Thread by @SteveKerfoot

First Dose!
I'm very excited to be joining #GenXZeneca . Even though it took a bit to get an appointment, the process itself was super fast and painless.

#FirstShotOffered

This week also marks the conclusion of the undergraduate immunology course I run. As getting vaccinated is basically a live-demo summary of the entire course, I thought I'd celebrate by live-tweeting my immune response to the vaccine.
#Nerdy , but fun!

(I'm not sure how many of my students would agree about the "fun" part, but I doubt any are on twitter anyway and so they get out of this impromptu lab component).
Let the #LiveTweet begin!

Day 0:
I got the #AstraZeneca vaccine which, as you have probably heard many times by now, is a "Viral Vector" vaccine. That means that they have used the backbone of another, safe virus as their foundation for the vaccine.

There are other ways to make vaccines, and we'll talk about some of those as we go, but for now lets stick with the viral vector design.

An ideal viral vector for vaccination is one that can infect your cells, but doesn't make you very sick. Also, it should be something that your immune system hasn't already encountered.

This is important because, if your immune system already knows how to deal with the virus your vaccine is based on, it would just fall back on what it already knows and not bother to learn anything new - which is the whole point of a vaccine.

As a backbone for its vaccine, #AstraZeneca chose an adenovirus (a common type of virus that can cause a cold-like illness in people), but found one that normally infects chimpanzees. This is to ensure that our immune systems wouldn't know about it already.

They then modified it in 2 important ways:
1) They made it "replication deficient", meaning that it can still infect your cells like a normal virus, but it gets stuck once it gets to the part where it would normally make a bunch more viruses.

They did this by removing the genetic code for an essential viral protein that is part of this process. In the end, this means that it's a real, but very limited infection.

2) [this is the really important part] They inserted the code for a very important protein from #SARSCoV2 (the famous #SpikeProtein ) into the vector backbone. We'll talk more about the implications of this as we move along our #LiveTweet timeline.

The big-picture purpose is to teach your immune system to attack the #SARSCoV2 #SpikeProtein while it's learning to get rid of the viral vector vaccine backbone.

If, in the future, you are exposed to the real #SARSCoV2 virus in the wild, your immune system will already know
about the Spike protein and will go about clearing the virus the natural way.

Back to our timeline:
Day 0 +1hr
The viral vector has been in my shoulder muscle for a bit and is starting to infect a few cells in the area. As with a viral infection, this means that it is injecting its own virus genetic code into my cells.

At this point, a few local immune cells might be getting a bit suspicious. They've detected a few molecules that they know shouldn't be there and that usually mean there's a pathogen around. Those immune cells are considering their next steps.

Day 0 +4hrs
[WARNING - we're basically trolling my #virology colleagues for the next bit. I'm likely to say things that are just wrong enough to sputtering balls of fury. It'll be fun]

Virus are pretty simple things.

Basically, they are made of a small number of proteins, maybe some lipids and carbohydrates that they've stolen from somewhere, all wrapped around some sort of genetic material.

That genetic material codes for those few virus proteins and maybe a couple of other proteins necessary to make more viruses. (deleted one of those in the AZ vaccine to make it non-replicating)

Our genetic material is, quite famously, made up of two strands of DNA wrapped around each other. Viral genetic material can be all sorts of things; DNA, RNA, one strand, two strands,... whatever.

The virologists will tell you that this is important, but I can never remember what is what, so we're just going to forget about that.

The important thing is that viruses are parasites. They can't make more of themselves themselves. Instead, they inject their genetic code (made up of whatever) into your cell and then have your cells make the necessary proteins and copy the genetic material for it.

A virus essentially turns your cell into a zombie virus factory, BUT FIRST... the virus genetic code has to be translated into the native genetic language that our cells understand. Rmb: DNA > mRNA > turned into protein by our 3D printers known as ribosomes.

Right, back to what's going on in my left shoulder:
The AZ vaccine tame-virus trojan horse has injected its genetic material into some muscle cells around the injection site.

Over the next couple of hours, it will start to take over and get the ribosomes in those cells to make virus proteins, INCLUDING the #SARSCoV2 #SpikeProtein that was inserted into that vaccine/virus code.

FYI, here is where the mRNA vaccines come in: the mRNA vaccines have already translated the code for 3D printing the spike protein into our cell's native language, so so it can bypass the above steps.

