Later, research showed that these tiny projections are actually the so-called spike protein, which all coronaviruses use to infect susceptible cells in mammals, including us. However, different coronaviruses have different spike proteins, which means that some of them can infect humans, while others can’t. Of the coronaviruses that infect humans, some have spike proteins that can gain entry only into the cells of the upper respiratory tract, while others (like SARS‑CoV‑2) have spike proteins that enable infection of the cells of both the upper and lower respiratory tract. SARS‑CoV-2 has also been shown to be capable of infecting other cell types, including the heart and brain.

Since the discovery of SARS-CoV-2 as the cause of COVID-19, a truly astonishing amount of research work has gone not only into understanding just the virus, but also in how our immune systems interact with it. This amazing worldwide effort has helped enable the rapid development of vaccines. A key learning from much of this work is that the spike protein is one of the major proteins that our immune systems recognise to begin to fight off the virus. This is why the leading vaccines are designed to use the spike protein to generate a protective immune response against future infections. We’re also fortunate that the technology underpinning these vaccines has been in development for more than 20 years, so there was already a strong biotechnological base to create these vaccines at the rapid pace that we’ve seen over the course of the last year.

As mentioned, the New Zealand Government has made advance purchase agreements with four vaccine manufacturers: Pfizer, AstraZeneca, Johnson & Johnson, and Novavax. Three of these vaccines involve artificial genes that encode the SARS-CoV-2 spike protein. Although the EPA doesn’t actually regulate any of these three, we have had a role in ensuring they can get into the country unimpeded. In this Science Corner, I’ll explain what I mean, beginning with the one that’s already here and being used – the Pfizer/BioNTech vaccine. I’ll cover the AstraZeneca and Johnson & Johnson vaccines in a second instalment.

The Pfizer/BioNTech vaccine BNT162b2 (COMIRNATY™)

The BNT162b2 vaccine is made up of engineered messenger RNA (mRNA) molecules encapsulated in a lipid nanoparticle capsule, as represented in Fig. 2. That’s quick enough to say, but to understand what it really means, we need to look at the parts in a bit more detail.

The capsule – the vehicle to vaccination

The lipid capsule that makes up the outer part of the vaccine BNT162b2 lipid nanoparticle is the vehicle that delivers the vaccine to our cells. Lipids are fat-like molecules, including fat itself! The contents of each of our cells are also held within a lipid membrane coat. But there are many different types of lipids, and those that make up our cell membranes can spontaneously arrange themselves so that they form a compartment that keeps most molecules on one side or the other. Although the vaccine uses some lipids that aren’t like those found in our own cells, they still have the ability to self-assemble like our cell membrane lipids. As with our cells, these lipid compartments keep what’s inside (that is, the vaccine messenger RNA) in, and what’s outside, out. The vaccine particles are very small indeed, only about 100 nanometres across, and so the name lipid nanoparticle.

The lipid encapsulation of the vaccine mRNA serves two important roles once it’s injected into someone. First, it helps to protect the mRNA molecules from being degraded in our bodies before they can do their jobs. It also aids in the vaccine fusing with our cell membranes, allowing the vaccine mRNA to enter a few of our cells near the injection site.

The messenger RNA – what’s under the bonnet?

So – our lipid vehicle has delivered the vaccine mRNA molecules into cells near the site of injection. Now what? First off, mRNA molecules are found naturally in our own cells. They’re RNA copies of the DNA “blueprints” in our cells, and huge numbers of mRNAs are made every day in most of our cells. Complex multiprotein/RNA machines called ribosomes can decipher the genetic code in the mRNA sequence, and use that information to make one of any of the tens of thousands of different proteins it takes to make and maintain a living person. The mRNA in the BNT162b2 vaccine contains the genetic code to make one (and only one) protein – the SARS-CoV-2 spike protein.  

So where do they get all this RNA for the vaccine? Biotechnological tools have been developed to the point that we don’t need cells to make specific mRNA molecules. Fundamentally, all that’s needed is lots of copies of the DNA blueprint for the spike protein, the building blocks of RNA (called nucleotides), and an enzyme called RNA polymerase. This enzyme assembles the building blocks in the right order, copying the nucleotide sequence of the DNA. Pfizer has scaled up this process to allow the production of enough RNA for millions of doses of the vaccine in one go.

