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So, do YOU know what's in your COVID vaccine?

As 2020 blurs into 2021, the one thing that has brought cheer and hope at the end of this gloomy year is headlines screaming "the COVID vaccine is 95% effective!" All of us, masked and sanitized, are understandably looking forward to the year ahead, anticipating our turn in the queue of billions for a life-changing shot that will, hopefully, give us back the freedoms we took for granted in a pre-pandemic world. There's a sentence I never thought I'd type.

So, for something that most people on earth are going to get sore arms for, which is going to save countless lives and bring us back from this plague-ridden isolation, how much do you really understand about what's in the vaccine, and the magnificently complex chain of events that leads to the generation of a near-invincible shield we call 'immunity'? Given the amount of misinformation spreading around on the subject, as well as (what I consider) a near-criminal underappreciation of the immune system, I will try my best to illustrate what this little marvel of modern science is actually going to do in your body.

The Central Dogma - the process that literally makes you who you are (biology folks feel free to skip)

We are all, technically, an extraordinarily complex collection of organic molecules interacting with each other. What differentiates us is slight differences in the ‘source code’ that dictates our exact biochemical composition - our DNA, which encodes for all the proteins found in our body. The process through which this DNA is converted to proteins is called ‘the central dogma of molecular biology’. DNA in the nucleus is converted by a set of proteins (themselves encoded by the DNA) into RNA which looks similar to DNA with some differences. RNA then travels out of the nucleus where another protein called ribosome latches on to it, and starts ‘reading’ the RNA and simultaneously synthesizing protein according to the RNA ‘code’ it is reading. We have tens of thousands of different proteins in our cells, that are essential to the functioning of the cell and ultimately life itself.

What does the coronavirus do in your body, really?

At its most fundamental level, viruses are little replicating machines. A coronavirus is just some RNA surrounded by a capsule of lipids (fatty acids that form cell membranes) and proteins (that encodes for its own proteins), without all the complex components that make our cells capable of producing proteins independently.

So what it does, upon entering a human cell, is hijack our own machinery to transfer information from DNA -> RNA -> protein to make more copies of itself. Viral RNA and human RNA looks identical to a ribosome (the protein structure that reads the RNA and makes proteins), so transferring viral RNA into a human cell will trigger the same machinery to 'read that RNA' and 'make the protein it's asking for' that we use to make our own proteins 24x7. These viral proteins are processed and assembled together to form more virus particles that are then ejected and this cycle is repeated in other cells. Often, the rate of viral replication is so high that it overwhelms the host cell with viral particles leading to cell ‘bursts’ and/or death.

While the coronavirus can directly damage the cells (primarily in the lungs, where it likes to stay), a lot of the clinical symptoms we observe in patients with severe disease (like respiratory failure, multi-systems organ dysfunction) are actually related to the immune system sending its own components to deal with this intruder in an aggressive and dysfunctional manner, causing damage to healthy tissues in a 'bystander effect'.

So what does the vaccine do in your body, really?

We've all learned in school that vaccines 'prime' our immune system for future attacks by the same pathogen. A vaccine gives us a weaker or inactivated, or partial fragment of the pathogen to stimulate our immune system to produce cells and proteins that can recognize the pathogen without eliciting the pathogenic effects of a live, replicating virus in our bodies. Depending on the company you get your shot from, there could actually be vastly different components in your vaccine, although they ultimately are going to stimulate the same chain of events that give you the superpower of 'immunity'.

The Pfizer/BioNTech and Moderna/NIH vaccines, which have been in the news recently for their Phase-3 data, are mRNA vaccines. If you look closely, the name Moderna is actually ModeRNA - this was a company founded on the promise of using mRNA in therapeutics. The cool thing about them is that these will be the first mRNA vaccines approved for use in humans. The design of an mRNA vaccine is very much like the design of the coronavirus itself: it is some RNA surrounded by a lipid capsule!

1. The lipid nanoparticle delivers the RNA to your cell's cytoplasm

The lipid nanoparticle carries, however, not the entire viral genome (that would start producing the whole virus), but only fragments of it that encode for specific viral proteins (the S-protein or spike protein found on the outer shell of the virus). The mRNA now needs to make its way into cell cytoplasm, so that ribosomal machinery that does the job of reading mRNA and making proteins from it can latch onto it and start producing the viral proteins. This is actually not a trivial problem, as naked mRNA is not very stable outside the cells (it is degraded rapidly) and it won't enter the cells on its own due to negative-charge repulsion between RNA and cell membrane. It has taken a lot of progress in nanotechnology to be able to efficiently deliver these genomic strands inside cells. The Moderna formulation is proprietary and consists of a mixture of 4 different lipids which stabilize the RNA in an envelope and help it 'fuse' with our own cell membranes to release the mRNA into the cytoplasm.

