFZ) has set up a task force with input from eleven departments and working groups. Their goal is to develop a vaccine as well as diagnostic methods. In addition, the task force is researching the mechanisms of how COVID-19 develops as a disease.

Scientists of the German Center for Neurodegenerative Diseases (DZNE)are investigating receptors on the cell surface that enable the fusion of the coronavirus SARS-CoV-2 with cell membranes, and they are also studying the immune system's response to infection. This serves to elucidate the virus' attack routes and to create the basis for therapies and active substances. DZNE researchers have also identified highly effective antibodies against the corona virus SARS-CoV-2 and are now pursuing the development of a passive vaccination.

Viruses enter the cell via specific receptor proteins to which they dock (key-lock principle). Researchers at Forschungszentrum Jülichare developing a molecule that binds specifically to the same receptor and thus competes with the viruses. In this way, the penetration of the viruses into the cells can be prevented. The same molecule will also be used as a probe in a rapid virus test that is currently being developed.  In addition, structural biologists are trying to decipher the 3D structure of other viral proteins and are testing how these proteins can be inhibited so that the virus can no longer multiply.

In a third project they are investigating how an important viral enzyme (main protease), which is essential for the reproduction of the virus, can be inhibited. For this purpose, extensive computer-based screening has already been carried out at the Jülich Supercomputer Centre. Promising drug candidates are currently being biochemically tested for their efficacy. Together with other structural biology and medical chemistry research groups at other institutes of the Helmholtz Association, Forschungszentrum Jülich is participating in the establishment of a Helmholtz-wide platform for structure-based drug research in order to be better prepared for future pandemics. In addition, the Jülich Supercomputing Centre, together with the other Gauss partners of the Research Association, is making computer resources available, for example to simulate the effect of potential drugs with computer support.

The Exscalate4CoV (E4C) project uses high-performance supercomputing resources in Europe to enable intelligent in silico drug design and strategies for redesigning drugs for the coronavirus pandemic, while increasing the accuracy and predictability of computer-aided drug design. To date, approximately 10,000 unique molecules have been studied against the major target proteins of SARS-CoV-2. Additional libraries have also been screened. This computational effort was combined with biochemical methods and phenotypic screening to select molecules that might be able to block virus replication in in vitro models. One promising drug candidate, raloxifene, proved to be "active" in the experimental tests. Raloxifene will undergo the first step of clinical trials in mid-October.

At the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), researchers are using various methods including single-cell biology to analyze how lung cells respond to infection with the novel coronavirus compared to the old SARS-CoV-1 – both at the level of the mRNA of the body’s cells and the virus’s RNA, as well as at the protein level. Other groups at MDC are examining the antibodies the body forms in response to COVID-19, and these teams of researchers are looking at ways of blocking the ACE2 receptor that the virus uses to penetrate the cells.

With the help of DESY's X-ray source PETRA III, a research team has identified several candidates for possible drugs that bind to an important protein of the coronavirus SARS-CoV-2 and thus could be a basis for a drug against the infection. After measuring more than 10,000 samples containing about 5,700 active substances, the scientists have so far been able to identify a total of 43 substances that bind to the viral protein. They are currently investigating whether these substances inhibit protein activity and slow down the multiplication of the virus. At the same time, the research team at DESY's synchrotron radiation source PETRA III is investigating the docking of the active ingredients to other proteins of the corona virus that are important for virus replication.

Scientists at Helmholtz Zentrum München (HMGU) are working in preclinical studies to identify biomolecules and antibodies with antiviral and neutralizing properties in order to move as quickly as possible into clinical development. With the help of AI-supported tools, they aim to predict viral target structures for therapeutic approaches. In addition, large-scale analyses of single cell atlases of the respiratory tract are underway to identify cell type-specific targets.

Researchers also want to use AI models to identify factors that predict the course and severity of COVID-19 disease. The aim is to better understand and characterize individual disease progression in order to develop a targeted therapy and aftercare for patients.

In order to develop vaccines using inactivated viruses, researchers need methods that kill off the virus while causing as little damage to its structure as possible, especially the viral envelope that’s key to the immune response. To strike this balance, researchers from HZI and the GSI Helmholtz Centre for Heavy Ion Research are using heavy ions rather than gamma rays to kill the virus. The heavy ions leave the viral envelope largely intact in comparison to conventional methods. Viruses that are destroyed using this method are then tested so new vaccines can be developed.

