How are flu vaccines made?

25 September 2018

Interview with

Othmar Engelhardt, National Institute for Biological Standards and Control

One powerful way we can defend ourselves against infections is through the use of vaccines; these educate your immune system so it can recognise an infection in future. They contain inactive components made from viruses, or bacteria, which stimulate the production of immune molecules called antibodies. This means that, if the infection is encountered for real later, these stick to the incoming disease agents and smother them, blocking the infection. But how are flu vaccines made? Izzie Clarke visited Othmar Engelhardt at the National Institute for Biological Standards and Control; they’re responsible for checking the quality and safety of UK medicines and treatments. Afterwards, it was back to historian Sean Lang who then explored other pandemics in the past 100 years. 

Othmar - Flu is a very special case because flu viruses change constantly. So if you’ve given a vaccine in a particular year you induce an immune response, you induce antibodies against the viruses of that year. But the virus evolves, changes and tries actually to escape the immune response in the population so one or two years later the virus will look different. It will have, if you want, a different coat with slightly different maybe patterns on its coat and, therefore, the antibodies are not so good at recognising it any more and you need to induce new antibodies and that’s why you give a new vaccine every year to keep up with the changes in the virus.

Izzie - And that’s the pesky thing about the flu virus. You can get vaccinated against flu but it can change and evolve or, as Othmar explains, disguise itself. And so our immune system doesn’t always react and attack it, which is why vaccines are so important. But how do we make them? It was off to the lab...

Othmar - We are in a room where we have incubators and fridges to keep chicken eggs.

Izzie - Chicken eggs; what have they got to do with the flu?

Othmar - Some viruses, and influenza virus in particular, grow very well in embryonated chicken eggs, and it’s technology for influenza that was developed in the 40s.

Izzie - Can we see any of these eggs?

Othmar - You can. We have an incubator here with uninfected eggs.

Izzie - Oh, wow! Oh, it’s quite warm in there as well actually.

Othmar - It is very warm. The eggs like to be warm. They are slightly different from eggs that you buy in your supermarket. We shine a strong light through the egg and then you can see the interior.

Izzie - The box that you’re using to shine this light literally just looks a bit like an old cinema projector. I feel like we’re going to get the slides out or something.

Othmar - Yes, it is a very simple equipment and you put the egg in front of it and, all of a sudden, you see the interior.

Izzie - Oh my goodness. That’s amazing!

Othmar - You can see the embryo, you can see blood vessels.

Izzie - The egg basically lights up to a sort of orangey red colour, and we can see all of these small blood vessels going through it.

Othmar - Yeah.

Izzie - Okay. So how do we take an egg and then actually get a flu vaccine by the end of it?

Othmar - Okay. You need a flu virus to start with. So you take viruses from patients which you analyse year round and you pick the ones that are most appropriate to be in the vaccine, and then we use a syringe to inject the virus. These viruses often don’t grow well in eggs so you need to change them, you need to manipulate them so that they grow better. And there are a few labs in the world, and one of them is our lab that does this process to change the viruses so that they can grow well in eggs.

Izzie - Okay. So we inject this virus into an egg and then what happens?

Othmar - Okay. The virus has grown in the egg so you have live virus in the main fluid in the egg. You can harvest this fluid from the egg, which is not yet suitable for a vaccine so you need to do further processing steps. You want to get rid of some of the egg components but you also want to concentrate the virus so that you have a higher amount of inactivated virus there to induce an immune response. And in many cases there’s further purification involved to enrich the components that you actually want in the vaccine. The coats of the virus that induce the relevant antibodies.

Izzie - How much of this vaccine could you get say from one egg?

Othmar - Not very much. Probably one or two doses depending on the yield.

Izzie - Oh wow! So we're going to need a lot of eggs to vaccinate the whole of the UK?

Othmar - Yes, millions.

Izzie - This is the most reliable way but what are some of the weaknesses to this method?

Othmar - One is dependence on eggs. If the chicken flocks were wiped out by a chicken disease there wouldn’t be a substrate to make vaccines so that would be a problem.

Izzie - And using eggs, is this the only way we can produce vaccines?

Othmar - No it isn’t. There are other methods. In recent years manufacturers started to use cell or tissue culture to make vaccines so they’re using cells, infect them with virus, harvest the virus again, and then the process is very similar to the egg based process.

Izzie - And it was off to a lab to explore this alternative method - cell culture…

Othmar led me to a corner of the room that had three incubators. They actually look like high tech mini fridges but they’d be the worst fridges ever considering they’re kept at 37 degrees celsius. And then he pulled out a rather surprising plastic container…

Othmar - In there are the plastic flasks with the cells inside.

Izzie - I wasn’t expecting it to look a bit like a clear hip flask. So we’ve got this plastic container with this orangey-looking liquid through it. What is actually in here?

Othmar - On one of the larger surfaces of this flask, the cells are attached to the surface, and then we have a liquid, a medium, which keeps the cells happy - gives them nutrients. We can take off the liquid on top, wash the cells, and then take virus in a small volume, put it on, add some more medium, and the virus will infect the cells in the flask and we put them back into the incubator. And two or three days later the viruses will have destroyed the cells and will be found in the liquid where we can harvest the liquid and then do with the virus what we need to do.

Izzie - Now that seems a more straightforward method than say all of the eggs?

Othmar - It is a more modern way and some other vaccines are made in cell culture, other than influenza virus. I’m sure this will be a method that increases in use, whether it will be the main method we’ll have to see.

Izzie - So whether our vaccines are using fertilized egg or whether it’s cell culture, who exactly needs these vaccines? Should we all be getting them?

Othmar - Many people need the influenza vaccine. Different countries have different vaccine recommendations. In the UK, it is recommended that the elderly get the influenza vaccine every year. It’s also recommended that ‘at risk’ groups of younger age so certain conditions; heart conditions, lung conditions, diabetes get the vaccine every year to protect them from influenza where in these people it can create a more serious disease, and also children. There is now a programme in the UK of vaccination for children that is expanding and lots of children are getting the vaccine.

Chris - That was amazing stuff. That was Othmar Engelhardt and he was speaking with Izzie Clarke

Georgia - Sean, are pandemics like this something we have to deal with often? Can you tell us about some of the other big pandemics that have hit since 1918?

Sean - Well luckily not too often. We haven’t had anything quite on the scale of the Spanish flu outbreak but, of course, there have been major outbreaks. In the Second World War, in the conditions of the war, you have things like the outbreak of typhus in camps and that sort of thing.

But more recently, the biggest one of course was AIDS in the 1980s, or starting in the 1980s. And then, of course, we’ve had the bird flu outbreak and more recently, I suppose, Ebola. So the age of the pandemic not only hasn’t passed but the judgement is that it’s highly likely, not say inevitable, they’ll be another major flu outbreak for which I hope from the sound of what we’ve been hearing we’re better prepared than we were in 1918, but you can never be complacent.

Georgia - Right, yeah. That’s quite scary because you think these are things from the past, but a lot of the pandemics you just mentioned are in very recent years?

Sean - Oh absolutely, yeah. Yes, it’s not just going back into long ago. And, of course, it is always changing and there are different variants of flu. And we tend to put a lot of faith of course that we just think science will solve it but the diseases or viruses respond to it and so new strains come in. And above all, I would say you’ve got to have international cooperation and the more that becomes under strain the harder it will be.

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