Krishnaa Mahbubani, University of Cambridge
Here in the UK we can usually just buy new drugs if they run over their shelf life - but we go to huge lengths to get vaccinations to remote parts of the developing world, keeping them refrigerated the whole way as part of a so-called ‘Cold Chain’.
Krishnaa Mahbubani who’s also from the Department of Chemical Engineering & Biotechnology at the University of Cambridge has been developing a way to put vaccines into suspended animation so they don’t need refrigerating, as she told Chris Smith...
Chris - So, how are you doing this?
Krishnaa - Well, we’re looking at different methods in which we can insure that cells are stable when we remove the need to keep them cold.
Chris - Why do we need to keep things in a constant cold chain when we’re trying to ship things? Why do they go off?
Krishnaa - Well, it depends what it is we’re trying to put through. If you were to imagine milk as very simple analogy to this, if you took milk from the shelves in the supermarket and left it in your car for a week, it wouldn’t quite live up to the shelf life that it says it would.
Chris - I don’t know. If you like cheese, it could be okay.
Krishnaa - Well possibly, but they don’t smell that grand when it comes out of milk bottle. But in the same way with the vaccines – they're designed and all the tests are always done within a temperature range of 2 to 8 degrees centigrade. So, when we’re transporting and then delivering them, we need to keep them at that temperature because that’s where we understand them. We know that they stay fairly stable. If we change the temperature and increase them, there's a chance especially for those that are live bacterial vaccines that they might replicate. And then we’ll be giving people a dose that is a little higher than we expect them to be getting. So, we’re not actually giving them an immune response. We’ll be actually giving them the full-blown infection which is not really ideal.
Chris - Not so good. So, how could you get around that? What are you trying to do to surmount the problem?
Krishnaa - So, I'm looking at several different manufacturing processes that we can use that we put the bacterial vaccines through in order to dry them and remove the water out of them. And by removing the water, we put them in a state of suspended animation and that allows us to actually maintain the bacterial vaccine in that form without needing to keep them cold.
Chris - Which bacteria are you doing this for?
Krishnaa - So, I'm working predominantly with a [Salmonella] typhi vaccine which is an attenuated Salmonella based vaccine, but we’ve also worked with a variety of E. coli bacteria and other things to show that it also works across the board.
Chris - So, this would stop things like typhoid.
Krishnaa - Yeah.
Chris - Okay, so when you say ‘works across the board’, are you saying that you could also use the bacteria to deliver other kinds of things to stimulate the immune response against things other than just typhoid or other sorts of infection? How did you do that?
Krishnaa - Absolutely. Well, the idea is that we can make use of genetically engineered attenuated bacteria so that it would then give you the same – go through the same mechanism as if it were a platform and deliver a variety of different immune responses to you. So, we can actually manufacture a [Salmonella] typhi vaccine, you can manufacture say, for example, something against cholera, something against travellers' disease. Pretty much, whatever we can actually manufacture to put into the strain of bacteria, we’ll be able to deliver it in this mechanism.
Chris - So, you would take the microorganism that is the one that you freeze dried your vaccine, you'd engineer it to be able to make the antigen – the thing that stimulates the immune response either for itself or for whatever you wanted to vaccinate against or maybe even a cocktail of those things. And then you're saying, you can put these things into this freeze-dried suspended animation state and then ship them…
Krishnaa - Well, they're actually vacuum-dried rather than freeze-dried, but it's a similar process.
Chris - And then the person who is the recipient would just need to eat this and it would come back to life in their stomach.
Krishnaa - Yeah. They just have to pop a pill, absolutely.
Chris - So, what happens? Why doesn’t it make them unwell?
Krishnaa - Well, I can't guarantee that it won't make them unwell at this point because we’re still trying to look into how much of a bacterial dose we need to give the patient so that they get the same immune response. Now, we normally give vaccines intramuscularly or through the bloodstream whereas my vaccines, the way we’ve designed it is, so that they would be taken orally and you'd get the same immune response through the small intestine where you have again, immune cells known as Peyer’s patches and M cells. And you'd get the similar immune response that would happen, should you get an intramuscular vaccination.
Chris - Very neat. So, in order to get the bacteria into this suspended animation state, you said you vacuum-dry them, you take away the water. So, tell me how that makes it possible to do what you're doing. Why does that make a difference?
Krishnaa - The main problem that we tend to have with keeping bacteria in a liquid format is that they tend to carry on going through their regular biochemical reactions. That means that they will take nutrients that are in the liquid, use them up, create toxins within that same liquid as they're respiring or as they're kind of going through their regular day to day activities, they'd also potentially replicate and multiply. That makes it very difficult to control. This is where the cold chain comes into it by slowing down all the biochemical processes. We then have a relative shelf life within which we know they stay at a particular range and it’s healthy and capable to be delivered to a person. When we dry it be removing all of the water in the system, we effectively stop these biochemical reactions. Bacteria are quite hardy little fellows and so, when you take the water out, they don’t die off. They just kind of sit in a nice state where you can just keep hold of them for a little while.
Chris - Will this work for any bacteria?
Krishnaa - There's a large chance that it’ll work for a variety of bacteria, but we don’t know which types it will work for. I've managed to try them on a variety. So, I've done them on a range of probiotic bacteria, some E. coli cells as well as a Salmonella type of bacteria. So, it seems to work fairly well for all of them, but they each have slight different flaws in the way they rehydrate and how well they rehydrate.
Chris - Once you’ve put them in this state, what will they tolerate? What sorts of conditions do they survive over, for how long?
Krishnaa - Well, they're quite happy if they go back into their natural conditions. So far, my tests have shown that they survive quite well on the shell for about a year which is not too bad, but I'm sure there's more improvements that can be made. In terms of what they can tolerate, they're not anywhere near as hardy as the spores. Any change in pH, so any acidic conditions, they wouldn’t survive very well. So, if we’re delivering these vaccines, they'd have to be an enterically coated capsule so that they go past the stomach acids. In terms of other conditions or heavily alkali conditions, they're also pretty alright, but sometimes they get inactivated by the bile acids that we have in our small intestines. So, we’ve managed to manufacture it with the different components who allow it to bypass all of these problems.
Chris - Unlike Graham’s spores which aren't yet quite at a stage where you can put them in a patient, are you at the stage where you have got something that could go into a person?
Krishnaa - They're currently at a pre-clinical stage. They're nowhere near going into people, but we've definitely got some pre-clinical trials being carried out by a different company at the moment.
Some can, most need refrigeration. Maintaining a "cold chain" for vaccines is a major problem when trying to vaccinate people in remote areas.