The GSI Helmholtz Centre for Heavy Ion Research together with international collaborators is working on the development of highly sensitive sensors based on nanopores to improve virus identification and to be able to detect infections with the SARS-CoV-2 virus faster. These sensors have the potential to detect viruses specifically and quickly. In another project, GSI plans to use these nanopores to develop safe mouth protection filters and thus improve breathing masks. With a diameter down to 10 to 20 nanometers, nanopores are significantly smaller than the corona virus SARS-CoV-2 and can therefore protect against virus infection.

In a preclinical study, GSI also plans to test whether pneumonia triggered by SARS-Cov-2 can be treated with low-dose radiation. The university hospitals in Frankfurt and Erlangen partner with the GSI for this study. For this purpose, the researchers are using a typical low-dose X-ray irradiation, as it has already been administered for the treatment of pneumonia, as well as whole-body exposure due to a slightly increased radon activity in the environment. The aim is to be able to treat pneumonia caused by SARS-CoV-2 more effectively in the future.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR)want to transfer an existing approach, which can be used to detect and combat tumor cells, to the imaging and therapy of viral infections such as the novel coronavirus. For this purpose, they are using modular, recombinant antibody derivatives that they have developed over the last three decades. The aim of the Dresden researchers is to redesign these antibody building blocks so that they can also be used for the detection and destruction of corona viruses. Building on this, they also want to use these modules to develop universal nanosensors that could enable rapid digital diagnosis, and to use imaging techniques to decipher acute cases of disease and long-term consequences of COVID-19 disease.

Spread of the infection among the population

The Helmholtz Centre for Infection Research is also looking at the dynamics of how the infection is spreading among the population. Developed at HZI, the SORMAS app is dedicated to disease control and risk assessment processes and can now be put into use for the SARS-CoV-2 pandemic as well. This new coronavirus module makes it possible to detect individual cases of COVID-19 patients at an early stage even in remote regions, to document clinical details and laboratory confirmations, to accompany all contact persons and to be able to offer them therapy at an early stage – in case they also fall ill. At the same time, SORMAS generates data in real time for ongoing risk assessment at national and international level. SORMAS has been established in regions with weak infrastructure; now the HZI and the Robert Koch Institute are working on making the system available to German health authorities.

A further app-based software development PIA (Prospective Monitoring of Acute Infection Application) from the HZI is currently being introduced in order to record regular self-reports on the health status of important contact persons using mobile phones. It focuses on the monitoring of immunocompromised patients. 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.

In order to detect antibodies in recovered COVID-19 patients, the HZI is developing tests for epidemiological studies to better track the viral disease and thus the possible acquired immunity against SARS-CoV-2. These tests help to determine the infection’s actual extent. In a population study coordinated by the HZI, the blood of more than 100,000 donors is also regularly analyzed for antibodies against the COVID-19 pathogen. These seroprevalence studies provide a more accurate picture of already acquired immunity and the further development of the pandemic. Together with the RKI, the HZI is investigating the actual spread of the virus in Germany in several large-scale studies in particularly affected areas.

Both the German Cancer Research Center (DKFZ) and the Helmholtz Centre for Infection Research (HZI) together with the Natural and Medical Sciences Institute at the University of Tübingen (NMI) are developing multiplex serological tests that represent a new diagnostic tool for measuring protective antibody reactions. These tests will generate high-resolution data to assess the specific serological prevalence of SARS-CoV-2 in comparison to other respiratory viruses and chronic infections, the duration of an immune response or the susceptibility to infection among study participants on a population level.

Researchers at Helmholtz Zentrum München establish precision monitoring tools to guide societal restrictions and future vaccination strategies. They identify risk factors for SARS-CoV-2 infection and complications in Diabetes and Chronic Lung Disease patients. They are using KORA, NAKO cohorts and available biobanks from diabetes and chronic lung disease patient cohorts.

Antibody tests against the new coronavirus SARS-CoV-2 are now also included in an established screening study to test children in Bavaria for early stages of type 1 diabetes. With their help, the HMGU scientists hope to obtain realistic values on the frequency of infection with the pathogen, distribution patterns and possible differences in region, age and sex.

County-specific corona predictions are available on the website https://covid19-bayesian.fz-juelich.de. Here, neuroinformaticians from the University of Osnabrück and data specialists from Forschungszentrum Jülich provide new model results every day. The results contain daily updated estimates of the reported new infections and a 5-day forecast for each German district. The forecasts are also based on data from the RKI, which are statistically analyzed using a new, probability-weighted model developed by Osnabrück neuroinformatic specialists on supercomputers at the Jülich Supercomputing Centre (JSC). The model also calculates the influence of neighboring regions.

