A research project led by Christian Freund is investigating how cells react to SARS-CoV-2. Professor Freund, a specialist in protein biochemistry, is carrying out basic research at Freie Universität that may help to validate vaccines against the novel coronavirus.

“Our aim is to identify the immunodominant T cell epitopes of SARS-CoV-2,” he explains. These epitopes are small fragments of proteins derived from the virus that trigger an especially vigorous reaction in the immune system. The immune system identifies them as foreign and reacts by producing killer or helper T cells to fight them. Viruses usually have several epitopes that can trigger this kind of T cell-related adaptive immune response. It is therefore important to identify the epitopes specific to each virus when developing vaccines.

Using Large Databases for Research

“There are already a number of studies that allow us to theoretically predict the T cell epitopes found in SARS-CoV-2,” explains Esam Abualrous, a physicist who is part of Christian Freund’s research team at Freie Universität. To identify possible SARS-CoV-2 epitopes, Dr. Abualrous also uses programs based on large databases. This “in-silico” approach – meaning that the work is carried out mainly on the computer – is complemented with an experimental laboratory procedure imitating the virus behaviors that lead to a cellular immune response.

The “spike” protein found in the SARS-CoV-2 virus (so called because it resembles the spikes of a crown, hence “corona”) is broken up into smaller fragments using protein-splitting enzymes or proteases. When the spike protein fragments are loaded onto the host cell’s humane leucocyte antigen (HLA) proteins, protein complexes are created which can later be used to identify and stimulate T cell production, Abualrous explains.

Professor Freund adds, “It’s interesting to see that the protein fragments recognized by the immune system differ from person to person. That’s because among humans, HLA proteins are found in numerous genetic variations.” Molecular biologist Miguel Álvaro-Benito, who set up the experimental system being used in the lab, agrees: “We can already see that different HLA proteins are especially good or especially bad at recognizing specific SARS-CoV-2 fragments. Now we need to find out to what extent this influences an individual’s T cell response.” The scientists are also interested in the related question of whether the genetic disposition of the HLA genes can influence how the virus develops in different people.

We Could Define Risk Groups or Adapt Therapies

In AIDS research, for example, we find a phenomenon known as the “elite controller.” “‘Elite controllers’ are HIV+ individuals who are better able to control the HI virus than others. This is often because their cells contain certain HLA molecules. Sometimes their immune response is so effective that they don’t even need to use medication,” says Freund. But other individuals may have a particularly weak level of T cell immunity based on their specific set of HLA genes. Freund’s group is working with another research group, led by Professor Monika Brunner-Weinzierl at the University Clinic in Magdeburg, to find out whether HLA antigens can influence the reactivity and response of T cells to Covid-19, similarly to how they influence the response to HIV. If this is the case, it could help to define risk groups or make the necessary changes to adapt therapies to individuals.

But the Institute of Chemistry and Biochemistry is not the only department at Freie Universität Berlin involved in investigating the immune system’s response to the coronavirus. With extensive experience of how the virus presents in animals, the Department of Veterinary Medicine is also playing its part. Professor Klaus Osterrieder, Managing Director of the Institute for Virology in the department, points out, “Just a few months ago, coronaviruses were seen as mainly harmless in terms of their effect on humans. But in veterinary medicine, it’s another story altogether; they’ve been known to represent a threat to animal health for a long time,” he says.

Chickens can develop infectious bronchitis, while pigs may come down with porcine epidemic diarrhea, an extremely contagious disease of the intestine. In cats, a coronavirus often triggers peritonitis, an infection that frequently proves fatal. All too often, serious illnesses in animals are caused by coronaviruses. “We’ve been working to understand coronaviruses for some years now,” says Professor Osterrieder. “As a result, we think that our research may be able to help researchers in finding solutions to the current crisis.”

Cloning the Genome of the SARS-CoV-2 Pathogen

One way veterinary research can help is in the search for a vaccine. Freie Universität’s Department of Veterinary Medicine plans to work with researchers at the University of Bern and Charité – Universitätsmedizin Berlin to clone the genome of the SARS-CoV-2 pathogen, by first isolating it and then reproducing it multiple times in order to be able to manipulate it. In this way, the researchers hope to produce weakened forms of viruses that could potentially be deployed as a universal vaccine to combat the original pathogen. Such “living vaccines” – which consist of living bacteria that are no longer able to cause illness – generally have not only fewer side effects than “dead” vaccines, but are also more effective. “Dead” vaccines are made of pathogens that have been “killed” and are thus unable to reproduce.

A living vaccine, if successful, would protect not only humans but also animals from becoming infected. “This is important, as there is growing evidence that the novel coronavirus can be transmitted from humans to animals, especially to cats, hamsters, and ferrets,” says Professor Osterrieder. The researchers are currently analyzing samples received from veterinary practices and clinics. So far, out of 300 samples one has proved positive.

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This text originally appeared in German on June 21, 2020, in the Tagesspiegel newspaper supplement published by Freie Universität.