This article about COVID-19 vaccine essentials was written by Dr. Frederik Lermyte, Ph.D. (Twitter) Dr. Lermyte is an assistant professor in the chemistry department at the Technical University of Darmstadt (Germany). He is interested in all things science, although he focuses on understanding the structure and chemistry of proteins, especially those relevant for human health and disease.

Disclaimer: While I’ve tried to make this discussion about COVID-19 vaccine essentials as accurate as possible for something meant for a general audience, one or two mistakes might have crept in. I’m obviously also simplifying some things here for brevity. Also, all of this is only my opinion, and obviously not medical advice.

Someone reached out to me a while ago through Twitter as they had an appointment to get the Pfizer COVID-19 vaccine and were feeling anxious. I explained some vaccine essentials to them as a series of direct messages.

I’m adapting and sharing this article on COVID-19 vaccine essentials now (with permission from the person who originally reached out to me) in case it’s still useful to anyone. I actually thought it was all fairly well known by now, but I’ve been hearing more nonsense about these vaccines again lately, so perhaps this is still useful after all.

COVID-19 vaccine essentials – immune system

On a very basic level, your immune system is great at killing things that shouldn’t be in your body, once it’s learned to recognise them. This takes time, which is why it takes weeks to get over the flu. Your body needs this time to produce a targeted weapon against the virus.

The weapon of choice? Antibodies (although there’s more to the immune system than that, so don’t panic if you hear reports that a new coronavirus variant isn’t efficiently neutralised by antibodies). For a cold, spending one or two weeks feeling poorly is usually OK, but COVID-19 can do irreparable damage.

I’d initially included flu as a “no big deal” illness along with a cold, but Professor Dorit Rubinstein Reiss rightly pointed out that influenza can have serious complications. That said, COVID-19 is significantly more dangerous, statistically speaking.

In any case, the trick is to develop antibodies in advance. Once your body’s made those, it remembers the recipe and can re-create them much faster. Think of a chef creating a new dish – lots of trial and error, but once they get it right, they can bang out dozens of orders in an evening.

So what you want is a way to “train” your immune system – to let it develop its recipe – without posing a serious danger to your health. No points for guessing that that’s pretty much exactly what a vaccine is for.

Vaccine basics

Some of the traditional vaccines are made by taking a virus or bacterium, killing or deactivating it, and introducing it into your body. That way, it doesn’t infect you, but your immune system gets the required target practice.

This is an art form though. The bug needs to be “dead” enough not to make you sick, but “threatening” enough for the immune system to mount a response. Most anti-vax claims are about the latter part (making the vaccine appear threatening).

This is what so-called adjuvants – for example, aluminium-based ones – are for. It’s also this triggering of an immune response that can cause side effects like fever, headache, muscle soreness, etc. It has nothing to do with actual infection (this is impossible, as we’ll get into) – it’s just that your body briefly has a similar reaction as to infection.

Another classic type of vaccine involves a weakened (or “attenuated”) version of the virus you need protection against – threatening enough to trigger a response, but not good enough at replicating inside a human host to cause illness.

Now, the key target for coronaviruses is a protein called “spike“. It’s important because it’s the part that binds to human cells and allows infection. So obviously, you want antibodies to attack that protein – if the virus can’t get into your cells, it can’t hurt you.

This is why you hear about “neutralising” antibodies – they bind to the spike and disable it. Antibodies that bind somewhere else and are non-neutralising will be less effective at protecting you, although they can still act as a “please destroy this thing” tag that alerts other parts of your immune system. In rare cases (most notably dengue) this can actually worsen the disease.

This is known as antibody-dependent enhancement (ADE) where non-neutralising antibody binding can make a virus more mobile within the body. As said, this is very rare, and having non-neutralising antibodies against a virus is not the only condition that needs to be met to trigger ADE. If it were, the hospitals would always be full of people who were reinfected with a new strain of influenza or one of the seasonal coronaviruses.

The fact that SARS-CoV-2 reinfections tend to result in mild or asymptomatic cases further shows that ADE is not a major issue with this virus. Similarly, the vaccines aren’t 100% effective (true for any vaccine, against any disease) but the people who got infected post-vaccination tended to have much milder illness thanks to their antibodies – they certainly didn’t have “enhanced” disease!

