13 May 2020

LiU scientists are working intensely to develop two different analysis methods for the immune response that follows infection by the SARS-CoV-2 virus, which causes COVID-19. One of the tests is now being used by the medical care services in Region Östergötland. The researchers hope the second will be ready in a couple of weeks.

Professor Jorma Hinkula BKV, diskuterar laboratorietest med två doktorander.Professor Jorma Hinkula discusses the tests with PhD students Melissa Govender and Cecilia Svanberg. Photo credit Magnus Johansson

The COVID-19 pandemic has stimulated many new interdisciplinary collaborations among researchers. At LiU, virologists have joined forces with protein chemists to achieve results that can help the medical care services.Professor Jorma Hinkula. BKV.Professor Jorma Hinkula. Photo credit Magnus Johansson

“The Division for Clinical Microbiology at Region Östergötland asked whether we could help to develop analysis methods that examine the functional properties of the antibodies that incapacitate viruses”, says Jorma Hinkula, professor in the Department of Biomedical and Clinical Sciences (BKV).

An interdisciplinary research team with members from both the Faculty of Medicine and Health Sciences and the Faculty of Science and Engineering started work to develop two different tests, based on the immune response that is triggered by infection with SARS-CoV-2. When the body discovers that a foreign object, such as a virus, has entered, a cascade of warning signals is initiated. The signal substances attract cells of the immune system, various types of white blood cell, that form, among other things, antibodies. Antibodies are Y-shaped proteins that can bind to special points on foreign substances, such as small protein fragments from a virus. The antibodies help cells of the immune system to combat the infection. Some antibodies, known as neutralising antibodies, can also block the ability of the virus to infect new cells.

“It is this type of neutralising antibodies that humans need to form in response to viral infection, such that we can eventually achieve herd immunity”, says Jorma Hinkula.

Protection against repeat infections?

The first test developed by the LiU scientists can show whether the immune defence that has been built up in a person who has been sick can stop a repeat infection. The researchers have used specimens from people with active virus when developing the analysis. In a high-containment laboratory, they have cultured the SARS-CoV-2 virus from the patient specimens.

The test itself is performed on blood from people who have tested positive for infection a few weeks previously. It is hoped that the body in the meantime has had enough time to build up an immune response, such that antibodies are present in the blood.In some wells, the cells (purple) have been protected against the virus by antibodies and thus survived. Photo credit Magnus Johansson

The researchers mix the blood with the cultured virus. If neutralising antibodies are present in the blood, they will bind to the virus and incapacitate it. The researchers test this by adding the mixture to test plates on which live cells are growing. If protective antibodies are not present, the virus will infect the cells and kill them. If, in contrast, the blood contains neutralising antibodies, the researchers can get an idea of how strong the protection is by determining the fraction of cells that survive infection after treatment with different amounts of the virus.

“This analysis method is already in use, mainly in the Division for Clinical Microbiology here. Other hospitals in southern Sweden have also asked whether we can help them with analyses”, says Jorma Hinkula.Professor Marie Larsson och professor Jorma Hinkula, båda BKV, diskuterar provresultat.Professor Marie Larsson and professor Jorma Hinkula. Photo credit Magnus Johansson

“The tests we have carried out here appear to agree well with the results that the Division for Clinical Microbiology were expecting, so far, which is, of course, positive. And it’s a great benefit for society that we obtain antibodies that may be able to prevent a repeat infection”, says Marie Larsson, professor at BKV.

One of the most important questions, of course, is whether the neutralising antibodies provide real protection against repeat infection with SARS-CoV-2, and how long the protection lasts. Is it a few months, or several years?“Right from the start, we planned to follow some people for many years, to find out whether the immunity remains protective, and how long the antibodies remain present in the body. This is extremely important knowledge”, says Marie Larsson.

Scientists make virus proteins

The second test is under development, and not yet ready to use. This analysis is designed to detect antibodies in the blood of a person, but not to determine whether the antibody can neutralise the virus. Several rapid tests are available today that can determine whether a person has been infected with the virus (possibly without feeling ill). The researchers are trying to build a test that gives more a reliable answer.

One alternative to using whole virus particles cultured from people with an ongoing infection is to use virus proteins in the analysis. It is, however, not easy to obtain virus protein, at a time when the whole world is battling to get rid of coronavirus.

“The whole world is buying up everything on the market, and it’s difficult for little Sweden to compete in the purchasing. So I contacted other researchers at LiU who had some promising ideas about how they could produce virus proteins”, says Jorma Hinkula.

The research group, led by Daniel Aili, provides molecules known as “peptides”, which are fragments of proteins.Daniel Aili

“We synthesise virus peptides that we believe contain the important parts of the virus proteins that the antibodies of people who have been exposed to SARS-CoV-2 recognise and bind to. The advantage of using peptides is that it is possible to scale up production and obtain fairly large amounts quickly. We require so much to be able to carry out large-scale testing”, says Daniel Aili, associate professor in the Department of Physics, Chemistry and Biology (IFM).

Other scientists working in parallel at LiU are Senior Lecturer Padraig Darcy from BKV, Research Fellow Eleonore von Castelmur and Professor Maria Sunnerhagen from IFM, and their doctoral students. The work is targeted at producing not only whole virus proteins but also important parts of them for the same purpose. The virus proteins that the researchers produce in the laboratory are intended for use in both types of antibody test. In addition to their use in the medical care system to test whether a person has been infected and whether they have developed immunity, the tests may also be useful for other purposes. The virologists see ways in which the analysis methods can be used in research, and in the long term to evaluate possible drug treatments for COVID-19.

The pandemic has led to the virologists shelving their normal research for a while.

“My group normally works on HIV, but we haven’t done any work on it since the start of March. When Region Östergötland asked whether we could help, we decided to devote some time to work with SARS-CoV-2. It’s an extremely important field, and we thought that we could do something useful. And we took it as a chance to learn something – as researchers we are more curious than the cat”, says Marie Larsson.

Marie Larsson would like to know why some individuals experience an extremely severe inflammation from the SARS-CoV-2 infection and undergo what are known as cytokine storms, which make them seriously ill. In parallel with their work on testing, the researchers are looking at why the immune system reacts in this way, and whether there are ways to suppress or stop the infection.

Translated by George Farrants. Jorma Hinkula and Marie Larsson were interviewed on 30 April 2020.


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