Amazing as all this is, the BNT162b2 mRNA has a couple of extra features designed to make it more effective as a vaccine. The thing about normal mRNAs in our cells is that a lot of them get made every day, but most of them are quickly broken down once they’ve done their jobs (some in only a matter of minutes!) and their building blocks are recycled in the cell. Also, since the spike protein mRNA is not an RNA encoded by one of our own genes, it is recognised and targeted by our immune systems to be broken down. Although we want a strong immune response to the vaccine, we want it to be against the spike protein, and not against its mRNA!

To solve this problem, the BNT162b2 mRNA has a modified nucleotide building block that doesn’t affect its ability to function as an mRNA, but instead makes it less of a target for our immune systems. It also turns out that this modification makes the mRNA easier to be deciphered into proteins by ribosomes, so they can make more of the spike protein faster. This means that the spike protein mRNA remains in our cells longer before it’s broken down, and at the same time allows more spike protein to be made at a faster rate.

So we’re almost there – only one more step from all that spike protein to a protective immune response – getting the protein out of the cell to where our immune systems can recognise it. This is where another feature of the vaccine mRNA comes in. At the beginning of the RNA code for the spike protein, there’s a special sequence that encodes something called a signal peptide. This sequence tells the cell that the protein the signal is attached to should be shuttled out of the cell. Once it’s out there, our immune cells recognise the secreted spike protein as foreign, and the immune response begins.

In this immune response is the beauty of vaccines – our immune systems are capable of “remembering” when they’ve been exposed to foreign proteins, like the SARS-CoV-2 spike protein. The next time our immune system sees the spike protein (if we’re exposed to the actual virus), our immune systems are ready for it and raise a quick response that neutralises the virus before it can take hold and make more copies of itself.

The Pfizer/BioNTech vaccine and the EPA

But wait – didn’t Medsafe provisionally approve BNT162b2 back at the end of January? What has all this got to do with EPA? The answer is: a lot, and nothing at all. Allow me to explain.

All the biotechnology that went into making BNT162b2 puts it at an intersection that has EPA at the corner, because one of our jobs is to regulate all genetically modified organisms (GMOs) in Aotearoa. This is part of our job in regulating new organisms under the Hazardous Substances and New Organisms (HSNO) Act. As I explained above, the Pfizer vaccine has mRNA that was created outside of cells, and this is one of criteria for saying whether something is a GMO. But it’s not the only criterion. That “something” also has to be an organism.

This “organism” criterion is why the EPA doesn’t generally regulate RNA, because it is a substance, and not an organism. But with the Pfizer vaccine, there’s clearly a lot more going on than just RNA, so a reasonable person at the border responsible for giving the regulatory tick to the vaccine might have some doubt about whether or not they were looking at a GMO. The remedy for this uncertainty is to ask the EPA. This is because the HSNO Act also allows us to determine whether or not an organism is a new organism – or if something is even an organism at all, if that is where the question lies.

To ensure the vaccine would not be held up at our border as a potential new organism, Pfizer agreed that going through the statutory procedure to determine if BNT162b2 is a new organism was an appropriate thing to do.

In the EPA’s determination process (which has a lot of moving parts, but I’m cutting a long story short), a Decision-Making Committee (DMC) thoroughly considered whether BNT162b2 could be seen as an organism at all. One criterion in the HSNO Act for being an organism is being capable of replicating itself. The DMC decided that the only thing that BNT162b2 was capable of producing was the SARS-CoV-2 spike protein, and not more copies of itself. On this basis, the DMC determined that BNT162b2 did not meet any of the criteria for it to be called an organism.

And this is what I meant by “a lot, and nothing at all”. A lot was done to determine that BNT162b2 is not regulated under the HSNO Act, and no EPA approval is required for its release into the environment – in this case, “release” means jabs in peoples’ arms.

In conjunction with the approval for its use as a medicine, and the relevant permissions under the Biosecurity Act given by the Ministry for Primary Industries, the determination cleared the path for the importation of the vaccine into Aotearoa, which happened the following week.

And thus began the end of our long isolation from the world.

Dr Tim Strabala's biography

Tim is a Kiwi by way of the USA. He earned a Bachelor’s degree in Chemistry at the University of Colorado, and PhD in Biochemistry at the University of Wisconsin. After a National Science Foundation postdoctoral fellowship, Tim arrived in New Zealand in 1996. After a 29-year research career, including a now defunct Auckland biotech company, and the Crown Research Institute Scion in Rotorua, Tim joined the EPA in 2014, where he is the Principal Scientist of the New Organisms team.