Large-scale real-world data on SARS-CoV-2 has therefore put the ADE idea to bed. Anyone claiming it’s a (vaccine-related) concern at this point is ignoring tons of recent real-world evidence in favour of hypothetical concerns and a few old studies on mice involving a vaccine candidate against the 2003 SARS virus.

Also, in dengue (where ADE does occur) it was discovered in reinfections. After all, the vaccine won’t cause your body to produce any antibodies that it wouldn’t produce during infection. A similar argument applies to claims about infertility or problems with endothelial cells.

DNA, RNA, and proteins

Now a small detour about proteins, DNA, and RNA – including mRNA. Just about everything in your body involves molecules called proteins. Antibodies are proteins. Enzymes are proteins. Proteins are responsible for making your muscles contract. Etc. etc. etc.

Proteins are basically long chains of molecules called amino acids. Think of them as beads on a string. Humans have 20 amino acids (20 colours of beads). You can make an infinite variety of proteins by changing the string length, and the colour/order of the beads (amino acids).

These proteins get made in parts of your cells called ribosomes. The ribosomes of course need to know the type and order of amino acids to string together, and this is actually what DNA is for, fundamentally. The “genetic code” is nothing but a set of instructions for making proteins! And in fact, each gene consists of the instructions for making a particular protein. The ribosomes (protein factories) are in a part of the cell called the cytoplasm, which is basically everything that’s not the nucleus of the cell.

And the DNA (which has the instructions that the ribosome needs) is in the nucleus. So how do the instructions get to the ribosome? Well, the DNA doesn’t leave the nucleus, and the ribosomes don’t enter it, since it’s a separate, well-protected compartment of the cell. Therefore, there has to be some intermediary. A “messenger” if you will. And this is how we get messenger RNA, also known as mRNA!

RNA is similar to DNA, but less stable, due to some chemistry I won’t get into. Just know that RNA breaks down in minutes under normal circumstances, while we’ve extracted DNA from millennia-old samples. Which is why it’s a good thing our “blueprint” is stored in DNA.

By the way, I’m going to be playing fast-and-loose with RNA vs. mRNA. The reason for the “m” is that RNA has a few other functions in our body – in fact, ribosomes consist largely of ribosomal RNA or rRNA. I’m glossing over some nuance, but just assume I’m always talking about mRNA. The important thing to keep in mind is that your cells use RNA as a temporary copy. Inside the nucleus, a gene (DNA blueprint) gets copied to RNA, which gets sent to the ribosome, which then makes the protein based on instructions in the mRNA. After this, the highly unstable mRNA breaks down quickly.

Viruses

When it comes to COVID-19 vaccine essentials, we need to talk about the virus that causes COVID-19, SARS-CoV-2.

The thing about viruses is they’re not really alive. That’s because they lack most of the machinery I just described above. SARS-CoV-2 is really just some fat (the “lipid envelope” to use the technical term) and protein (including spike protein) surrounding a bit of RNA. Once the spike protein docks with a human cell (specifically a receptor protein on the cell surface called ACE2) it injects its RNA.

That RNA then finds a ribosome and – since the ribosome does nothing but translate RNA to protein – it starts cranking out virus protein. This has lots of effects: The coronavirus RNA has around 25 genes, so that is the number of proteins that are produced.

Broadly, this results in:

1. virus RNA being copied,
2. more fat/protein shells being built, and
3. assembling protein, fat, and RNA to make more coronavirus copies.

Obviously, having your cells’ machinery hijacked is bad, which is why you get sick. Now, like I said, the coronavirus RNA has about 25 genes. What do you imagine would happen if your cells get injected with just one? Specifically, let’s say the gene for spike protein?

Well, your ribosomes would make that protein, because translating RNA to protein is all they know how to do. Your immune system would recognise it as being foreign though. And your body would mount an immune response. The beauty is, there’s never any intact virus involved in the whole procedure.

Except for the gene for the spike protein, none of the genes the virus needs to reproduce are ever introduced into your body! This is why this type of vaccine is very safe and also exquisitely targeted.

COVID-19 vaccine essentials – all you need to know

Now, I’m going to move into the critical essentials about the COVID-19-19 vaccine.

