What’s in the COVID-19 vaccines?

COVID-19 vaccines are very likely the most discussed topic at the moment. Because I have played with very similar stuff in my lab days, I thought I’d share some insight in the technology and, particularly, the single ingredients used in the vaccine formulation. I got the Moderna shot, so let’s discuss Spikevax. As you probably have heard, this is based on the delivery of messenger RNA (mRNA), a ribonucleic acid that all living beings possess in one form or another. However, the mRNA molecule cannot be injected into our bodies “as is”: our cells possess enzymes tailored to recognize and destroy any exogenous (external) RNA and DNA material. For this reason, it needs to be encapsulated (contained) in a carrier or vector. In this case, the vector is a nano-sized (approximately 0,1 microns) sphere made of lipid (fat) molecules, which is referred to generically as a nanoparticle or, more specifically, a liposome or vesicle. These vesicles, depicted in the illustration on the left, are dispersed in and aqueous medium so that they can be injected. Please notice that this is not a particularly new technology: the encapsulation of RNA and DNA molecules in lipid vesicles has been studied since the 1990s.

Here is what is used to make these vesicles, i.e., the ingredients of Spikevax as listed in the official leaflet.

Single-stranded, 5’-capped messenger RNA (mRNA). This is the active substance, i.e., the one that encodes the viral spike protein of SARS-CoV-2. This doesn’t mean that you’re getting the virus or any infectious components. The mRNA will instruct your cells to produce the spike protein only. Once this is in your bloodstream, your body will recognize it and produce appropriate antibodies (defenses). Therefore, should you be infected with the real virus, you’ll already have what you need to fight it.

The infographic on the left is a reminder of the differences between RNA and DNA.

How does mRNA work exactly? As we are taught in middle- or high-school biology, the DNA in our cell nuclei undergoes transcription to make a copy of its stored information in the form of mRNA. The mRNA molecule leaves the nucleus and performs its role in the ribosomes, organelles that can translate the code contained in the mRNA into proteins. Check out this video for more details.

Lipid SM-102 (heptadecan-9-yl 8-{(2-hydroxyethyl)[6-oxo-6-
(undecyloxy)hexyl]amino}octanoate).
Lipid SM-102 is a proprietary compound, meaning that it was developed and patented by Moderna. This is a so-called “ionizable lipid:” the molecule within the vesicle has a positive charge (a protonated amine group, i.e., ammonium) so that it can hold the mRNA, which is negatively charged. As we know, positive and negative charges are attracted to each other, so these two molecules will stick to each other. When the vesicle dissolves within our cells, Lipid SM-102 loses its positive charge, because it reverts to a neutral (uncharged) form at a physiological pH. In doing so, it releases the mRNA, which is then free to complete its intended task.

This molecule has caused turmoil all over the web due to the misinterpretation of a safety sheet. You will probably still find articles telling you that Lipid SM-102 is extremely toxic and should not be used with animals. This is not true, and here is why. If you head over to the safety sheet provided by a seller, you won’t be able to miss the scary pictograms and warnings: Acute Tox. 3 H331 (Toxic if inhaled); H351 (Suspected of causing cancer); H361 (Suspected of damaging fertility or the unborn child); H372 (Causes damage to the central nervous system, the kidneys, the liver and the respiratory system through prolonged or repeated exposure)… However, please don’t make the mistake of stopping at the first page and do go to page 2, where we can read: “Hazard-determining components of labeling: Chloroform.” Yes. This safety sheet is specific for a solution of Lipid SM-102 in chloroform, not the pure compound. The seller is required to provide the safety information of the preparation as a whole, and all the scary pictograms and warnings are related to chloroform only: Lipid SM-102 is not responsible for any of the listed hazards. Of course, should this specific preparation be used to obtain any medicine, chloroform is completely removed before use. Luckily, chloroform evaporates very quickly and easily even at room temperature.

1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). This is another lipid molecule, and it belongs to the family of phospholipids. You probably know this word from school biology classes: phospholipids are the major components of our cell membranes (see picture above). They place themselves in double layers where the “tails”, which don’t like to be in contact with water (hydrophobic parts), touch each other; in contrast, the “heads” (hydrophilic parts) face either the inside or the outside of the cells. This phospholipid does exactly the same thing in our vaccine: its molecules are the building blocks of the vesicles. These vesicles actually mimic our cell membranes: this is done to facilitate their entering in our cells, where they will carry out their function.

1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000). This molecule is a special type of lipid. It is based on a glycerol moiety to which two fatty acid chains have been attached (esterified). In this aspect, it is similar to the phospholipid DSPC described above. However, the glycerol part also carries a small polymer called PEG (abbreviation of polyethylene glycol, which you may also find as polyethylene oxide). PEG is present in a lot of our daily life products including shower gels. In this case, its scope is to make our vaccine carrier “invisible” to the body’s immune system. Indeed, we know that a lot of what we introduce in our bloodstream is easily recognized and destroyed by some white blood cells. They are just doing their job, of course; however, in this case, we need to trick them so that the RNA-carrying vesicles can enter our cells. The PEG polymer is quite hydrophilic, so it stays at the surface of the vesicles, immersed in the aqueous solution; here, it attracts many water molecules (it is swollen with water) and forms a sort of “cloud” that “hides” the rest of the vesicle, increasing its residence time in the bloodstream.

Cholesterol. It is probably not necessary to explain what cholesterol is, so I’ll be brief. This is also a lipid molecule, and it is present in our bodies, where it acts as a precursor of some vital hormones (including sexual hormones) and a component of the cell membranes. Cholesterol has the same role here as it does in our cells: it places itself among the phospholipid chains and “stiffens” the membranes to avoid excessive fluidity. “Could this increase my blood cholesterol levels and become a risk factor?” No: if you’re a healthy person, your body is capable of balancing the amount of cholesterol it produces by itself against that introduced with your diet or, like in this case, with medicine. If you have high blood cholesterol and this worries you, please refer to your doctor.

Trometamol and trometamol hydrochloride. Better known as TRIS buffer, this substance regulates the pH (acidity level) of the formulation. A very similar role is played by acetic acid, the substance that gives vinegar its typical flavor, and its salt, sodium acetate trihydrate. Finally, sucrose, our very own table sugar, is used as a stabilizer to avoid the destruction of the lipid vesicles during storage at very low temperatures. The last ingredient is water for injections.

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