Gunilla Karlsson Hedestam, Karolinska Institutet

A BETTER PICTURE OF THE IMMUNE RESPONSE TO COVID-19

In this project Gunilla Karlsson Hedestam will map our immune response to new variants of the coronavirus, SARS-CoV-2, to understand how immunity is built up in the population – thereby putting us in a better position to respond to new virus variants and plan for future vaccinations.

When the corona pandemic was a fact in March 2020, Gunilla Karlsson Hedestam, professor of vaccine immunology at Karolinska Institutet, already had a good idea of how viruses and anti-viral immune responses generally behave.

“I’ve been working with antibodies to viruses since the early 1990s – particularly antibodies that target the outer structures of viruses, known as spike proteins. I spent a long time researching how antibodies bind HIV, a particularly tricky virus. You could say spike proteins have followed me throughout my career,” she says.

Both coronavirus and HIV use their spike proteins to get into their respective host cells and they are important targets for antibodies that in the best case block the virus’s ability to infect new cells.

“When Covid-19 arrived we had the tools to quickly begin making spike proteins in the laboratory and we were able to rapidly set up various tests to investigate the occurrence of both antibodies and memory B cells in samples from infected individuals,” says Gunilla Karlsson Hedestam.

Memory B cells act as a long-term archive that stores information from previous infections and vaccinations. The memory cells do not produce antibodies themselves, but they can be activated to become antibody-producing cells very quickly if we are infected by a substance that the immune system has seen before.

In collaboration with Ben Murrell, her research group is investigating how different antibodies bind and block (neutralise) viruses. Spike proteins are big, so there are hundreds of different ways an antibody can bind to them. “The immune system responds with its whole arsenal, but only a small proportion of all the antibodies that the body produces in response to an infection or vaccination can actually neutralise the virus. We are interested in qualitative differences between different neutralising antibodies, and also whether individuals differ in terms of the type of antibodies they make,” she says.

To analyse how the antibodies bind the virus at a detailed level Gunilla Karlsson Hedestam’s group has developed methods of isolating individual antibodies – known as monoclonal antibodies – from memory B cells to investigate which types of antibodies can neutralise different virus variants.

“Our results to date have shown that certain antibodies only neutralise the original virus, while other antibodies also neutralise the so-called variants,” she says.

The project now receiving support from the Erling-Persson Foundation is called ‘Future-proofing against COVID-19’ and has various parts.

“First we need to understand what the different virus variants are like, by analysing their family tree,” she says. “With sufficient volumes of data it is possible to distinguish which types of mutations the virus allows or does not allow,” says Gunilla Karlsson Hedestam.

Here advanced modelling is required – something that her colleague Ben Murrell is expert at, having published data on the Alpha, Beta and Gamma virus variants in the scientific journal Cell. This type of monitoring is important for being able to predict how the virus may impact.

The next part of the project involves tracking the levels of antibodies in the population to get an overview, as the group did during the first year of the pandemic and published in the Journal of Internal Medicine.

To get further information they then measure neutralising antibodies against the different virus variants, which tells them more about the protective effect. The group then analyses both blood samples and panels of monoclonal antibodies to understand the immune response in detail. How relevant and important this research is became clear when the Omicron variant caught the world napping at the end of November 2021. As early as December the research group was able to share data showing that Omicron could evade the vaccines in certain cases, while in other cases the protection remained. Great differences could be seen in the study: a 25-fold reduction in protection in some samples, while others had no decrease at all. The study was published recently in The Lancet Infectious Diseases. Gunilla Karlsson Hedestam says the financial support is very important.

“Together with Ben Murrell and Gerald McInerney at KI I’ve had a substantial two-year EU grant for SARSCoV-2 research which runs out in March 2022, so the donation from the Erling-Persson Foundation is an important bridge from that grant,” she says, continuing:

“It means we can retain existing employees who are here working with us on the specialist methods we’ve built up, so we don’t have to slacken the pace. That means we can continue to contribute to Covid research, which we are very grateful for.”

32

The number of mutations that the Omicron variant had in its spike protein – as compared with the Delta variant’s nine.

462

In March 2022 a total of 462 million cases of SARS-CoV-2 infection had been reported globally.

4

The number of different vaccine production technologies behind the Covid-19 vaccines approved within the EU. mRNA vaccines have been used the most so far.

ABOUT THE PROJECT Project manager: Gunilla Karlsson Hedestam is Professor of Vaccine Immunology at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

Title: ‘Future-proofing against COVID-19’.

What it involves: Monitoring which new variants of coronavirus arise and investigating how the population’s immune response to new variants develops.

Funding: The Erling-Persson Foundation is supporting the project with a total of SEK 8 million over three years.

Professor Gunilla Karlsson Hedestam with doctoral student Marco Mandolesi, who is researching memory B cells and investigating how the immune response matures after booster doses of vaccine.

Research specialist Xaquin Castro Dopico works in the cell cultivation lab and has mapped the antibody response in Stockholm during different periods of the pandemic.

Professor Gunilla Karlsson Hedestam with Ben Murrell and Jonathan Coquet, both assistant professors. The research team is investigating what type of antibodies give the best protection against SARS-CoV-2.

Research specialist Martin Corcoran and doctoral student Sanjana Narang map human antibody genes, which vary between different individuals. The differences may partly explain why we handle infections more or less effectively.