We come to the fundamental difference between the Pfizer, Moderna, AstraZeneca, and Johnson and Johnson (JNJ) jabs. And it’s actually quite simple. See, all of those use the gene that encodes the spike gene, and relies on getting spike-encoding RNA into your ribosomes, in order to produce the protein and train your immune system.

The Pfizer and Moderna vaccines (“mRNA vaccines”) are just the mRNA in a fat droplet (“lipid nanoparticle”). The AstraZeneca and JNJ vaccines are more-or-less “hollowed out” common cold viruses known as an adenovirus, and genetic info for the spike protein are engineered into the virus.

Here is a list of the Pfizer vaccine ingredients (other than the mRNA itself), according to information provided by the manufacturer to the MHRA and FDA:

• ALC-0315 = (4-hydroxybutyl) azanediyl)bis (hexane-6,1-diyl)bis(2-hexyldecanoate)
• ALC-0159 = 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
• 1,2-Distearoyl-sn-glycero-3-phosphocholine
• cholesterol
• potassium chloride
• potassium dihydrogen phosphate
• sodium chloride
• disodium hydrogen phosphate dihydrate
• sucrose
• water for injections

The Moderna mRNA vaccine has similar ingredients. Cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine are very well known and aren’t at all worrying. ALC-0315 is more novel and helps stabilise the mRNA. ALC-0159 is a surfactant. It has an end that likes to hang out with water molecules and another end that prefers oily molecules.

This makes it perfect for stabilising oily lipid molecules (like the ones surrounding the mRNA) in water. It’s basically the same way soap lets you rinse off grease. ALC-0159 is also the molecule that has a poly(ethylene glycol) (or PEG) group, which is suspected to cause allergic reactions in very rare cases.

PEG is an extremely common molecule in daily life though – I see it as a contaminant when analysing samples in my lab all the time. I should note that this includes when I’m looking at samples that have been artificially produced and purified in a laboratory environment – PEG is just everywhere, and if it were seriously toxic or allergenic to a significant part of the population, we’d know about it!

The components with ‘phosphate’ in the name help stabilise the pH (mRNA doesn’t survive in acidic or alkaline conditions, and you wouldn’t want to inject an acid or base into people anyway). Sodium chloride and potassium chloride are kitchen salt and fancy sodium-free salt, respectively. The mix of those last four components is known as phosphate-buffered saline (PBS) and used in biology everywhere. Sucrose is ordinary sugar, and helps protect the nanoparticles during freezing and thawing. Finally, water is… well I hope I don’t need to explain that!

So that’s the mRNA vaccine. Fancy delivery platform, probably some future Nobel prizes, but none of the components are particularly worrying to a (bio)chemist. Also, they all get eliminated from your body in days/weeks.

The mRNA persistence question was actually addressed by Moderna’s Chief Scientific Officer (CSO during the meeting where the scientific decision about  Emergency Use Authorization (EUA) in the US was made. There’s a transcript of the entire meeting, and on page 234, the CSO clarifies that the mRNA is gone after 24 hours, and the protein after 72.

For all three FDA-approved vaccines, the meetings of the relevant  Vaccines and Related Biological Products Advisory Committee (VRBPAC) were live-streamed in their entirety and are archived on YouTube. Fair warning though, it’s about eight hours per meeting.

In the hollowed-out adenovirus vaccines, it “infects” your cells, acting as a tiny syringe, but instead of introducing all the genes to make more adenovirus, it introduces the gene for a coronavirus spike. After that, the process is similar to the mRNA vaccines.

In both cases, the vaccine itself (viral RNA or adenovirus) sets off enough alarm bells in your body that no adjuvant is needed, which also helps out with safety (even though modern adjuvants are already very safe). For adenovirus vaccines, the concern is that your body might already have antibodies against the adenovirus “shell” which might neutralise it before it can inject its payload, so the trick is to use an unusual one that your immune system won’t recognise.

This is why the Oxford vaccine uses the shell of a chimpanzee adenovirus. Any talk of “chimpanzee DNA” or “monkey cells” is nonsense.

