Viral Vector Vaccines – More Fun Things I’ve Learned

In this post, I shared what I had learned about how the AstraZeneca ‘viral vector’ vaccine worked and how endlessly fascinating I found it. But I was struggling to understand why it takes so long for the immune system to ‘learn’ about the new threat that the vaccine is trying to teach it about… why it seems to take “weeks” to gain any protection. I still don’t understand but I’ve learned a few more things that others might find interesting too!

Recap of the basic idea

The basic idea behind Viral Vector vaccines such as the AstraZeneca and Johnson & Johnson products is that a harmless virus is genetically modified so that, if it were to infect a human cell, the cell would start producing protein fragments that look a lot like the spike proteins on real Covid viruses. These ‘fake’ spikes become visible to your immune system, which mounts a response. Thus, if you subsequently become infected with the ‘real’ Covid, your immune system is already primed to destroy it.

Do those fifty billion viruses replicate once inside me? Answer: no

When I read that the vaccine relies on injecting a harmless ‘carrier’ virus, my immediate thought was: “I wonder if that virus is able to replicate like normal viruses do?” I saw on my ‘vaccine record’ that there were fifty billion copies of it in my dose, which made me suspect not… after all, why would you need to inject so many if each one had the ability to replicate? The human body only has about 15 trillion cells, so 50 billion viruses is enough for one in 300 cells! Surely you’d need far fewer if each one could trigger the creation of many many copies?

Turns out I was right about this: the modified ‘adenovirus’ that is injected into me is unable to replicate: those fifty billion copies are the only ones I’ll ever have as a result of that shot.

This infographic (click for better image), from The Royal Society of Chemistry, has a nice explainer on CompoundChem:

As that article explains, it seems like the decision to use a non-replicating virus was a choice, presumably on safety and public acceptance grounds: it would have been possible to design a vaccine where the virus could replicate, and some vaccines for other diseases do work that way. The advantage of the latter, I guess, is that far fewer copies would have had to be injected to start with. It’s interesting to speculate (based on absolutely zero knowledge of the science or of where the bottleneck in production actually is…) whether vaccine rollouts could have been quicker if they’d been based on replicating viruses. Would it have meant any quantity of production could have been spread more broadly?

Note: I’m still not yet clear on what happens to my cells that are infected by one of these non-replicating vector viruses… are these cells then destroyed by my immune system because they present the spike protein? Or are they allowed to live? Can they divide? If so, do their daughters also produce the spike protein?

What happens if my body already has antibodies to the vector virus?

I made a throwaway comment in my last post about how the ‘carrier’ virus has to be carefully selected: if you’ve been exposed to it – or something like it – in the past, your body will attack the virus particles before they have a chance to infect your cells… and so you’ll produce no (or fewer) spike proteins and you’ll presumably develop weaker protection against Covid than would otherwise have been the case. This piece in The Scientist explains more. It explains that this was why the AstraZeneca vaccine uses a modified chimp virus – it’s far less likely the average human has seen it before. And it points out that there’s a downstream consequence: that virus can’t now be used for a malaria vaccine. You really do have to use a different one for each vaccine.

There were a few other interesting tidbits in that article. It was the first time I’d seen an argument that one possible reason for milder side-effects from the AZ vaccine amongst older people is that the older you are the more pathogens you’ve been exposed to and so the more chance there is that your immune system has seen something like the vector virus before. And so relatively more of the fifty billion particles will be destroyed before entering a cell. So I’m even more pleased about my feverish sleepless night now!

Why are vaccines injected into muscle? How long does it take for the virus particles to get to work?

The question that triggered my attempts to learn about this stuff was why does it take weeks for me to gain any meaningful protection from the vaccine when it’s clear that my body was fully responding to the onslaught after barely twelve hours?

It got me wondering whether the mechanism of injection had anything to do with it. For example, if the vector virus is injected into a muscle, how long does it take for all fifty billion virus particles to get to work? And where do they operate? In that muscle? Or do they circulate round the body?

Was the first night reaction in response to all fifty billion viruses going to work at once? Or were only a few of them at work that night and it wasn’t yet enough to persuade my immune system that this is something it should lay down ‘memories’ about? Perhaps it’s going to take a few more weeks until they’ve all infected a cell and enough spike proteins have been produced to get my immune system finally to say “Fine! You win! Stop already! I’ll file this one with all the others on the ‘things we should be on alert for in the future’ shelf. Now stop bothering me!!”?

I was surprised how little definitive information there is about this sort of stuff online. I guess because it’s ‘obvious’ to medical professionals, and they don’t learn their trade from quick skims of Wikipedia and Quora. (I hope).

From what I can tell, the main reason vaccines are injected into the muscle are for convenience: the shoulder is at just the right height for a clinician to reach without much effort, it’s an easy target to hit, there’s no need to mess around trying to find a vein, and the risk of complications (eg inflammation of a vein or whatnot) is lower. This literature review makes for an interesting skim.

I’d also wondered if injection into muscle, rather than veins, results in the vaccine having a localised effect… eg is it only my shoulder muscle that churns out the spike proteins? Turns out the answer to that is no: muscle is chosen over, say, fat precisely because it is rich in blood vessels. The vaccine designers want the vaccine vector virus to enter the bloodstream and rush round the body.

And I’d wondered if injection into muscle was in order to create a ‘slow drip drip’ of vaccine into the bloodstream over time and perhaps that would explain why it took so long for the body to develop full immunity. Turns out the answer to that is also ‘no’. It seems that injections into the deltoid muscle (shoulder) are absorbed quicker than those into other commonly used injection sites. Implication: if the manufacturers wanted slow absorption, they wouldn’t be telling doctors to stab patients in the shoulder!

So when I bring all that together, I still remain confused… injecting the vaccine into my shoulder results in quick absorption, and my body was in full ‘fightback’ mode after twelve hours, so it’s hard to imagine there was any meaningful amount of vaccine lingering in my shoulder after, say, 24 hours… it must, by then, all surely have been whizzing round my veins and happily infecting my cells.

So what gives? Why does it take weeks after billions of my cells have been turned into zombie spike protein factories and my immune system has gone on a frenzied counterattack for me to have a meaningful level of ‘protection’ against Covid? (I’m ignoring the relevance of the ‘second dose’ here for simplicity)

I guess the answer must be ‘because that’s just how the immune system works!’