John Tregoning: How nucleic acid vaccines can protect us from infectious disease
Image courtesy of John Tregoning
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The history of vaccination against infectious diseases goes back a long way - possibly more than 2,000 years - as people tried to carefully expose themselves to just a little bit of an infection in order to provide protection, primarily from smallpox. The first proper vaccine that we know of came in May 1796, when English doctor Edward Jenner injected 8-year-old James Phipps with pus from a milkmaid’s cowpox sore. Gross, I know, but it worked to protect the kid when Jenner later injected him with smallpox.
From there came a whole host of innovations, from injecting people with killed bacteria or viruses, or other molecules from pathogens that had been treated in some way to make them harmless, through to recombinant protein vaccines made in the lab with genetic engineering on to today’s cutting edge DNA and RNA vaccines.
But whether it’s Jenner’s cowpox jab or the Pfizer BioNTech mRNA COVID19 vaccine, they all work in the same basic way - as a kind of biological training programme teaching your immune cells what to look out for and react to when they encounter that particular pathogen for real. But while it seems obvious how dead bacteria or viruses could be effective as a vaccine, it’s a bit more complicated when it comes to nucleic acids.
To find out more, I sat down for a chat with Dr John Tregoning from Imperial College London. He’s an expert on vaccines and respiratory infections, and is also the author of the book Infectious, which is a fascinating tour of all the ways that nature is trying to kill us and how we’re fighting back against it. I started by asking him how RNA and DNA vaccines actually work.
John: DNA is the material that your cells use to instruct them how to make proteins. It's like the library in the centre of the cell that has the information, the instructions of how a cell is. So human DNA will tell your cells to be human, mouse DNA will tell a mouse to be a mouse. It encodes life itself.
John: And the way it does that is like a library, it can have little copies which are taken out. And the RNA is the books that are taken out of the library and taken to the protein factories in the cell called the ribosomes, where the proteins are made.
John: What's really key is that DNA is universal. So everything alive on earth uses DNA. So the instructions from one type of organism can actually be moved into a cell of a different one, and you'll start making that protein. And so the way that DNA and RNA vaccines work, is that it's changing where you are making the protein from the pathogen for the vaccines.
John: What we're doing with DNA and RNA vaccines is instead of making the protein in a glass bottle, you are making the protein in your arm muscle. And so the difference between the two platforms is that DNA, you need to go from DNA to RNA to protein. And RNA kind of shortcuts one step and goes from RNA to protein.
Kat: Are there any other particular differences, advantages or disadvantages of using mRNA versus DNA as a vaccine?
John: I think what we've seen is that the mRNA has been much more effective as a human vaccine platform. The DNA approach has been around for much longer. So the underpinning idea of it came about in about the sixties, seventies, where somebody took some DNA from one organism, injected it into a mouse and could see an immune response happening.
John: This idea has been around for a long time. There have been a lot of clinical trials trying to make a good DNA vaccine, but they haven't quite worked as effectively as the RNA. So the RNA maybe benefits from not having to go through as many steps to be made into a protein. The fact that you have this DNA to RNA to protein versus RNA to protein, it may be just by shortcutting one step it can be more effective.
Kat: But the one thing I do know about DNA is like DNA gets everywhere, it lasts for ages, we can dig up DNA from thousands of thousands of years ago and it's fine. And then having worked in a lab with RNA - that stuff is fussy! You just look at it and it's degraded, right. So I guess there is a difference there in the actual, the stability of the vaccines.
John: Yeah, I think so. And in terms of the manufacturing process, potentially DNA could either be made more stably or last longer. Maybe one of the challenges of the vaccine rollout with the RNA vaccines was that it needed very, very cold freezers, sort of minus 80 freezers that aren't universally available. It may be that if a DNA vaccine could be found to be effective, it would be easier to more widely roll out.
Kat: So where are we now with using these kinds of nucleic acid vaccines? What's the kind of state of the field right now?
John: The biggest step was what happened during the COVID Pandemic and actually RNA and viral vectors were one of almost 200 different platforms. There were so many vaccines trialed during that early first six to nine months of 2020 when the virus first emerged properly. We saw lots of different things being tested, and that was great because actually it's like lottery tickets. The more you buy, the more chances you have of winning.
John: I think the next steps will be people thinking about using RNA vaccines either for other pandemic preparedness. So the advantage of RNA and DNA is the speed at which you can make a completely different vaccine. The amount of time from when the first sequence came out for the virus to when the first vaccine was made was about two months.
John: And so that can be used for the future. If there's another, for example, influenza pandemic in 10 years time, you could sequence the influenza virus and make an RNA vaccine or a DNA vaccine very, very quickly. So that kind of pandemic preparedness is really important.
John: The other advantage of these approaches is that the manufacturing is the same regardless of what you're making a vaccine against. So a flu RNA vaccine is the same as a hepatitis B RNA vaccine or a streptococcus pneumonia RNA vaccine. You can use one factory and the plant in one factory to make all these different things, with the earlier types of vaccines, you may need different growing conditions. You can't grow a bacteria in the same way as a virus, so there's much more flexibility.
John: I think the first step is continuing in pandemic preparedness with these nucleic acid vaccines. The next thing we might see then is new vaccines for old pathogens. So it may be that some of the viruses and bacteria that we don't have vaccines for, maybe an RNA vaccine would help with that, or at least in the kind of understanding the immune response that you want to generate for that.
John: And then the last one is that, would it be useful for what might be seasonal endemic viruses such as influenza? There's a kind of range of things within infection that these vaccines might be useful for.
Kat: Yeah, universal flu vaccine, that’s a one and done. That would be great.
John: Yeah. And that's been a long goal and maybe the platforms will help in that. But also, it's about understanding more about viral proteins.
John: I think actually we learned a lot during the pandemic about what vaccines can do and, and this kind of opportunity for learning was really important and will shape what happens in the next pandemic, or as they're rolled out for other non pandemic vaccines.
Kat: And finally looking at the vaccines that are coming through the pipeline, what are you most excited about coming out of this field? The next disease that we're likely to have a nucleic acid vaccine against coming through?
John: The really exciting stuff, I think, is some of the stuff around shingles and chickenpox. There's some data that's just come out relatively recently that the chickenpox vaccine seems to reduce the rate of progression to dementia. By not getting shingles, you're less likely to get dementia.
John: So actually it's another thing that vaccines don't just stop short-term disease. They can shape your whole health future. I think we've seen that with the Human papillomavirus and the massive reduction in cervical cancer. I think seeing vaccines as a platform for lifelong health, I think that's the most exciting thing.
John: And then I think for me, the next big exciting vaccine, it may not be RNA or DNA yet, but there is a huge TB vaccine trial that's just been announced. I think if there's a vaccine against TB, that's a huge force for good.
Kat: Fingers crossed.
