In this post we will be looking at newer methods of vaccine design, including the vaccines expected to be used in Australia for the current SARS-CoV-2 pandemic. The common thread with these vaccines is that they all harness genetic engineering to ‘code’ for an immune system target (proteins herein).
The beauty of this new way of thinking when it comes to vaccines is that you can use the same ‘platform’ repeatedly to package and deliver your choice genetic component and get the human (or other ‘host’ cell) machinery to produce the protein of interest.
We will be discussing three main platforms:
- Recombinant vaccine technology
- Viral vectors
- DNA and RNA vaccines
We start with the Recombinant Vaccines which are already in widespread use globally. If you have ever received a Hepatitis B vaccine, Bexsero (Meningitis B vaccine), or Gardasil vaccine (primarily for cervical cancer), you have been given a recombinant vaccine. In this technology, target proteins (antigens) are manufactured by a ‘host’ cell that has had been genetically altered to produce the antigen into solution. The solution is collected, a protein purified and hey presto, you have your immune targets. As these antigens are pure protein, they often need a bit of help to stimulate the immune system and so an adjuvant is added (see prior post) usually in the form of aluminium hydroxide.
It is important to note that the ‘host’ cell producing the proteins is not the original organism in question ie we do not use the meningococcus bacteria to produce Meningococcal B vaccine. Mostly yeast cells are used for this purpose, but occasionally insect or mammalian cells are used. Some of the advantages of this type of technology is that the antigen is often in a purer form compared with other methods., This avoids the difficulties of having to obtain large quantities of ‘wild type’ antigen from the organism.
The next two vaccine platforms can get a little technical so to help, so included is a picture from the US National library of medicine to show how the human cell makes proteins for its own purposes in a ‘normal’ context.
Nucleus – where the cell holds its genetic material
Cytoplasm – where the cell proteins are made (along with other processes)
DNA – source genetic instruction manual
Transcription – ‘decoding’ the manual for a specific product/purpose and making (mRNA)
mRNA – interim messenger molecule
Translation – the process by which proteins are made from mRNA
Ribosome – Cell structures able to read mRNA and make proteins
tRNA – carries building blocks of proteins (amino acids) to the ribosome
With this new appreciation for cell biology on board (you can thank me later), we can discuss viral vectors using the Oxford/AstraZeneca COVID vaccine is an example.
This vaccine uses a chimpanzee adenovirus (more about this later) which essentially acts as a miniature Trojan horse. From the outside it looks like a standard virus and can enter a cell like a standard virus, but inside they have been genetically altered to carry instructions telling the host cell to manufacture a protein antigen of choice. In the case of the Oxford/AstraZeneca vaccine, the adenovirus carries the DNA for the spike protein from the SARS-CoV-2 virus which has been identified as a potent stimulator of the immune system. When the DNA message reaches the nucleus of human cells it is transcribed and modified into messenger RNA (or mRNA for short), then transported to the cytoplasm where it is translated into spike protein. This then displays on the human cell signalling to the immune system, inducing the coveted immune response.
With me so far? At this point you may be wondering a few things like; why did they choose a chimpanzee virus or, how to you keep the invading virus from reproducing and going nuts? Both important questions!
There are around 53 types of adenovirus that commonly infect humans and give us the common cold. As we are likely to have been exposed to these human viruses already, we have antibodies that would jump in and neutralise the virus before it has delivered its message to our cell, rendering the vaccine useless – cue chimpanzee. The viral replication question is an important one and, in this instance, the virus has had its replication abilities removed through genetic modification of its DNA.
Now that you know a little about the inner workings of the cell and how viral vectors work, it should not be too much of a stretch to talk about mRNA and DNA vaccines. In this method, there is direct delivery of mRNA and DNA into the human cell. This can be quite tricky as leaving a floating piece of genetic material hanging outside of a cell rarely does much to get it across the cell membrane. There are two main ways to get around this in a vaccine setting.
The first (and the one used in the Pfizer/bioNTech and Moderna mRNA vaccines) encapsulates the mRNA material in a micelle (dual layer of fat forming a sphere with the mRNA in the centre) that then merges with a human cell membrane to extrude the mRNA into it. A little confused? Imagine watching two drops of oil join in water. This is very similar to how the micelle joins with the human cell membrane (which is also largely made of a dual fat layer).
The second way to get RNA or DNA into cells is with electroporation; this is where after injection of the potential vaccine into the muscle, a small electrical current is applied to the site causing pores to develop in the human cell membrane that the genetic material can travel through.
Electroporation is not something any of the potential Australian vaccines are using, but there are several in development stages.
Once the mRNA or DNA is in the cell, it can proceed to its usual site of operation (the cytoplasm with mRNA and nucleus with DNA) to then start the process of protein manufacture. When the spike protein is eventually made, it is displayed on the surface of the human cell, thus signalling the immune system.
Up until now, RNA/DNA vaccines have never made it to market anywhere in the world before and viral vector vaccines are new to the market, only having been used in Ebola outbreaks since 2019.
That is not to say that they have not been used or studied before, just not in this context. It is for this reason that when you ask your GP curly questions such as “what will happen to my immunity levels in 10 years,” you are likely to hear us reply with a resounding “we don’t know.”
In the next COVID vaccine blog update I will be talking a little more around the logistics of the COVID 19 vaccines, how they are given, side effects and what their interim data shows us. I will also try to anticipate (and hopefully answer) some questions you may have about these vaccines.
Dr Kati Davies YourGP@Denman