The wrap the mRNA-encoded instructions into some fatty-lipid droplets to help them get into the cells.

in BOTH cases: mRNA vaccines and viral vector vaccines (and also live attenuated vaccines for those who have done the reading) - the protein target that we want to educate our immune system to attack, is made by our own cells! tricky.

But not really tricky, because that's what happens in a "natural" viral infection. It's totally normal to the immune system.

Anyway, that's what's currently going on in my shoulder vaccine - wise. There still isn't a lot to see from the immune perspective.

Some of the local cells are really starting to pay attention: there is some tissue damage from the needle (it was pretty small, so not a lot to go one there), there is some virus debris lying around and immune cells have detectors for that.

Over the next few hours some of the infected cells are going to start acting a bit funny, and other immune cells have detectors for that too,...

Local immune cells are concerned enough that they've sent out a message asking for backup. Some new immune cells will be recruited from local blood vessels and will help cleanup and with the investigation. We'll see how that goes in the morning.

Once again, I should proof read before tweeting. Maybe I'm just trolling an entirely different field?

Day 0, +~18hrs.

Some important activity to report:
The vaccine has infected local cells around the injection site and converted them into factories producing viral proteins, including spike.

The immune system doesn't know anything about that yet though.

Instead, the local and newly recruited immune cells have detectors for the types of molecules that viruses are made of (very different than the stuff we're made of).

They've also detected that some of the cells in the area are acting weird.

They've seen enough, put a call in to central, and declared an emergency.

While they don't know exactly where, or how wide spread it is, the immune cells know there is a virus on the loose.

There are a few things the immune system can do in this state of emergency:
It can flood the area with anti viral compounds to limit spread. Your temp might spike which can also limit viral replication.

It can declare a global shutdown and you might get super tired and achey and want to do nothing more than stay in bed.

All of these are emergency procedures that immune system can enact to try to keep an infection in check in the short term. Everyone will respond differently.

I got the full ride at 2am this morning, which I admit wasn't much fun, but I'm mostly recovered now.

Some people have asked me if a strong early response like this this matters to the efficacy of the vaccine, which is a great question!

I can't find anything to suggest that it does, so don't worry if you were one of the people who didn't notice anything. Your immune system is still hard at work.

In general, younger people are more likely to have a powerful early systemic inflammatory response, but it's not a hard rule, and the current vaccines have been shown to be effective in younger and older people.

Anyway, there is one last, very important thing that happened last night:

A high ranking Decider Cell (DC - bad immunology joke there) determined that this non-specific defence against the infection they think they've detected just isn't going to cut it.

We need some immune intelligence if we're going to be able to figure out where the virus is hiding and clear it out.

So, the local DCs collected a bunch of evidence from the debris of the early attack that might help identify the culprit.

Included in this evidence is some of the #SARSCoV2 spike protein that our infected cells have been making under instruction from the vaccine.

The DCs are taking this evidence off to the local immune training centre and barracks i.e. a lymph node. Some very important things are going to happen there to set up for the immune response that will protect us (me in this case) from COVID.

We'll check in with the Decider Cell / DC in a couple of hours to see what it gets up to.

Day 1:
It's been a big 24 hrs with lots going on in my left arm. The most significant of which, from the perspective of getting to the end goal of a protective immune response against #SARSCoV2 , is that 1) there is now a bunch of spike protein in the area,

and 2) that my immune system is convinced that there is a dangerous virus on the loose (there isn't, it's just the vaccine, but it's sufficiently convincing to my immune system that it's in full defence mode).

Some DCs (really called Dendritic Cells, but "Decider Cells" is a good way to think of them) have collected some spike and carried off to the local lymph node.

Lymph nodes are important meeting and education places for the types of immune cells we need to get involved in this response: T cells and B cells. Let's start with the T cells.

I (we all) have millions of T cells and [OVERSIMPLIFICATION ALERT] each one has it's own unique detector that recognizes a unique bit of a different random protein. It just has no idea if what it recognizes is important, or part of a virus. It needs help to sort this out.

The DCs go to the part of the lymph node where the T cells are and start showing off the spike protein they found. T cells need another cell to present the "antigen" (that's what we call these immune targets) to them in order to see anything.