In addition, scientists from the HZI and Forschungszentrum Jülich, together with the University of Heidelberg and the Frankfurt Institute for Advanced Studies (FIAS), are modeling the effect of various measures on the development of the corona epidemic in Germany. In order to describe the spread of the pathogen more precisely, the researchers have extended a classical model from mathematical epidemiology to include SARS-CoV-2-specific factors. By integrating data on the number of patients admitted to hospital and receiving intensive care into the model, they are able to predict the burden on the German healthcare system in various spread scenarios. These data have also been incorporated into the Helmholtz position paper on the epidemiological situation for the German government. The results of the model developed at the Jülich Supercomputing Centre (JSC) and FIAS are also included in the Forecast Hub initiated by the Karlsruhe Institute of Technology (KIT). In addition, the JSC, together with its partners at the Gauss Centre for Supercomputing (GCS), provides computing time.

Together with several other international research institutions and companies, Forschungszentrum Jülich has joined an initiative of the Canadian quantum computer manufacturer D-Wave Systems Inc. The aim is to support researchers in developing solutions to combat the corona pandemic. D-Wave provides free access to quantum computer systems for users conducting research on COVID-19.

The Global Consortium for Chemosensory Research (GCCR), co-founded by Kathrin Ohla (Forschungszentrum Jülich), is investigating the connection between olfactory and taste disorders and COVID-19. The online survey is available in 32 languages. In addition, the researchers have developed the so-called Smell & Taste Check (in German), which enables interested parties to test, train and observe their senses at home over time. The consortium currently has 592 members from 59 countries.

In addition to the development of a vaccine and intensive contact tracing, the best possible use of existing testing capacities is a key factor in containing and controlling the spread of the COVID 19 pandemic. At the Center for Advanced Systems Understanding (CASUS) – a joint project of the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), the Helmholtz Centre for Environmental Research (UFZ), the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), the Technical University of Dresden and the University of Wroclaw – researchers are therefore developing software to optimize the use of test kits in terms of space, time and strategy. Based on "what-if" scenarios, they integrate different test strategies, such as combining tests with close contact tracking, the use of test pooling or the use of new, fast test procedures, into the software – which is to be made available as an open source application. This open architecture could also make it quickly adaptable to future pandemics.

A team of scientists and operators of sewage treatment plants wants to draw conclusions from wastewater samples about the SARS-CoV-2 infection level of the population. In the project, more than 20 wastewater experts, microbiologists, virologists and modelers from the Helmholtz Centre for Environmental Research (UFZ), the German Association for Water, Wastewater and Waste (DWA) and the Technical University of Dresden are working together with wastewater treatment plant operators. The aim of a campaign taking place in October and November 2020 is to systematically record virus concentrations in wastewater samples from 100 wastewater treatment plants in Germany. With the help of accompanying model calculations, the COVID-19 dynamics of the connected regions will be illustrated. The accuracy and, if necessary, the predictive power of the wastewater monitoring will be determined by comparison with results of patient testing.

The CISPA - Helmholtz Centre for Information Security was involved in the development of the Corona-Warn-App, which is available free of charge since mid-June 2020. The app helps to determine whether one has come into contact with an infected person and whether there is a risk of infection. In this way, chains of infection can be interrupted more quickly. The CISPA was asked by the German government to provide scientific support to SAP and Telekom in implementing the project with regard to data protection and IT security.

Scientists of the Karlsruhe Institute of Technology (KIT)and the FZI Forschungszentrum Informatik, an innovation partner of KIT, have investigated how so-called corona tracing apps can be designed in a data protection-friendly way. Their proposal combines the advantages of centralized and decentralized approaches and thus offers higher data protection.

KIT researchers investigate how air-borne particles and droplets are formed, spread, and separated. They are also investigating the effect of filters. For example, they have evaluated the use of mobile and stationary room air cleaners in classrooms. The result: Room air cleaners can greatly reduce the particle concentration in closed rooms. Using simulations, the KIT scientists also analyze aerosols, their distribution and separation in rooms, filters, and also in the human respiratory tract. Aerosols play an important role in the transmission of SARS-CoV-2. To ensure that authorities comply with the mask obligation in public spaces such as restaurants or streetcar stops, KIT researchers are also developing a novel concept for a data protection-friendly mask recognition video system based on artificial intelligence.

