When the coronavirus pandemic struck Ireland and the world, it sent most people into a panic. But not the immunology researchers at the Trinity Biomedical Sciences Institute (TBSI) and Trinity Translational Medicine Institute (TTMI).
Once coronavirus reached Ireland, TBSI Director Prof Kingston Mills along with TTMI Director Prof Aideen Long gathered 14 of Trinity’s top scientists to form the COVID-19 Research Hub. Their goal is to leverage Trinity’s expertise in immunology and infectious disease to answer the big immunological questions surrounding the virus and contribute to the global efforts developing treatments and vaccines.
“There are not too many experts around the world on SARS viruses, but everybody has suddenly become an expert in COVID-19,” remarked Mills. “None of us obviously worked on SARS viruses before, so we’re adapting our expertise to cope with that.”
Under the group’s main €4.8 million grant from Science Foundation Ireland (SFI), individual researchers are exploring a number of areas, from anti-inflammatories to vaccine efficacy. “We’re bringing our own strengths, our own specific areas of interest to bear on COVID,” says Prof Luke O’Neill, the chair of Trinity’s School of Biochemistry and Immunology.
None of us obviously worked on SARS viruses before, so we’re adapting our expertise to cope with that
O’Neill’s current area of interest is on the role of inflammation in disease. Inflammation is part of the body’s natural response to clear an infection but can cause severe damage if it gets out of control. In coronavirus patients, overactive production of immune molecules called cytokines can produce a “cytokine storm”, overstimulating the inflammatory response and damaging the lungs and other tissues.
But most of the time, the immune system naturally regulates levels of inflammation. In 2018, O’Neill’s lab published in Nature that a molecule called itaconate, produced as part of the body’s natural metabolism, creates some of these natural anti-inflammatory effects.
Although the discovery of the anti-inflammatory role of itaconate is exciting on its own, in 2019, a lab unrelated to O’Neill’s group published in Immunity that itaconate also has antiviral effects against Zika virus in brain cells. Following those findings, O’Neill was approached by a SARS virus expert to collaborate on testing itaconate against the coronavirus, with promising early results.
“What we’re showing is that itaconate can block the virus,” says O’Neill. “It could be antiviral directly in some way, and secondly, the anti-inflammatory bit might help because obviously it will limit inflammation when this becomes a severe disease.”
O’Neill explains that the coronavirus uses a spike protein to enter human cells, binding to a receptor called ACE2 found on many cell types including lung and heart cells. Itaconate appears to lower ACE2 expression, thus preventing the virus from entering cells. “If this molecule can block ACE2 and be anti-inflammatory – double whammy. You’re going to have a very interesting prospect there”, says O’Neill.
Although the initial data is intriguing, O’Neill is quick to point out that it is “early days”, both in terms of how recently itaconate was discovered and in testing its effects against the coronavirus. O’Neill’s lab has several parallel projects also focused on anti-inflammatory therapies, and he says: “Any one of our projects could be made relevant and have an impact on COVID. So whatever we do is going to feed in ultimately. The whole lab is kind of working on COVID with some directly, some indirectly.”
If this molecule can block ACE2 and be anti-inflammatory – double whammy, you’re going to have a very interesting prospect there
O’Neill’s research covers just one of the four main areas being explored by the COVID-19 Research Hub. Mills and his lab are focusing on vaccines, but not in the way you might think.
“We won’t be developing a vaccine on our own, but we’ve been working with pharmaceutical companies to help them to improve the way that the vaccines work,” explains Mills, “and how they can induce more sustained immune responses.” This is frequently done by testing different adjuvants, which are additions to a vaccine that help stimulate a stronger immune response.
It’s still unclear exactly how long immunity to the coronavirus lasts after an infection or administration of the vaccine, but O’Neill says the goal of a vaccination programme is to ideally create herd immunity and in the process, prevent fatal cases of the disease.
What has become increasingly clear about the coronavirus, however, is that people vary widely in their immune response to the infection. A further research area is examining why some people who are exposed to the virus do not get infected, and why some people who do get infected go on to develop a severe disease.