Out of the millions of different T cells in my lymph node, maybe 3-4 recognize this spike protein. That's not enough - we need a lot more. The DCs already know that they've found something important, so they give these cells another signal to start dividing.

We're literally making a clone army of identical T cells that all recognize the same spike protein.

So, right now, that's what's happening in my lymph node. A small number of spike-specific T cells are starting to divide so that I get a lot more of them.

It's going to take some time though.

There's one more very important cell to mention, and that's the B cell. Like T cells, we all have millions of them and [OVERSIMPLIFICATION] each has its own unique detector that binds to one specific thing.

Unlike T cells, B cells don't need a cell to show things to it - it can stick to antigen targets directly, thank you very much.

B cells hang out in a different part of the lymph node away from the T cells.

Right now, a few B cells have run across some errant spike protein that's filtered in to where they are. It sticks to their antigen-detector, but probably not very well.

These B cells aren't really sure what to do with it though, so they pick it up and take it with them. Maybe some other cell will know if it's important or not?

Check in again for Day 2 to see what happens next.

DAY 2:
Let's check in on the action in my lymph nodes:

#PG #IPromise

DCs are still showing off the #SARSCoV2 Spike protein that they found, and telling every T cell that recognizes it that it's dangerous.

Rare T cells that do recognize the spike protein are continuing to proliferate. I have a lot more of them today than I did yesterday, but not nearly enough.

I (we all) have two different kinds of T cells [OVERSIMPLIFICATION]:
One type is called "Killer T cells" [OMINOUS]
Their job is to go our and track down cells in the body that have been converted into covert zombie factories making more that one virus they know how to recognize.

If I do encounter #SARSCoV2 in the future, these hunter/killers clone warriors will be very useful to have.
I'll take more of those please.

The other type are called "Helper T cells" [THEY SOUND NICE]
Their job is to go out into the body, find other immune cells that have found bits of SARSCoV2 in the area, and help activate them and point them in the right direction.

This clone army is made up of very important coordinators of the immune defence against a future infection, so I want more of them as well.

That also brings us back to those few B cells that I introduced you to yesterday. A couple of them found some spike protein laying around and picked it up, but didn't know what to do with it. They have wondered off to see if any other cells know if it is dangerous or not.

I told you that T and B cells hang out in different parts of the lymph node. Well, the B cells head over to the border between these two neighbourhoods. At the same time, some of those activated Helper T cells also head to this border zone.

The B cells show off the spike protein they found to the activated, spike-recognizing T helper cells. They confirm that it's something dangerous and tell those B cells to start dividing.

We're now starting on yet a third clone army. The B cells are about a day behind, but they'll catch up fast.

Check in for Day 3. We're finally going to talk about antibodies. Unfortunately, the ones we meet tomorrow wont be very good.

IMPORTANT UPDATE:
because everything moves so fast...
A paper just published in @SciImmunology by @rishirajgoel takes a look at these questions.

Rmb, we've never had this many people this interested in the minutia of vaccine responses, so we suddenly have the opportunity to learn new things. Great!

They found that there is a measurable but small difference in the antibody response in people who suffered the chills and aches post vaccination.

https://twitter.com/rishirajgoel/status/1382788113685094400

However, the memory B cell response was not different, so likely those who didn't get the fever are just as protected.

Note they were looking at responses to mRNA vaccines, and not the viral vector vaccine that I got. These findings may be transferable, but maybe not.

Because everyone is asking, they also looked at age related difference in the response.
Not surprisingly, antibody responses tended to be higher in younger people, but in general responses were sufficient across the board.

https://twitter.com/rishirajgoel/status/1382788111827042304

I've been using words like "antibody responses" and "Memory B cells",...
If you don't know what those are or where they come from, stay tuned to the main thread. They're really important and we'll get to them soon.
Maybe even sooner than you might think.

This is what it looks like:
Cool 3D video generated in my lab by Dr. @KateAParham
Red are the Helper T cells, green are the B cells being told to get on it and start dividing.
Blue cells are B cells that don't recognize the specific antigen, and don't get to be involved.

DAY 3:
Brief check in with the goings-on in my lymph node:
Killer and Helper T cells that know how to identify #SARSCoV2 spike protein (if another cell shows it to them - this seems odd, but it's important to remember) are still dividing.