The German Aerospace Center (DLR)is investigating how virus particles spread in airplanes and trains. The findings can help to better understand the challenges to mobility in times of a pandemic and thus contribute to possible solutions. Work is also being carried out on reconfigurable and modular cabin designs in aircraft that allow changes in seat arrangement to reduce passenger density. DLR scientists are also working on the integration of intelligent materials for quick and easy cleaning and disinfection of the seat area. Passengers' health is to be monitored using infrared cameras and sensors.

In a research flight mission, DLR and partners such as the Karlsruhe Institute of Technology (KIT) investigated corona-induced changes in the Earth's atmosphere. Measurements of reduced emissions from industry, transport and aviation contribute to a better understanding of the anthropogenic influence on the composition of the Earth's atmosphere. With the help of two research aircraft, the scientists want to find out how the reduced emission of pollutants affects atmospheric chemistry and physics. Together with the HZI, DLR is currently developing a software package that allows the influence of protective measures such as contact bans or curfews on the development of corona infection rates over several months to be simulated. In the field of transport research, current and future effects of the corona virus on the logistics sector are being investigated.

Atmosphere researchers at Forschungszentrum Jülich started extensive measurement campaigns to document the change in air quality during the shutdown in spring and also in the period after. Initial results show that the shutdown had no major impact on the CO₂ content in the upper troposphere and stratosphere at an altitude of around 15 kilometers. Further measurements are currently underway. The results are being incorporated into several climate models in order to close existing gaps in knowledge and, for example, to predict the effects of a radical traffic turnaround on air quality in various regions.

The Center for Disaster Management and Risk Reduction Technology (CEDIM) at Karlsruhe Institute of Technology (KIT) is teaming up with Risklayer GmbH, an analysis database that conducts risk assessments, to collect current data on the development of the coronavirus pandemic. The maps created by the team provide an overview of how the virus is spreading in Germany and around the world and also identify risk areas down to the district level.

In addition, KIT researchers have developed a method for estimating the reproduction R number that avoids time delays and compensates for weekday-related fluctuations. For this purpose, the scientists use an acausal filter with a filter length of seven days that uses not only past and present values but also future values.

Researchers at MDC have developed a new online tool (in German) that maps the progression of the COVID-19 epidemic in Germany as a whole as well as broken down by the individual federal states. The map and timeline showing the spread of coronavirus are accessible free of charge. The map and timeline now also show the case numbers for all countries worldwide.

A postdoc at DESY was one of the winning teams of the "MIT CoVID-19 Challenge 2020". For the competition, his international team designed a software based on AI algorithms that estimates the probability of immunity based on COVID-19 contacts and recovery rates of infected persons. The algorithms, which actually originate from theoretical particle physics, can be used to better target test capacities to high-risk groups.

Structural biology / synchrotron radiation / cryo-electron microscopy

Using the high-intensity X-ray light from the synchrotron source BESSY II at the Helmholtz-Zentrum Berlin (HZB), a team from the University of Lübeck was able to decode the three-dimensional architecture of an enzyme. This enzyme is the main viral protease of SARS-CoV-2, which is involved in the replication of viruses. This could lead to concrete points of attack in order to develop active substances that prevent the viruses from multiplying. The results also make it possible to determine which fragments actually dock in the active center of the viral protease. To this end, a team at BESSY II, together with partners from the University of Marburg, has developed the fragment screening method: Enzyme crystals are saturated with different molecules and analyzed until the best components for a suitable drug are identified. Some candidates have already been identified and now need to be further investigated. They can be considered as components for an active substance.

At the Deutsches Elektronen-Synchrotron DESY, a series of experiments is underway to investigate three key proteins of the pathogen. If the investigation is successful, it could considerably shorten the search for a drug. DESY is working closely with several infection research organizations in Northern Germany. With "super microscopes" of the synchrotron radiation source PETRA III and so-called cryo-electron microscopes at the Center for Structural Systems Biology (CSSB) at DESY, researchers can examine biological samples in various ways; from the structural analysis of single molecules to the real-time representation of processes in living cells.

Also at PETRA III, a team of researchers succeeded in examining damaged lung tissue and displaying the changes in the pulmonary alveoli and blood vessels caused by the virus in high resolution and in 3D. The scientists were able to show that deposits of proteins and dead cell residues are deposited on the inside of the pulmonary alveoli. They reduce gas exchange and cause breathing difficulties.