2. Ribosome start producing viral proteins which are then 'presented' to the immune system

Once the mRNA is delivered to the cytosol, the ribosomes bump into it, latch on, and start the production of viral protein chains. These viral proteins have 2 possible outcomes:

  1. They are either released as it is by the cells extracellularly where they may be taken up by other cells

  2. They enter pathways that our cells have evolved to 'display' proteins inside the cell in small fragments outside the cell. The viral proteins are chopped up by proteasomes and these fragments are loaded onto MHC molecules, which then travel all the way to the cell membrane and 'show' these bits outside the cell.

Some specialized cells, like macrophages or dendritic cells, can also sample the free-floating extracellular proteins (as released in step 1 above), chop them up and present them in MHC molecules outside the cell surface. These cells which can do both types of ‘presentations’ are called antigen-presenting cells.

MHC molecules are like billboards advertising the contents in and around the cell - 'Look at a sampling of the proteins inside and around me! Does anything look strange to you?'

Dendritic cells are special because they function as travelling salesmen and move around the body carrying both types of protein samples to inform the immune-cells that there's company. Dendritic cells live inside tissue, but immune cells do not, and only arrive when they are alerted and called to the site of infection. So this ability of dendritic cells to travel to where the immune cells reside (in the lymphatic system) and 'show them' foreign antigens is critical in this entire process.

3. B-cells and T-cells, key players of the immune system, are activated

These dendritic cells travel to the lymph nodes, where clusters of B-cells (antibody producers) and T-cells (killer cells) are waiting for them.

T-cells have very specific receptors on their surfaces (helpfully called T-cell receptors) which can bind very specific protein fragments that are presented on the antigen-presenting cells. Each T-cell clone can only bind ONE specific protein fragment, like a jigsaw piece. So if the dendritic cell carrying a viral antigen meets the right T-cell clone with a receptor exactly matching the viral antigen it is carrying, the T-cell gets 'activated' and starts dividing rapidly. It is needed!

Cellular and Molecular Immunology - Abbas, Lichtman, Pillai

The most extraordinary thing here is that T-cells obviously do not know in advance which protein fragments are pathogenic and which aren't. So in the T-cell formation process, there is a completely random combinatorial process that generates surface receptors to identify virtually ANY protein in the universe! There is then selected to ensure that if you generate receptors against your own native proteins (let's say hemoglobin, because that would suck), that T-cell is killed off by specialized systems to make sure your immune system does not attack your own body. So there is some 'education' of the T-cells by elimination, but billions of naive T-cells specific to millions of unknown antigens (!!) patiently lie, waiting, for the dendritic cell to carry their 'matching antigen' to come along and say "Yes! You, with this specific receptor! It's your time to shine!"

A similar process occurs for the activation of B-cells, though it is more complex and requires the help of certain T-cells, appropriately called 'helper T-cells'. Just like a T-cell, each B-cell has receptors for ONE specific molecular fragment, and billions of B-cells specific to millions of unknown antigens (!!) lie waiting for activation signals. They also follow a random combinatorial process (called VDJ recombination) to generate receptors to millions of molecules they have never encountered before!

The fundamental difference between B and T-cells is that activated B-cells produce antibodies, while activated T-cells hunt down the viral antigens (on cells that display them via MHC molecules) and kill the infected cell.

The most amazing thing here is that the hard work has already been done by your body. You already have T-cells and B-cells specific to the coronavirus. In fact, you already have T-cells and B-cells for EVERY virus out there, most of which you will never see. The vaccine is simply acting as a ‘trigger’ to activate these cells.

4. B-cells and T-cells get to work

Once the activation of B-cells and T-cells has occurred under the 'coaching' of dendritic cells telling them which viral antigen is posing danger, they launch a multi-pronged attack to neutralize the foreign agent.

B-cells make antibodies: Since we have already 'selected' the specific kind of antibody we need by activating only that 'specific' type of B-cell, this B-cell clone will proliferate rapidly and transform into an antibody-production factory, pumping out as many as 2,000 antibody molecules per second! These antibodies will bind to the viral particle (S-protein in this case) and block its entry into the cells. They also attract the attention of other immune cells (like macrophages) to engulf and kill the virus.

