Are there other benefits of developing so many different vaccines against one disease? 

I was recently asked to write an article about ongoing opportunities provided by COVID-19 for science education, as the pandemic continues. The exercise got me to think about silver linings for once rather than the usual wearying analysis of the problems. The writing of the article also made me think more broadly about how the virus has evolved, how some attitudes to the virus and to vaccines have not changed and, more specifically, how our range of vaccines will develop.

We are all now familiar with the more transmissible delta variant of SARS-CoV-2. It joins a whole raft of other Greek-lettered variants, although currently delta is the one causing the most trouble. I doubt that delta will be the last ‘variant of concern’ to spread across the planet, and the World Health Organisation is tracking 13 ‘variants of interest’ as I write this. The longer the virus continues to spread, the more variants will arise, and some of those will undoubtedly cause additional problems to individuals, governments and health services around the globe.

Our best defence continues to be vaccination. Yet, there are still the same old howls of protest from people saying that the vaccines aren’t safe because:

• they have been developed too quickly (the initial concept of using mRNA for vaccines was proposed in 1990, and the first vaccines using mRNA technology were administered in 2012)

• they haven’t been properly tested (over 5 billion doses of COVID-19 vaccines have been given, with extremely low rates of serious side-effects (between 2 and 8 people per million for AstraZeneca, for example)).

Perhaps, once vaccines that use more ‘traditional’ approaches become more widely available, some of the hesitaters will be reassured. At the time of writing there are another 92 vaccines undergoing clinical trials, so there will be plenty of choice.

Vaccination revolves around molecules called proteins. All our cells have proteins sticking out of them. Patrolling white cells continuously check our other cells by ‘examining’ those proteins. If cells have ‘non-you’ proteins sticking out of them, your white cells mark those cells for destruction. Bacterial cells and virus particles also have proteins on their surfaces and when spotted, the bacteria and virus particles are also tagged for annihilation. Crucially, the body develops a memory for previously detected foreign proteins and so the next time they are discovered, destruction is much faster and much more effective. A vaccine is used to show foreign proteins to the white cell bodyguards so that future detection of the proteins results in immediate elimination of infected cells, bacteria or virus particles.

There are many ways in which white cells can be trained using a vaccine, but they can be divided into three main categories:

• using whole viruses

• using proteins from a virus

• using genetic information from a virus.

To make a ‘whole virus’ vaccine for COVID-19 you can take real virus particles and ‘kill’ them. This is an ‘inactivated vaccine’. It’s the same approach used for the polio vaccine. It takes quite a long time to work out how best to ‘grow’ the viruses, how to ‘kill’ them and then to get sufficient quantities of the virus. Sinovac is a vaccine of this type, and others will become available shortly.

Other ‘whole virus’ approaches involve weakening the COVID-19 virus, so that it is still capable of invading cells but does not cause the disease. This ‘live-attenuated vaccine’ approach is used against measles, for example, and the Codagenix vaccine is of this type.

The last of the ‘whole virus’ approaches involves taking a harmless virus and modifying it so that proteins from the COVID-19 virus are on its surface. These are ‘recombinant live-attenuated’ vaccines. A vaccine produced by Meissa uses this technology.

Many of today’s common vaccines (e.g. for whooping cough, tetanus) just use the proteins from a virus. These proteins may be from smashed up virus particles but are usually specific proteins made using genetically modified bacteria. The proteins are extracted and purified and then made into vaccines. These ‘subunit vaccines’ often need what’s called an adjuvant; essentially another substance that gets the proteins to stick together in clumps, which makes it easier for the white cells to detect them. Some adjuvants form the proteins into a ‘virus like particle’, which mimics the shape of a virus (but contains no genetic material). The Novavax vaccine is a subunit vaccine.

Then there are the vaccines based on genetic material. Our cells contain DNA, which is divided into 20 000 or so genes. Each gene can produce a protein. However, to make a protein, the DNA information is copied onto another molecule called mRNA. It is the mRNA that is then read by protein factories in our cells, and proteins are produced.

The Pfizer and AstraZeneca vaccines use this approach. They put genetic information into cells, which instruct them to make copies of the COVID-19 ‘spike’ protein (the protein that sticks out of the virus particles). The Pfizer approach gets mRNA into your cells, the AstraZeneca approach uses DNA (which cells copy onto mRNA). These bits of mRNA and DNA only last for an hour or so and once they have disintegrated, the production of spike proteins stops. However, that is long enough to make enough spike proteins for the white cells to recognise.

There are different ways of getting DNA or mRNA into cells. Pfizer uses blobs of fat with the mRNA inside. The fatty blobs fuse with cells and deliver their mRNA contents. AstraZeneca use a live, harmless virus, which infects cells and so delivers the DNA. Another approach is to use ‘electroporation’, in which you give cells a brief electric shock that makes them absorb loops of genetic material. All sorts of different permutations of these approaches are being trialled, but the result is the same; they get your own cells to make COVID-19 virus spike proteins for a short period of time.

A problem with the spike protein is that it changes quite often (and these ‘mutations’ are the cause of the new variants). A mutated spike protein is different to the unmutated version, and so the white cells may not recognise the mutated spike protein on a real COVID-19 virus even if a person has been vaccinated. However, scientists have discovered that one of the other virus proteins (the N protein) does not mutate very quickly. This protein is found inside the virus and so is hidden from white cells. Importantly, though, scientists have found that once a COVID-19 virus has infected a cell, the cell posts N proteins on its surface (advertising to passing white cells that it is under attack). So, other vaccines in the pipeline use the N protein, which may mean that those vaccines will work against many more different variants of the disease.

Finally, the delivery of vaccines is also being investigated. For example, scientists are looking at squirting vaccines up your nose rather than injecting them. Injected vaccines teach white cells to produce substances called IgG antibodies. The IgG antibodies help in the annihilation of foreign cells and virus particles, but only inside the body and not on body surfaces (such as the inside of the nose). On these surfaces, different antibodies come into play – the IgA antibodies. Results show that nasally administered vaccines can cause the production of both IgA and IgG antibodies, providing an extra type of immunity, called ‘mucosal immunity’ – essentially a first line of defence inside the nose, where the virus particles are likely to first enter. The Codagenix and Meissa vaccines, and a version of the AstraZeneca vaccine are all being trailed for nasal delivery.

To some, the development of around 100 vaccines to counter one virus may sound like overkill. However, the amount of money and effort that has gone into the development of all these different approaches will undoubtedly spill over into the development of new and cheap vaccines for other diseases that cause pain and suffering in many parts of the world (such as HIV, Zika, Lassa fever). A definite silver lining, eventually.