How to make a vaccine: From chimp poo to my left arm

Today I had my first dose of the Oxford AstraZeneca vaccine. Waiting for it in the queue at the G Live vaccination centre felt a bit like Christmas morning when I was kid – the same anticipation of receiving an exciting gift, although in this case it is an 80% reduced chance of death in case of COVID-19 infection. I feel very grateful to all the people at Oxford University, AstraZeneca, the G Live vaccination centre, and in other organisations that together made it possible. The centre gave me some paperwork on the vaccine to read, with side effects etc. It also said that the dose is 0.5 ml, which contains 50 billion viral particles. This got me thinking. The world population is about 7.5 billion, and at two doses per person, we need about 10 million litres of vaccine, or about four Olympic swimming pools full of vaccine.

That is a lot of vaccine. So how is it made? I did a bit of Googling*, and I think it is made as follows.

First thing we question we need to answer is: What actually is the Oxford AstraVaccine? It is a GMO essentially, a genetically modified virus. The virus is a type of virus called an adenovirus, and I have read that the Oxford people found it originally in chimpanzee poo**. Adenoviruses are common, you have likely been infected by one at some point, they are one cause of colds. In other words, Oxford and AstraZeneca are using one (genetically modified) virus to help protect me from another: SARS-CoV-2 – the cause of COVID-19.

The Oxford AstraZeneca virus is genetically modified in two ways: 1) They have inserted into the virus’s genes the gene for the spike protein for SARS-CoV-2. 2) they have deleted the adenovirus’s E1 gene to cripple it.

The first modification is why the vaccine teaches my immune system to fight SARS-CoV-2. We humans have a sophisticated immune system that can tell the difference between our proteins inside our body, and foreign proteins. Hopefully, even as I type this, the Oxford AstraZeneca adenovirus is infecting my cells, causing these cells to make proteins including the SARS-CoV-2 spike protein. My immune system can then detect these proteins and learn how to detect them, and that they are foreign. Once a couple of weeks have passed and my immune response has taken its course, this will tilt the odds in the favour of my immune system, if I am unlucky enough to be exposed to SARS-CoV-2.

The second change is for vaccine safety but poses a problem for vaccine production. By deleting the adenoviruses’s E1 gene, the adenonvirus cannot multiply, i.e., when it infects one of my cells, it triggers the production of proteins including the SARS-CoV-2 spike protein, but it cannot make more adenoviruses. Thus some of the 50 billion adenoviruses injected into my arm will infect some of my cells, but each infected cell will just make some proteins, then at some point the cell will stop doing that or die. Infection only occurs when a virus enters a cell, makes that cell produce lots more virus that burst of the cell, these viruses then enter more cells, and so on.

So the virus injected into my arm cannot infect me. Good. But the problem is that rampant reproduction of a virus is the last thing you want in a patient but is the very thing you want when you need to make four Olympic-size swimming pools of vaccine. So, how is this circle squared?

Viruses like the Oxford AstraZeneca adenovirus are not made but grown, in large growth vats in which cells grow. In this case the cells are a type of mutant kidney cell called HEK 293 – these came originally from a kidney cell but are like cancer cells in that they grow like weeds. The trick is to also genetically modify these HEK 293 cells, so these cells (unlike yours or mine) produce the adenoviral protein E1. Then with the help of the E1 protein already made by these genetically modified cells, the adenovirus can reproduce and grow like crazy in these cells – but not in yours. That is the clever trick needed to grow huge amounts of virus, that cannot grow in you.

With the aid of this trick millions and then billions of doses can be produced, which is what we need to protect us all.

* Some good sources are a blog post by Brianna Birbel, another one by Derek Lowe. Both are very good, Birbel’s is great for the science while Lowe’s also looks at the industry. There is also this article in the NY Times which looks at the virus with some great graphics.

** I don’t know why they were looking in chimp poo. But there is an advantage to using a chimp adenovirus not a human one. Your immune system may have already one that is already going about infecting humans, but is much less likely to have come across a chimp one. This can help the adenovirus infect your cells before your immune system attacks it.

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