Illustration: Toby Morris

Siouxsie Wiles & Toby Morris: The race for a Covid-19 vaccine, explained

Well over 150 vaccine candidates for Covid-19 are in development, and they take a myriad of forms. Siouxsie Wiles helps make sense of the different approaches, with illustration by Toby Morris.

For more Siouxsie-Toby collaborations, see here.

With the exciting news that two Covid-19 vaccine candidates (Oxford/AstraZeneca and CanSino Biological Inc/Beijing Institute of Biotechnology) have done well in early-phase human trials, here’s a quick guide to the different types of vaccines under development.

According to a recent analysis by the World Health Organisation, there are currently well over 150 vaccine candidates for Covid-19 being developed. About 140 of these are currently undergoing what is known as “preclinical” testing. This means they are still at the lab stage, perhaps getting as far as being tested to see if they work in animals. The more exciting news is that more than 20 candidates are already in various stages of being tested in people.

The different clinical trial phases

Before I explain a little more about the different Covid-19 vaccine candidates, here’s a very quick summary of the different stages of testing in people that they’ll need to go through.

A phase 1 clinical vaccine trial usually involves fewer than 100 healthy people. They will be given the experimental vaccine, perhaps at different doses, to find out if it is safe and whether there are any serious side effects. A phase 2 trial involves more people, again looking for common side effects, but also looking to see if people’s immune systems recognise it and mount a response. If they don’t then that’s the end of the road.

But if people do mount an immune response, then the candidate can move onto a phase 3 trial. Here the number of people vaccinated increases into the thousands to tens of thousands and we start to get information on whether the vaccine might actually work.

The different types of vaccines

There are three main approaches to making a vaccine. What makes them different is whether they use a whole virus or bacterium, just the parts of them that trigger our immune system, or just the genetic material that codes for the parts that trigger our immune system.

The whole microbe approach

The first way to make a vaccine is to take the offending virus or bacterium, or one very similar to it, and kill it using chemicals, heat, or radiation. This is what is known as a dead or inactivated vaccine. The advantages of this approach are that it’s well established technology that we know works in people – this is the way the flu and polio vaccines are made – and vaccines can be manufactured on a reasonable scale. The downsides, though, are that it requires special laboratory facilities to grow the microbe safely, can have a relatively long production time, will likely require multiple doses to be administered, and may need to be given alongside an immune enhancer known as an adjuvant.

Covid-19 vaccine candidates currently in clinical trials that fall into this category include those developed by Wuhan Institute of Biological Products/Sinopharm, Beijing Institute of Biological Products/Sinopharm, Bharat Biotech, Chinese Academy of Medical Sciences, and Sinovac.

Another way to make a whole microbe vaccine is to use a living but weakened version of the microbe or again one that’s very similar. This is what is known as a live-attenuated vaccine. Again, this is well-established technology which has proved to be highly effective and the vaccines can be manufactured at a reasonable scale. The measles, mumps and rubella (MMR) vaccine and the chickenpox and shingles vaccine are good examples. The disadvantages are similar in that it still requires special laboratory facilities to grow the microbe safely, and can have a relatively long production time. More importantly though, vaccines like this may not be suitable for people with compromised immune systems.

Covid-19 vaccine candidates that fall into this category and are currently in clinical trials include those developed by Mehmet Ali Aydinlar University/Acıbadem Labmed Health Services, Codagenix/Serum Institute of India, and Indian Immunologicals Ltd/Griffith University.

A variation on the live-attenuated vaccine approach is to develop what is known as a chimeric vaccine. For this, we use the backbone of a less harmful or weakened microbe but engineer it to contain the protein(s) of the harmful microbe that the immune system recognises. Again, there are vaccines like this already in use in people, including for Ebola and dengue fever, and they have been shown to trigger really good immune responses. These vaccines also have the advantage that they don’t need the same level of specialist lab to grow the microbe and so are relatively quick to scale up.

This is the strategy of the University of Oxford/AstraZeneca vaccine which is a chimpanzee adenovirus backbone engineered to have the spike protein from the SARS-Cov-2 responsible for Covid-19. Adenoviruses are viruses that cause the common cold. The CanSino Biological Inc/Beijing Institute of Biotechnology Ad5 vaccine candidate uses a similar strategy, only instead of a chimpanzee adenovirus they have used a human adenovirus as the backbone. The disadvantage of using a human adenovirus is that people may have already been exposed to it in the past so they may have pre-existing antibodies which means they are less likely to mount a good immune response to the engineered version.

The protein/subunit approach

The next approach to making a vaccine is to just use the proteins (or sometimes sugars) from the virus or bacterium that the immune system needs to recognise. There are two strategies here. The first is to deliver the specific proteins – referred to as subunit vaccines. Most of the vaccines on the childhood schedule are this type, protecting us from diseases such as whooping cough, tetanus, diphtheria, and meningococcal meningitis.

Covid-19 vaccine candidates that fall into this category and are currently in clinical trials include those developed by Novavax, Anhui Zhifei Longcom Biopharmaceutical/Chinese Academy of Sciences, Clover Biopharmaceuticals Inc/GSK/Dynavax, Vaxine Pty Ltd/Medytox, and University of Queensland/CSL/Seqirus.

The second strategy is to use virus-like particles (VLPs) instead. These are self-assembled structures made from viral proteins that mimic the architecture of viruses. Importantly, they lack genetic material so aren’t able to replicate in host cells like an infectious virus would. Examples of this type of vaccine are the HPV and Hepatitis B vaccines. Medicago Inc are currently carrying out a phase 1 clinical trial of a plant derived VLP administered with an immune enhancing adjuvant.

The advantages of the protein subunit and VLP approach are that it’s well established technology that we know works in people, doesn’t involve growing any dangerous microbes, and the vaccines can be manufactured at a reasonable scale. The downsides are that they are expensive, and like the inactivated approaches the vaccines usually need to be given alongside an immune enhancing adjuvant which adds to the manufacturing process.

The genetic approach

The final approach to making a vaccine is to just use the genetic material that codes for the parts of the microbe that trigger our immune system. The idea is that by introducing the genetic material into our body, our cells will read the code and make the protein for our immune system to see. Again, there are two strategies here, the first is to use DNA, and the second to use RNA. If DNA is used, the cell makes RNA from that DNA and then protein from the RNA. Using RNA obviously skips the DNA to RNA step.

The advantages of this approach are that it is really quick to develop and really easy to upscale and manufacture. The main downside is that no vaccines developed using this technology have yet been approved for use in humans, though there have been human trials of DNA vaccines including those for cancer. The DNA approach also has the added downsides that delivery of the vaccine is quite difficult and there is the hypothetical risk that the DNA could integrate into the human genome whereas the RNA version cannot.

Inovio Pharmaceuticals/International Vaccine Institute, Osaka University/AnGes/Takara Bio, Cadila Healthcare Limited, and Genexine Consortium all have DNA vaccine candidates for Covid-19 in clinical trials. Moderna/NIAID, Imperial College London, Curevac, BioNTech/Fosun Pharma/Pfizer, and the People’s Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech all have RNA candidates in clinical trials.

It’s incredible how quickly all of these vaccine candidates have been developed and how fast they are progressing into clinical trials. What’s crucial now is that those trials are well-designed and transparent so that we can be confident that that any vaccine that gets the green light is safe and  effective.



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