B cells with special spike protein-detectors are really starting to divide in response to helpful instructions they continue to receive from those Helper T cells.

We need millions of each of these kinds of cell, and we're starting from maybe less than 10, so it's not going to happen over night.

It will take several overnights, in fact. [heh]

I know I said that I'd get to antibodies today, but there's really not much to see with them just yet, so we'll wait on those.

Instead, as with lots of journeys, it's worth considering the (my) destination.

First, I obviously want my immune system to defeat the #SARSCoV2 virus if it infects me. I'm definitely making progress there, especially with those hunter-killer T cells.

Second, I'm really hoping that my immune system is going to protect me from getting infected in the first place. That would be nice. I'm definitely not there yet, and there's a long ways to go.

Finally, I really want this protection to last a while. I want my immune system to remember the Spike protein and attack it months or, better yet, years from now.

You might think that this is the final stage of the journey, but it isn't.

"Immune Memory", which is really the basis of "Immunity", is the result of lots of different processes. One of the most important is the development of specialized T and B cells that take themselves out of the game, so to speak, and wait for the next round.

Their job is to live a long time, and if #SARSCoV2 shows up, I will have ready-made, pre-trained clone armies of T and B cells ready to respond and expand at a moment's notice.

In my lymph node, even at this early stage of the response, there are already spike-attacking clones of T cells and B cells that are selected for this fate.

Generating memory cells is one of the first priorities of the immune response, not an afterthought.

Check in tomorrow for Day 4 and the first appearance of antibodies.

DAY 4:
Up until now, the priority action in my lymph node post-vax has been to increase the number of T cells and B cells that specifically recognize the #SARSCoV2 spike protein.

My clone armies are coming along nicely, and early waves are nearly ready to deploy.

You've likely heard of " #antibodies " and wondering when they are going to show up.

(primer from the awesome @ravenscimaven )

We've already said that individual B cell clones have unique antigen detectors on their surface. These are called "B cell Receptors" which, while not very creative, is a rare example of something in immunology with a name that actually helps to remember what it is.

[looking at you, MHC and your HLA loci]

By today, those individual clones have replicated themselves many times over and I now have a lot of B cells that have some ability to catch spike protein with their BCRs. I can spare a few for a first-wave attack.

A small number of these B cells have bee selected to morph into little factories committed to one thing: making bucket loads of their unique BCR that sticks to spike protein.

BUT... and this is the biggie,...

They make a version that isn't stuck to the cell and instead can float free. These free floating BCRs get dumped into the blood stream so they can circulate around the body to wherever an infection might be.

[note there's no infection - it's just the vaccine - but my immune system doesn't know that and is proceeding as if there is. That is, of course, the point]

But now, because we're immunologists , we're not going to call them "activated B cells" and "soluble BCRs" or anything obvious and descriptive like that.

We're going to call them "Plasma Cells" and "antibodies". [We do this to intimidate the other scientists]

So, that's all an #antibody is: a soluble version of the antigen specific BCR.

Today marks the first day that my immune system makes some antibodies to spike.
Good!
However, antibodies come in several different forms, and this initial version isn't very helpful against viruses.
Bad!

Even worse, most of the useful things an antibody can do require it to bind really strongly to its target, and this anti-spike antibody 1.0 does not.

This is a big problem and I'm going to have to do something drastic to fix it.

[foreshadowing for Day 5]

DAY 5:

This is a very big day in my immune response to that #SARSCoV2 #vaccine. In fact, it's almost impossible to be overly dramatic about the absolutely bonkers events that are kicking off in my lymph node as I write this.

If this was a superhero movie featuring my B cells [#Avengers for sure], this would be the part where the plucky underdog protagonist, asked to achieve the impossible, realizes that it's not up to the task and that dramatic sacrifices must be made.

I've alluded to the fact that I have some B cells that are able to bind spike protein with their BCR, but they can't bind very strongly. We need antibodies, but these don't bind well enough to do the job.

Well, today marks that scene where our proto-hero enters some dark layer to undergo a terribly-risky procedure, hoping to emerge with the necessary superpowers to defeat its nemesis.

Much like the processes that converted Captain America, Wanda Maximoff, and Deadpool from mere humans into Superheroes, most that endure them will not survive. Those B cells that do will be thousands of times stronger.

And what is this procedure? Well, it's the most cliche source of every superhero's power.

