Editor’s note: Anne Moore is a senior lecturer in biochemistry and cell biology at University College Cork and a specialist in vaccine development. We spoke to her for episode 3 of The Conversation Weekly podcast on vaccine manufacturing.
Below are excerpts from our conversation that have been edited for length and clarity.
First, are all the vaccines the same?
No. Different COVID-19 vaccines use different technologies, or “platforms”. The most conventional one is the inactivated vaccine. It contains dead virus. Because the virus is still whole, it has all of the parts, in the correct shape, that can stimulate a response from the immune system – what we call the antigens. The immune response can be against multiple antigens.
The Chinese vaccines – from Sinovac and Sinopharm – are the main ones using this platform. It’s a great technology, it works for some human and veterinary vaccines. The same approach was used for seasonal flu vaccines some years ago.
Then there are the viral-vectored vaccines, such as the Oxford/AstraZeneca vaccine and the Sputnik V vaccine from Russia’s Gamaleya Institute. This is where you take a harmless virus, such as a virus that gives you a cold, and you alter it so that it can infect one cell, but can’t reproduce and go on to infect other cells.
You then get that virus to carry the gene for a protein of interest, such as the spike protein of SARS-CoV-2, with the DNA sequence for the spike protein combined into the virus’s DNA. The virus is thus a vehicle for bringing the genetic instructions on how to make the spike protein into the body.
When you vaccinate someone with this harmless virus, it infects cells. The cells then read the gene the virus is carrying and start producing the spike protein, and the immune system mounts a response against this. And because the body recognises that there’s a virus present, the response it mounts is very strong to the protein of interest and also to the viral vector.
The final vaccines authorised are the new kids on the block, the nucleic acid vaccines from Pfizer/BioNTech and Moderna. These are just a sequence of RNA wrapped up in a lipid droplet to stop it being degraded in the body and help it get inside a cell. RNA is a really sensitive little molecule and is chopped up very easily and quickly if not protected. Once the RNA gets into a cell, again, it instructs the cell to make the SARS-CoV-2 spike protein for the immune system to respond to.
So how do you make these vaccines?
It depends on the platform. For viral-vectored vaccines, you take some of your harmless cold virus after you have added the spike protein DNA to it and grow it in a cell culture. Although the virus has been altered so it can’t reproduce in the body, it can still replicate in the specially designed cells in this cell culture.
You’ll then have this bulking up of the virus over the course of a few days, anywhere from four litres of cell culture up to maybe 20, 30 litres. Really high-scale production can be carried out in steel tanks – the manufacturing environment can look a bit similar to a super-clean, sterile brewery. You have to make sure that your cells are in the best environment possible for them to live and to allow the virus to grow. This requires monitoring many environmental factors in and around the cell culture – temperature, oxygen and CO₂ levels, acidity and so on.
You end up with this liquid that is full of the virus that you’re interested in. But it’s also full of materials that you don’t want. So then you have what we call downstream processing, where you’re purifying the virus vaccine away from all of the other components that you’re not interested in.
That downstream process is very important and is highly controlled and evaluated. It involves a lot of filtration and chromatography. At the end you have to have a very safe sterile product that contains only what you want.
There are multiple steps, and at each stage you’re taking samples and running experiments to show that you’re purifying your product as you go along. Even though it can take only a few days to grow a batch of virus, it can take a long time to purify it and prove that it’s pure, sterile and is what you say it is. The vaccine will only be released when you can prove that it’s the exact purity, sterility and composition that you’re claiming.
For inactivated vaccines, the process is similar. You grow up litres of the virus itself. And then you kill it in a specific way so that you maintain the structure of that dead virus. And then you take that and you inject it into people.
But making an mRNA vaccine is different?
Yes, with the nucleic acid vaccines you don’t have any cells. You don’t need any vats to grow anything in. You use a machine, a synthesiser, to add each nucleic acid onto the next in the right sequence so that you end up with the full-length RNA sequence that encodes the spike protein.
Then you have to take that and mix it with your little lipid droplets. You mix these components together in a very controlled way so that you’ve produced these tiny little droplets that are at the nanometre scale, with your RNA on the inside, covered by these lipids.
And again, you have to analyse them and show that they meet a very tight specification of size and what they’re composed of and be able to prove the quality of your product.