Cellular and Molecular Immunology - Abbas, Lichtman, Pillai

Killer T-cells kill infected cells: Activated T-cells (a specific subtype called 'killer T-cells') that have been 'selected' as we discussed above move out of the lymph nodes after rapidly multiplying and throng the site of infection. How?

There is often cellular damage at the site of viral/bacterial infection (or vaccination) due to activation of local inflammatory pathways (pain, redness, swelling are all signs of that). Macrophages and dendritic cells that start sampling strange foreign antigens also release certain chemicals called 'cytokines' and 'chemokines' which attract circulating immune cells to the site. They're like the red flashing lights and traffic cones you see at the site of car accidents, informing concerned parties where the problem is!

Killer T-cells follow these trails of chemicals and reach the sites where local cells are displaying the chopped up fragments of the foreign antigen on their surface (“Look at a sampling of the proteins inside me! Does anything look strange to you?”). Since it's receptor is specific to that antigen fragment, it binds the cell displaying the foreign antigen on its surface and releases chemicals that cause cell death! So the infected cell dies along with the virus load that it has been carrying thereby preventing further multiplication and spread of the virus.

Cellular and Molecular Immunology - Abbas, Lichtman, Pillai

Immunological Memory

A key and extremely important feature of the immune system (and why vaccines work so well) is the existence of immunological memory.

Cellular and Molecular Immunology - Abbas, Lichtman, Pillai

Both B-cells and T-cells do not remain activated forever. After all, once your infection has been brought under control, you do not need to be pumped with antibodies for a specific virus that is no longer in your system, or killer T-cells patrolling by the thousands looking for something that is no longer there. In fact, most of these activated immune cells will die within a few weeks after doing their jobs.

However, some B-cells and T-cells will make the 'career choice' to become what we call memory T-cells or memory B-cells. Memory immune cells are special because they are like trained and battle-hardened soldiers. Having 'seen' the foreign antigen before, they are much more efficient at mounting an immune response compared to naïve B-cells and T-cells.

=> Memory B-cells produce antibodies much faster, in higher quantities, and with much higher binding affinities compared to those produced by B-cells in the primary immune response.

=> Memory T-cells react much more rapidly and vigorously to repeat antigen exposure compared to naïve T-cells.

Cellular and Molecular Immunology - Abbas, Lichtman, Pillai

This enhanced immune response is called a secondary immune response and is why vaccines protect us from severe disease. This is also why vaccines often have a booster dose (both the Pfizer and Moderna vaccines require 2 doses) to ensure robustness of response. Memory T-cells and B-cells can survive in our bodies for decades, giving us long-lasting memory of past infections.

Not all COVID vaccines contain mRNA

The mRNA is simply one of many ways we can deliver viral antigens to our cells. A summary of vaccine candidates illustrates the many methods we have developed to do it: 1) Using DNA instead of mRNA 2) Encapsulating the DNA/RNA in non-pathogenic viruses (such as AAV) that help entry into the cells 3) Inactivated COVID virus that do not cause severe disease. All of them, however, will follow the same chain of events above via antigen presentation, T/B-cell activation, and generation of memory.

Then why are we just hearing about the mRNA vaccine? mRNA is manufactured by a chemical process (rather than biological synthesis of viruses under highly specialized and controlled environments), so the process to design, scale-up, and mass-produce these vaccines is much faster and more efficient. This is why Moderna and Pfizer were able to formulate candidates as soon as the COVID genome was sequenced, and get a headstart in clinical trials compared to conventional vaccine candidates.

The issue with mRNA however, is that it is very sensitive to degradation by super-villain enzymes called RNAses. All cells and organisms have them, so they are literally everywhere, on every surface, floating in the air (and particularly painful for scientists in labs working with RNA >.<). This is why both the Pfizer and Moderna vaccines have cold storage (-20 C or -80 C) requirements because low temperatures reduce this rate of degradation.

What now?

The distribution of the vaccine has begun, but it is going to be a long, messy road filled with medical, socioeconomic, and political challenges. If you’re in the US, estimate your place in line with this handy article, which covers the considerations in place when deciding distribution policies. Until then, wear a mask, wash your hands, and stay 6 feet away from your fellow protein-filled sentient meat bags.

Spring is coming.

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