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TCD immunology project at cutting edge of Irish Covid-19 research

Anna Wedderburn reports on a recent Trinity College Dublin webinar about immunological research into Covid-19

In April, the Trinity Covid-19 Immunology Project received €2.4 million in funding from AIB. A webinar was held on 27 May to discuss this project in detail. The session was chaired by Prof Veronica Campbell, Director of Strategic Initiative at Trinity College Dublin (TCD). Speakers included Prof Kingston Mills, Head of the Centre for the Study of Immunology at Trinity Biomedical Sciences Institute (TBSI), Prof Aideen Long, Director of Trinity Translational Medicine Institute (TTMI), and Prof Luke O’Neill, Chair of Biochemistry at TCD.

Prof Mills and Prof Long are the leading principal investigators (PIs) of the project, while Prof O’Neill is one of 14 co-PIs. There are 11 international collaborators involved in this project. It is based in Trinity College due to its expertise in immunology.

Prof Mills began the presentation by highlighting the four main areas of Covid-19 that the Trinity project is focusing on: New testing technology; the immunology of the disease; informing vaccine design; and developing novel therapies to block inflammation.

The team of researchers hope to design a test that is as accurate as real-time RT-PCR, the test currently used to detect SARS-CoV-2, but that takes less time and requires less equipment. They also hope to develop an accurate antibody detection assay, to be used to assess who has been infected and therefore who is likely to have protection against the virus. Prof Mills said this test will assist in informing who will be the most safe to return to work.

Prof Mills stated that as Covid-19 is “very much an immunology-based disease”, they will be looking at the different immune responses of individuals. Prof Mills has a particular interest in those who were infected with the virus but were asymptomatic. He said these individuals may give some clues as to what the important immunological parameters might be for controlling infection.

TCD will not be designing vaccines. However, Prof Mills said Trinity’s research will feed into the pharmaceutical companies’ attempts by providing novel expertise, such as how to better induce memory responses in vaccines, and how vaccinating through the nasal route may induce better local immunity in the respiratory tract.

As inflammation causes lethality in some individuals, the project is also investigating novel therapies to block inflammation. Prof Mills stated that blocking inflammation will provide “a good chance of preventing deaths from Covid-19”.

Patient-centered research

Prof Long was the next speaker. She discussed the “patient-centered research” being carried out in the TTMI, located on the St James’s Hospital campus. She began by drawing attention to the state-of-the-art sequencing technologies in use at TTMI, highlighting a machine called BP Rhapsody that can isolate single immune cells and sequence their genetic profiles. This technology will allow researchers to observe how SARS-CoV-2 affects genes within immune cells. Through this research, TCD hopes to not only predict who might be likely to develop a severe form of Covid-19, but also what treatments might work against this disease, and which patients will be likely to respond to these treatments.

Biobank

Prof Long went on to reveal the work that has already been carried out over the last month by Trinity. Blood samples have been collected from Covid-19 patients with their serum and immune cells isolated to create a ‘biobank’ of Covid-19 patient samples. Prof Long described what information they hope to acquire from this biobank. These include: An understanding of why some people get severe forms of this disease while others only have mild symptoms; discovery of novel biomarkers and predictors of severity and disease outcomes; and identification of novel pathways for therapeutic targeting. The biobank will also be used to observe the effect pre-existing conditions have on SARS-CoV-2 infection, such as diabetes, autoimmunity, immunodeficiency, lung disease, and individuals undergoing immunosuppressive therapy. It will also be used to investigate why this disease is so age-dependent; why males are more affected than females; why obese people suffer greater severity; what effect smoking has on this disease; and why socioeconomic status has been demonstrated as a risk factor.

Prof Long then opened the floor to Prof O’Neill, who addressed some of the global efforts being made against Covid-19, and the role his lab is playing in Trinity’s project. He noted that there are four main ways to fight this disease: Vaccines, antiviral drugs, antibodies, and anti-inflammatory drugs.

BCG vaccine and remdesivir

Prof O’Neill stated that the BCG vaccine could be “the bridge” to a real vaccine — which is predicted to be at least a year away. There are currently seven clinical trials investigating the effect of the BCG vaccine on SARS-CoV-2 infection. If clinical trials go well, Prof O’Neill said the BCG vaccine will be given to older individuals and others classified as high-risk to protect them against this disease.

He went on to highlight a promising drug called remdesivir — a broad-spectrum antiviral drug that prevents viral replication within cells. He mentioned a clinical trial that showed a 30 per cent response rate to this drug in patients with early-stage Covid-19. The drug did not work in later-stage patients, as the disease was already in progress. Prof O’Neill stated that if this antiviral works, it will change everything because “the fear goes away”. To emphasise this, he pointed out that there has never been a vaccine made for HIV, a disease that is managed through antiviral drugs.

Prof O’Neill briefly touched on the use of antibodies to kill SARS-CoV-2, before concluding that if any prevention or treatment method is proven to work, it will make a significant difference to the world.

Itaconate

Prof O’Neill then moved on to discuss the Covid-19 research being carried out in his own lab in collaboration with labs in Holland and Belgium. Three years ago, Prof O’Neill discovered a molecule called itaconate — a profound anti-inflammatory molecule that our bodies naturally make — one of the ‘off-switches’ for inflammation. Itaconate has since been proven to suppress inflammation in different contexts. It has been used to prevent death in mice with sepsis, and was shown to be effective against Zika virus in murine neurons, demonstrating not only the anti-inflammatory effects of this molecule, but also potentially antiviral effects. He remarked that the molecule could be seen as “two for the price of one”.

Although Prof O’Neill did not want to discuss the research in detail, as it is still “early days”, he said that his team had already produced some hopeful data. When asked about the future of itaconate, Prof O’Neill told the Medical Independent that “if it all works out (and that’s a big ‘if’), it will be an orally-active drug.” Although he said it is difficult to predict the timeline, he hypothesised that “a year or so from now, we might start trials if everything goes according to plan. It would then be the equivalent of Tamiflu, which is used for influenza, although we think it might be better than that in terms of limiting inflammation in patients who have a more difficult course with Covid-19.”

Prof O’Neill’s lab will also be using the biobank discussed by Prof Long to measure itaconate levels in these samples, alongside inflammatory markers.

The webinar ended with a 25-minute questions and answers session. During this session, Prof Long and Prof O’Neill both mentioned that the project is looking to develop a rapid molecular test for SARS-CoV-2 infection that could be used in places such as airports — in order to enter a country, a person might have to first test negative for the virus.

Prof Mills discussed how the cytokine IL-17 is thought to be potentially one of the pathogenic cytokines in Covid-19. A drug that blocks IL-17 is already in use in patients with psoriasis. As part of the Trinity project, Prof Mark Little, Consultant in Nephrology at Beaumont Hospital, Dublin, is investigating the use of this drug in Covid-19 patients.

The webinar can be found in full on the TCD Alumni Facebook page and YouTube account.

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