“[We are] looking at patients that have been exposed, and yet, spontaneously clear the virus”, says Long. “What is it about their innate immune system that helps them to do that?”, she asks, citing examples of partners of coronavirus patients who did not become sick after exposure to the virus.
We won’t be developing a vaccine on our own, but we’ve been working with pharmaceutical companies to help them to improve the way that the vaccines work and how they can induce more sustained immune responses
Long theorises that these patients’ innate immune systems (the non-specific first line of defense of our immune systems) may have some unique features that make them especially effective. Determining what those features are could lead to a better understanding of how to protect people from the virus.
Around 15 per cent of coronavirus cases globally are classified as severe, and a further five per cent are classified as critical, according to the World Health Organisation, but scientists still don’t know why some people are more susceptible to serious illness than others. Long says the group is exploring the effects of diabetes, obesity and age, factors which have already been shown to potentially link to coronavirus susceptibility. But the group is going beyond these factors, also looking at differences in infection between genders as well as socioeconomic status.
Long says she brings the patient-focused angle to the research hub via TTMI which is based in St James’s Hospital, allowing for a close collaboration between the lab-based scientists of the TBSI and the clinicians based in St James’s.
“It’s nice to have a situation where you have clinicians that are dealing with the patients, that are making clinical observations that we don’t see that form scientific questions that then we can try and answer in the lab,” says Long. “I think that’s a really nice dimension.”
Underpinning all the work being done in the COVID-19 Research Hub is a continued focus on testing, an area that has improved dramatically since March and April when the research hub was formed but can be improved even further.
It’s nice to have a situation where you have clinicians that are dealing with the patients, that are making clinical observations that we don’t see that form scientific questions that then we can try and answer in the lab
“What we’re developing is a high throughput assay that will be completed in two hours and doesn’t require a swab, you only need saliva”, says Mills. A faster, less invasive test like this could significantly improve testing capacity and shorten the current wait time to receive test results which is currently around two to three days, according to the HSE.
Antibody tests are also being developed, which can identify what percentage of the population has been exposed to and produced an immune response to the virus. Those who have antibodies against the coronavirus are less likely to become reinfected, says Mills.
All of these research areas complement the existing vaccine clinical trials that have resulted in the first non-trial patient in the UK receiving the Pfizer-BioNTech vaccine this past week. Pfizer and their competitor Moderna are both using mRNA-based vaccines, a technology never before approved for use as a drug.
“The RNA vaccines are pretty interesting because they were seen as fringe in the vaccine world for a long time,” commented O’Neill. He said he and the whole scientific community are waiting to see more hard data as the vaccines are rolled out but there is no reason not to trust the results coming out so far.
As enthusiastic as these researchers are about the progress being made, Long acknowledges that “these things don’t happen overnight. These things are slow, and things are moving relatively quickly. They’re not as quick as we would like,” she says. “But these are unprecedented times. I am optimistic.” O’Neill agrees: “I’ve no doubt at all, if we fast forward even three months from now, there’ll be progress that’ll give us hope.”
O’Neill thinks one of the most critical parts of making progress over the next few months will be an effective information campaign from the government about what to expect from a coronavirus vaccination. He thinks letting people know that there may be mild side effects that can be managed with paracetamol, releasing all the efficacy data about the vaccines to the public and ensuring that taking the vaccine is voluntary will be essential.
The RNA vaccines are pretty interesting because they were seen as fringe in the vaccine world for a long time
“You say look, if you take this vaccine, you’re protecting the community – it’s not about you,” he said. “Because remember, 97, 98 per cent of people get over this virus and wouldn’t need a vaccine anyway. It’s the three per cent you want to protect with the vaccination program.” He hopes that this approach will inspire people to respond to the “greater good” and get vaccinated for the benefit of the community.
Buoyed by the SFI grant after an initial investment of €2.4 million from Allied Irish Banks, the COVID-19 Research Hub scientists are also involved in several international collaborations with labs in the US, the UK, the Netherlands and Hong Kong.
Ultimately, these researchers hope that the establishment of the COVID-19 Research Hub will not just help fight the current pandemic, but future diseases as well. “That’s sort of the long-term aim: to be ready to deal with the next pandemic, which may not be a SARS virus. It could be something else we don’t know that’s coming down the line,” says Mills.
