In conversation with James Thaventhiran

Dr James Thaventhiran is a clinical immunologist and Lister Prize Fellow 2025 based at the University of Cambridge. His work spans rare genetic disease, vaccine immunology and the emerging field of RNA therapeutics, with a particular focus on how personalised treatments can be made safer by design.

We spoke to James about his journey into immunology, the discoveries shaping his research, and how the Lister Prize is helping him explore new directions.

Q: What first drew you to immunology and clinical research?
A: When I was younger I wasn’t really sure what I wanted to do. I trained as a doctor, still unsure about specialising. But that changed when I worked on an HIV unit run by clinical immunologists. I saw the profound impact that HIV treatment could have on people’s lives, and that made me want to specialise in the research behind what they were doing.

So, I went to Cambridge for my PhD to understand how viral infections are controlled, working on CD8 T cell biology. By the time I finished, HIV treatment had become so effective that, for most patients, it wasn’t really an immunological problem anymore. So I shifted my focus to inherited immunodeficiency, which remains a major clinical challenge.

This period coincided with genome sequencing becoming widely available, and I got involved in using sequencing to diagnose rare immune disorders. We set up a national collaboration to identify genetic causes of antibody deficiency, which was incredibly rewarding. That surprising finding has led to a national framework for genetic testing in these conditions.

For many patients, we were able to provide a diagnosis for the first time. In some cases, identifying the mutation meant we could offer a bone marrow transplant, functionally curing their condition. Seeing research have that kind of direct clinical impact was hugely motivating and shaped how I think about science.

Q: What have been some of the other key breakthroughs in your research so far?
A: In another study our work has shown that people with obesity – which is about a third of the population – have different immune responses to vaccines. That raises important questions about whether we need tailored vaccination strategies for different groups.

And most recently, we’ve identified a phenomenon in modified mRNA where the ribosome can shift its reading frame, leading to the production of unintended proteins. That finding has opened up a new area of research for us around RNA biology and safety which is the focus of my Lister Prize Fellowship.

In preliminary collaborative studies, we found that a modification used in mRNA vaccines – replacing uridine with methyl-pseudouridine – can affect how the ribosome reads the RNA. In some cases, it can slip into a different reading frame and generate peptides that weren’t originally intended.

Q: Tell us more about this frameshift translation of mRNA. What does it mean for vaccine safety?
A: I want to emphasise that the mRNA vaccines we know, most significantly the COVID-19 vaccines – are safe. We know that from the real-world data of billions of doses given globally.

What our work highlights is not a problem with those vaccines, but a biological phenomenon that becomes more relevant as we move towards personalised therapies, where each RNA sequence may only be given to a small number of patients. Off-frame peptides can trigger immune responses in people and we need to know what immunological effects these may cause. A key example of this work is our recent study in Nature, which describes these frame-shifted translation products and the immune responses they can generate.

Q: How can your research help make RNA-based therapies safer?
A: The principle in drug development is that you should give the patient what you intend, and nothing else. As we move into personalised medicine, we won’t have large-scale safety data for every sequence we design, so we need to build safety in from the outset: safety by design.

One approach we’re exploring is using stop codons in alternative reading frames to prevent the production of these unintended peptides. By optimising the sequence in this way, we think we can reduce off-target effects. That’s really the ambition of my Lister-funded work – developing rules for RNA design that minimise unintended biological effects before they ever reach a patient.

Q: What has winning the Lister Prize enabled you to do?
A: For me, it has been quite a personal achievement. I’d seen many people I admired receive the Lister Prize earlier in my career, so it was something I really wanted to achieve myself.

It’s also been incredible from a community perspective. Just attending the Annual Meeting led to several new collaborations, and the mentorship has been hugely valuable. The sense of support is striking. I had conversations with Fellows and senior scientists that really encouraged me to step into roles I might not have felt confident about before. It’s a community where people genuinely want to see each other succeed, and that has a big impact on how you approach your research and career.

But most importantly, the Prize gives me the freedom to take risks. It allows me to pursue ideas that wouldn’t necessarily be funded through traditional routes, not least my radical shift towards RNA safety.

So what excites me now is the possibility of designing safe treatments for individual patients that this research opens up. We recently described a very rare condition, IL-6 receptor deficiency, where there may only be a handful of patients in the world. We’ve already developed an mRNA approach that could correct that defect in a preclinical model. That kind of rapid progress – from diagnosis to potential therapy – just wasn’t possible a few years ago.

The challenge now is to make sure that when we deliver those personalised treatments, they are as safe as they can possibly be.

Q: Vaccination has become quite a polarising topic. How do you communicate your science with people’s sensitivities and concerns in mind?
A: It’s something I think about a lot. With our work on mRNA, we were very careful about how we communicated it. We shared the findings with the MHRA and the Science Media Centre, and followed their advice, before publication to get advice on responsible communication.

I’m very aware that scientific findings can be misinterpreted, particularly around vaccines. As scientists, we have a responsibility to communicate clearly, accurately and in a way that reflects the totality of the evidence.

Thanks to the Lister Prize, I’ve learned to be bold in the questions I ask, but careful in how I share my findings with others. That would be my advice to anyone in research. Have confidence to pursue ambitious ideas, but ground the way you answer those big questions as robustly and careful as possible.