Now when I originally wrote this as an explainer to someone who was feeling anxious, those were the only vaccines making headlines in Western media. The newcomer since then is of course Novavax, who recently announced excellent Phase 3 results! Theirs is more similar to “classic” vaccines in that they inject virus protein with an adjuvant, rather than have your own ribosomes produce anything.

However, it’s important to note that the spike protein is produced artificially (similar to how insulin is made) so again, no intact, disease-causing virus is ever involved. The adjuvant is a non-traditional one, made of extract from the Q. saponins tree, formulated with cholesterol and phospholipids. Nothing in that recipe worries me as a biochemist, but I’d love to know how they came up with this. It seems very effective though!

COVID-19 vaccine essentials – the spike

For the sake of completeness, it’s worth devoting a few sentences to the structure of the spike protein. When it’s sticking out of the coronavirus in those electron microscopy images we’ve all seen by now, what’s visible is actually an assembly of three copies of the spike.

It only has this characteristic shape when it’s part of the virus – if you take it out and put it in water (for example, when it’s expressed by your ribosomes after vaccination and there’s no coronavirus shell around) the structure actually collapses. This can be taken quite literally – there’s some similarity to a failed soufflé.

It still works but offers a slightly less realistic target to train your immune system. This property of coronaviruses was known long before the pandemic, and in 2017 it was discovered that the spike protein of the related MERS coronavirus could be stabilised in its non-collapsed form by replacing two amino acids.

This trick turns out to work for the SARS-CoV-2 coronavirus that’s currently bothering us, and so most of the vaccines (including Pfizer and Moderna) use this slightly modified version. Some also remove a few of the amino acids for similar reasons. As said though, the unmodified version also works and is used in the Oxford/AstraZeneca vaccine.

Anti-vaccine claims

I want to make a point about “person X had a vax and then Y happened” anecdotes. “Y” being, “got COVID-19”, “died in the next month”, etc.

One of the essentials is to remember there are over 150 million “persons X” who received the COVID-19 vaccine by now, and coincidences happen. Case in point, a Moderna Phase 3 trial subject was struck by lightning.

Also, Bob Wachter made the point a few months ago that out of any group of 10,000,000 people, we can expect that 4000 will have a heart attack, 9,500 will have a stroke, and 14,000 will die over the next two months. This is just what you expect based on population averages (data for the US, but probably not too different for other Western nations) – doesn’t matter if those 10,000,000 people are “selected” based on vaccination status, hair colour, or favourite ice cream flavour.

So it’s extremely likely that all the so-called vaccine side effects are statistical blips, and as meaningful as saying “person X said that “scone” rhymes with “gone” and they got hit by a bus!”

Second-to-last point, you might hear about “modified nucleosides” when talking about mRNA vaccines. Nucleosides are the building blocks of DNA and RNA, just like amino acids are the building blocks of proteins. There’s a class of HIV inhibitors with nasty side effects that are based on modified nucleosides, but these use a completely different principle than modified RNA and are chemically totally different.

Not even apples and oranges to compare the two – more like oranges and goldfish. Sometimes mRNA needs to hang around for a while, to make more copies of a protein.

Also, I mentioned earlier that there are other types of RNA in the body, and some of that stuff also needs to be stable for a longer time. Your body actually regulates RNA longevity by chemically modifying it to make it more stable. Vaccines use this natural RNA stabilisation trick to make more spike protein to train your immune system. As already pointed out, it’s still a matter of hours or days before the modified mRNA gets cleared though.

And – since all of this happens in the cytoplasm – there’s basically zero chance of the RNA doing anything to your DNA (so it won’t turn you into a GMO, despite what some claim).

Two resources for COVID-19 vaccine essentials I want to point out before closing:

• An in-depth look at the ingredients of both mRNA vaccines, along with their development and supply chain,
• an analysis of the specific RNA sequence used by BioNTech/Pfizer that goes into far more detail than I have.

Final point

The best vaccine is the one that goes in your arm. All have been proven to be safe, and very effective at preventing COVID-19 illness, hospitalisation, and death. Data also very strongly indicate that they stop/reduce transmission.

If you have the chance to get a vaccine in the near future, 90% of the world envies you. This pandemic will end sooner or later regardless of what we do, but we’ll get through it a lot faster with high vaccine uptake, and a lot of lives will be saved in the process.

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