Interview with a Researcher: Associate Professor Siobhán McClean

Image Credit: Siobhán McClean

Jana Joha sits down with Associate Professor Siobhán McClean to discuss her research on bacterial vaccines and on signing an option agreement with Poolbeg Pharma to develop and licence vaccines discovered by Dr McClean and her team.

Associate Professor Siobhán McClean is a researcher and lecturer in the School of Biomolecular and Biomedical Sciences at UCD. She is also the Head of Biochemistry and her research focuses on chronic infections, particularly in cystic fibrosis, and on the development of vaccines against bacterial lung infections. On December 6th 2021, Poolbeg Pharma, a clinical-stage infectious disease pharmaceutical company signed an Option Agreement to licence MelioVac with UCD and its inventor, Dr McClean. MelioVac is a vaccine for melioidosis, also known as Whitmore’s disease, which is a potentially fatal infectious disease that is caused by a bacterium called Burkholderia pseudomallei. Melioidosis is endemic in Southeast Asia, particularly in Thailand and in northern Australia. The incidence of the disease is increasing and climate change is having a substantial impact on the spread of the disease to non-tropical regions. 

‘We started to look at it as a potential vaccine’ but ‘the sad part was that there was no commercial interest in developing a vaccine for cystic fibrosis infections’.

Speaking to University Observer, Dr McClean discussed how she started research on chronic infections and how that led to the development of MelioVac. Dr McClean completed her BSc in UCD in Biochemistry and received her PhD from Imperial College London. Between 1995 and 2000, she was a senior scientist at Elan Pharmaceutical Technologies where she was interested in looking “at how to get drugs delivered across… the lung and across the gut epithelium (the internal surface of lungs and the gut)” and “as part of that [she] was involved in vaccine… delivery”. However, Dr McClean ‘wanted to start an independent research career’ and therefore joined the Institute of Technology, Tallaght as a lecturer and principal investigator in 2000. Having a background in drug delivery and a “really good understanding of the epithelium” she was interested in investigating how bacteria involved in cystic fibrosis cause infection. “I understood the epithelium and how to use particles to deliver drugs across this surface, so I used this knowledge to  look at how bacteria interact with the epithelium and try to understand the mechanism of infection and… invasion”. Dr McClean further explained that these pathogens in cystic fibrosis “cause chronic infections and one of the hallmarks of chronic cystic fibrosis infections is that they’re highly antibiotic resistant”. She began to wonder if it’s possible to prevent these infections as “people with cystic fibrosis are on cocktails of antibiotics throughout their lives… so, what if we can prevent infections?”. 

Dr McClean and her team are eager to begin vaccine development because ‘if it improves [patients’] survival and outcome… and can reduce antibiotic use… then that will have a global impact everywhere’

That’s when Dr McClean explained, she started to investigate how these bacterial pathogens interact with the lung epithelium. “If we understand what’s causing the interaction (how they attach to the surfaces of the lungs) we may be able to develop a vaccine antigen”. She began research on a cystic fibrosis pathogen called Burkholderia cepacia complex and was successful in identifying the proteins that this bacterium uses to bind to lung cells and cause infection in the lungs. “We started to look at it as a potential vaccine” but “the sad part was that there was no commercial interest in developing a vaccine for cystic fibrosis infections”. 