A team of researchers from Germany and Sweden is using PETRA III to search for innovative methods of administering very precisely dosed drugs to patients for diseases such as COVID-19. Many of the current candidates for possible drugs have strong side effects. With the help of the investigation, new administration methods are to be found so that the active ingredients can be taken by those affected in exactly the ideal concentration.

The PETRA III research light source, which is now back in regular operation, has been started up in the meantime especially for coronavirus-relevant measurements. In addition, a fast-track access mode for corona-relevant research at DESY's light sources has been established. Several SARS-CoV-2-relevant research projects are in preparation. Examples are the structural elucidation of virus proteins or X-ray fluorescence tracking of the spread of viruses in tissues.

Information for risk groups and their relatives

The Cancer Information Service at the German Cancer Research Center (DKFZ) and the Pulmonary Information Service at the Helmholtz Zentrum München (HMGU) respond to queries from people who may have a compromised immune system, including cancer patients or individuals with underlying medical conditions affecting the lungs, as well as their relatives. Information pages on the novel coronavirus and the COVID-19 lung disease caused by the virus have also been created. The Allergy Information Service offers further information about coronavirus for people with allergies and asthma (in German).

People with diabetes can obtain scientifically verified information relating to their questions on coronavirus on diabinfo, the diabetes information portal launched by the Helmholtz Zentrum München and its partners.

EU-Projects

The European Commission has announced the funding of 17 new projects with a total volume of 47.5 million euros to help fight the coronavirus pandemic. All projects are international in scope and deal with monitoring, testing, treatment and vaccine development. The 17 projects were selected from 90 submitted applications. Helmholtz scientists coordinate two of these projects:

The Helmholtz Zentrum München, German Research Center for Environmental Health, coordinates RiPCoN ("Rapid interaction profiling of 2019 nCoV for network based deep drug repurpose learning"). Together with partners from France and Spain, the researchers will determine whether currently approved drugs are suitable for the treatment of COVID-19. The researchers initially hope to find out which proteins, signaling pathways and molecular structures the virus exploits and alters in the human body. On the basis of this information, they will model – supported by artificial intelligence and machine learning – which drugs have a chance of success and are promising for subsequent laboratory tests and studies. In the project’s second phase, they want to use experiments to find out what effects naturally occurring genetic differences of interacting human and viral proteins have on the individual course of the disease. Combined with further data on epidemics and human genes, these findings will be used for future COVID-19 risk management and resource planning of hospitals.

The Helmholtz Centre for Infection Research (HZI) coordinates 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, Côte d'Ivoire and Nepal are working together to achieve this goal. They intend to obtain real-time clinical data via the SORMAS app developed by the HZI together with national and international partners since 2014, which will allow data on disease outbreaks to be recorded locally and transmitted to health authorities. The focus here is on particularly endangered countries, including Ivory Coast, Ghana and Nigeria. At the same time, investigations will be carried out in Germany and Nepal to determine whether infections with other human corona viruses lead to cross-immunity against the novel SARS-CoV-2. The data collected will help to better assess the transmission of the virus and to evaluate the effectiveness of measures against its spread.

The Helmholtz Centre for Infection Research is also involved in the SCORE project; Forschungszentrum Jülich is involved in the Exscalate4CoV project. "SCORE" is intended to develop antiviral drugs that can be used in the short to medium term to treat patients and contain the spread of coronaviruses. The "Exscalate" platform is already aiming to use supercomputing resources and link them with life science research laboratories in order to respond more quickly and efficiently to international pandemics. The project is now being expanded to include COVID-19; this also involves the identification of active substances against the virus.

All EU-projects at a glance

The Helmholtz Association’s alliance-wide activities

The Alliance of Science Organizations is an association of the major non-university science organizations in Germany. The majority of the Helmholtz Association's alliance activities take place in close cooperation with the German Centers for Health Research (DZG). The German Center for Infection Research (DZIF) plays a coordinating role.

The platform "Lean European Open Survey on SARS-CoV-2 Infected Patients" (LEOSS) established at DZIF is used by all DZG as a central IT platform for anonymized patient data.

In addition, central DZG-wide clinical studies are initiated, taking into account special risk groups (patients with lung or cardiovascular diseases, diabetes and cancer). The DZIF also coordinates German participation in international studies such as the WHO Solidarity Trial.

In addition to these overarching measures, the DZG provides infrastructure for clinical studies, substance libraries for testing SARS-CoV-2 and expertise in medicinal chemistry and good manufacturing practice (GMP).