MUTATION

I'm going to make super mutants to fight #SARSCoV2 . I'm not even kidding.

Today is that day it all begins. First, the B cells set up their lair, but it's not very hidden; it's right in the middle of where the other B cells hang out. We call it a "Germinal Centre", and it's going to be the centre of the action for the next few days.

Tune in for Day 6 to see how things are going for my little mutants.

DAY 6:

I've realized that, if I'm going to be able to explain the mutation-thing properly, I have to introduce you to one more amazing thing about my B cells.

Don' worry, your B cells are similarly amazing.

What makes you, you, and not me?

[MAJOR OVERSIMPLIFICATION ALERT]

One answer is our unique individual DNA; you have yours and I have mine.

All of the different cells that make me have my genetic code. They might be kidney cells, brain cells, or whatever, but genetically they are all the same.

Except, when it comes to B cells and T cells...

THIS IS WRONG

Remember those unique antigen detectors that we talked about that are on each of my millions of T cells and B cells? The gene for that TCR or BCR is unique in each of those cells.

Those genes specifically are different and unique from all the other cells in my body.

Mind blowing huh? [NERD]

Anyway, the TCRs on the T cells are fine as they are, but I've already said that the BCRs don't bind spike protein nearly strongly enough. To make them better, I'm going to specifically mutate that one BCR gene in those specific B cells.

B cells have a way of generating random mutations targeted specifically to the part of the BCR gene that codes for bit that's sticky for spike protein.

Also mind blowing, right? [STILL NERD]

But anyone who's well-versed in hero movies and sci-fi knows that mutations are bad more often than they are good. Just mutating my BCR isn't enough; I need a way to pick the ones that are actually better at binding spike.

We'll talk about that tomorrow.

DAY 7:

It's been 1 week since I got my #SARSCoV2 vaccine, and what a week it's been! Thanks to anyone still following along.

I'm getting close to having a protective immune defence against the virus, but I still have a couple of days to go.

Let's check in with the B cells in my lymph node:
Remember, I started with ~5-10 B cells with some ability to grab onto spike protein, but the binding wasn't very strong.

Still, we made a lot of copies of those original few. I now have millions, but because they are copies of the original clones, lots of them are identical to each other.

That's not going to help much if I'm going to make better antibodies, so yesterday we talked about adding directed random mutations to the BCR gene - this gives me some diversity to work with - but how do I pick the best ones?

Right now all of this is happening in a structure in my lymph node called the Germinal Centre. It's basically a big swarming ball of dividing and mutating B cell clones. Every time a B cell clone divides, it adds a couple of mutations to its BCR gene [OVERSIMPLIFICATION].

Then, between divisions, readies itself for a big death-match against the other clones [THAT TURNED UGLY FAST].

In order to survive, the mutant has to receive a signal from one of those helper T cells we talked about earlier. They are acting as the refs.

To get that signal, the mutant clones have to compete with each other for more of that spike protein so that they can show it off to the T cell.

Those clones can bind spike protein more strongly and win the approval of the T cell get to live, divide, and mutate again.

The rest - the vast majority - die.

This #ThunderDome death match has been going on in my lymph node since Day 5, and already my B cells are getting much stronger.

In a couple of more days, the emerging victors will be thousands of times stronger than the candidates that entered. It's like going from the grip of a toddler to that of... idk, Hulk? Thor? [STRONGEST AVENGER]

My Immunology Avenger team is nearly ready to defend me.

DAY 8:

Just a quick check in on my lymph node today, is it's basically more of the same:

Killer T cells that recognize #SARSCoV2 Spike protein sticking out of zombie virus factories are much greater in number and nearly ready for deployment.

Helper T cells are in training to know how o direct immune other tissue immune cells to respond if they find spike.

A special operations division of the Helper T cells are overseeing the Germinal Center production of B cell super-soldiers. All are nearly ready for full deployment.

As mentioned on an earlier day, T cell and B cell clones are being diverted into a long term memory cohort. We'll talk more about them next week.

Before then, we're going to have to talk about one more big subject. We've alluded to it a bunch of times, and it's pretty much all anyone wants to talk about in the news. You've heard of #Antibodies ,...

But what do they actually do???

Check in tomorrow for Day 9, otherwise known as "The Day Before The Big Day".
#ImmuneEVE