However, these antigens that Dr McClean identified for Burkholderia cepacia complex “were really good at preventing infection” and she realised that they could potentially work against a related bug, Burkholderia pseudomallei, which causes melioidosis. Dr McClean and her team received “funding from SFI (Science Foundation Ireland) to try this” and were successful in showing that the vaccine for the cystic fibrosis pathogen was also effective against melioidosis. “So that started the melioidosis vaccine”. Following this, Dr McClean received funding from the Wellcome Trust Foundation to take the vaccine to the stage where they are ready for human trials. Dr McClean further explained that “to do that we had to really understand how it’s working and so in the last few years we’ve focused on trying to understand the mechanisms of action and trying to de-risk the project”, such as checking for potential toxicity of the vaccines. This led to the signing of the option agreement with Poolbeg Pharma. “Poolbeg are a clinical infectious disease company”, Dr McClean remarked and having “a good background in clinical trials” they aim to “take early-stage products in the infectious disease field through the first human trials so that they can then progress quickly to stage two”. She explained that “we’ve been working on this vaccine since 2012… and to get to human trials there’s a huge   gap that needs to be bridged… and [Poolbeg’s] agreement with us is an option to licence, which means that they’re doing due diligence at the moment”. Dr McClean and her team hope that in the coming few months MelioVac will be licenced.

Alongside the development of MelioVac, the option agreement also includes the development of five other potential vaccines. The method that was used to identify antigens for MelioVac is also able to identify antigens for other pathogens and so Dr McClean and her team have “taken that to look at other difficult to treat infections”. Vaccines for Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Burkholderia cepacia complex and Escherichia coli (O157) are also being developed. “These are difficult to treat infections and there are no vaccines available for them, so we again wanted  to see if we could identify vaccine antigens”. The idea behind how these vaccines work is that by introducing the antigens that bacteria use to attach and infect the body, it will induce a T-cell response. T-cells are integral in mediating the immune response against infections in our bodies. Dr McClean discussed that having a “good T-cell response is important” and that the antigens they use in their vaccines are able to activate T-cells. “Our method looks at the proteins that bacteria use to t interact with lung cells but somehow - and we’re trying to work out why - it identifies proteins that are good T-cell antigens”. Dr McClean gave more detail on how these vaccines work: “by introducing these surface proteins on the bacteria to the individual they will then mount a really strong immune response… and then if they encounter the bacterium or the infection later, they can recognise that this is something that they’ve a good immune response for”. 

Dr McClean and her team hope to move onto phase one trials by the end of this year where they can begin testing the vaccines on a small group of volunteers before progressing to phase two trials, “where you’ll have a much larger number of people… that will probably take place in Thailand… somewhere that it’s endemic”. The Ebola outbreak and more recently, the pandemic have greatly accelerated the development of vaccines, and thanks to this Dr McClean and her team hope to have their vaccines approved for human use in 2-3 years time. 

‘These are difficult to treat infections and there are no vaccines available for them, so we again wanted  to see if we could identify vaccine antigens’.

Alongside vaccine development, Dr McClean’s lab is continuing research on chronic infections in cystic fibrosis. When people with cystic fibrosis get colonised by bacteria it first results in acute infections but for many people with cystic fibrosis these infections tend to persist resulting in chronic infection. Dr McClean explained that “the bacteria change and evolve in the cystic fibrosis lung and we’re trying to understand that mechanism because if we can understand the mechanism we can maybe prevent what we call ‘the switch’ from acute to chronic infection”. 

Dr McClean and her team hope that their vaccines and research on melioidosis and other difficult to treat, antibiotic resistant diseases will help prevent infections and potentially save lives in areas most affected around the world. Climate change and the increased spread of disease highlight the urgency of developing vaccines that can protect against these pathogens. “One of the issues with melioidosis is that it causes up to 40% mortality in people in Thailand… and even in northern Australia it has a mortality rate of about 10%”. Dr McClean highlighted that the “other issue is that people with diabetes have a much higher risk of getting melioidosis and a poor outcome… and diabetes is on the increase right throughout the tropical countries where melioidosis is endemic”. Dr McClean and her team hope to not only prevent infection but also prevent the disease from reemerging as it can survive within the body for decades before causing infection later in life. In addition, the advantage of these vaccines is that they can reduce the use of antibiotics that drive antibiotic resistance. Dr McClean and her team are eager to begin vaccine development because “if it improves [patients’] survival and outcome… and can reduce antibiotic use… then that will have a global impact everywhere”.