How are 'Flu Vaccines Produced?

How are 'flu vaccines prepared, how long does it take and how is the technology evolving?...
13 December 2009

Interview with 

Tarit Mukhopadhyay, University College London; John Dillon, GlaxoSmithKline; Rino Rappuoli, Novartis


Healthcare worker drawing up influenza (flu) vaccine shot


Chris -   This week, Meera Senthilingam has been down to find out how flu vaccines work and just what's involved in making them.

Meera -   pandemrix flu vaccineIn light of the current swine flu pandemic, pharmaceutical companies have had to step up the production of their vaccines in order to protect the population.  But just what's inside a flu vaccine to give us immunity to this potentially deadly virus and how are they kept up to date with what's currently circulating in our population?  To find out, I met Tarit Mukhopadhyay from University College London.

Tarit -   So the main component of every flu vaccine is the HA - haemagglutinin - protein.  It's a surface protein on the top of the virus.  It's split from the virus then purified and made safe for injection into human beings.  It's this protein that forms the basis of the immune response.  So the immune system recognise this protein, assimilates it, and then should you be infected by the influenza strain carrying the same protein, it will seek to attack it and destroy it.

Meera -   What are the main challenges facing a flu vaccine production?

Tarit -   So I guess the first challenge is producing the vaccine strain, the production strain of the influenza.  There are two techniques that you can use.  One is classical re-assortment and the other is reverse genetics.  With the re-assortment, what you want to create is a high-yielding production strain that encodes for the HA protein that's circulating on the the wild-type strain.  With reverse genetics, because of our ability to manipulate genes the way we can, we essentially engineer six plasmids for the production strain and two plasmids that will have the HA and NA - neuraminidase [another viral surface protein] genes; these are combined in a cell to produce the virus of interest.

Meera -   So essentially, the production strain that's generally used is something that's good at reproducing.  And then this is being combined with a strain that's in circulation and found in our environment at the moment so that you get a high-yielding vaccine that will stimulate the immune response that you want.

Tarit -   That's exactly right.  So you want those virus components, those virus surface proteins that will help to stimulate the immune system.  But you also need to have them in a format that can grow well in whatever culture method you are using.

Meera -   Tarit Mukhopadhyay from University College London.  And as Tarit mentioned, once you have the strain of virus that you want to replicate, it then needs to be cultured to multiply the amount you have available for vaccines.  Chicken eggs have been used for tens of years.  They're a trusted and known method used by many pharmaceutical companies including GlaxoSmithKline (GSK).  Explaining more about this egg-based technique, here's John Dillon, medical director of GlaxoSmithKline's Pandemic Center of Excellence.

John -   Well, we use millions of eggs; we take the seed [production viral] strain and we inject it into the eggs, and the eggs will replicate the virus so that you get lots of copies of the virus within the eggs.  And then we essentially harvest them, purify it and we then inactivate the viruses, and we make sure that we've got enough antigen as a result of the inoculation of all of those millions of fertilised eggs.

Meera -   When the chick eggs are ready to be injected with these viruses?  So what age are they used?

John -   So the fertilised embryos are usually around 10 or 11 days after they are injected. Then the viruses are allowed to grow for several more days before the virus is then harvested from the eggs.

Meera -   It's obviously quite labour intensive.  It requires a lot of chick embryos.  So how do you, kind of, scale up this process when a pandemic occurs?

John -   I can't pretend that it has been a major effort and ramping up to that level of production - probably a tenfold increase - is part of the challenge overall of trying to respond to a pandemic.  But we have been prepared for it.  You know, we're now in a situation where we're able to fortunately meet the demand that has been created by governments around the world.

Meera -   John Dillon from GlaxoSmithKline.  So whilst the use of chicken eggs has helped us to meet the demand for both our seasonal and pandemic flu vaccines, it still has its limitations.  And as a result, companies such as Baxter Pharmaceuticals and Novartis have begun using cell culture methods as well.  And so to find out more about this newer technique, I spoke to Rino Rappuoli, head of vaccine research at Novartis.

Rino -   The technology that we came up with is based on culturing the virus in mammalian cells, growing in fermentors instead of using eggs.  We let the virus grow into the cells and then, about 48 hours later, when the virus multiplied to very high yields, we harvest the virus, purify and then kill it.  Then we purify the essential components of the virus which are important to make a vaccine, which are the haemagglutinin (HA) and the neuraminidase (NA). In a week we can be ready for large scale manufacturing. 

But the majority of H1N1 pandemic influenza vaccine production is still largely being carried out using egg-based influenza vaccine.  For the future, I see cell culture will slowly become the method of choice.  But today, for this pandemic, we are still largely dependent on egg-based manufacturing.

Helen -   That was Rino Rappuoli from Novartis Pharmaceuticals and before that, University College London's Tarit Mukhopadhyay and GSK's Medical Director, John Dillon speaking to Meera Senthilingam about the challenges facing flu vaccine production today and how this looks set to change in the future.


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