The vaccine pipeline
Vaccine development usually follows a series of linear steps because of the high costs and failure rate. Then, the potential vaccine has to be approved for use by relevant regulatory bodies and then manufactured in sufficient amounts and distributed around the world. If we were to follow this approach, a traditional vaccine could take more than 10 years to be developed - this is not fast enough for a COVID-19 vaccine.
Developing a vaccine quickly and safely needed a new model.
Hitting the vaccine accelerator
To accelerate vaccine production, researchers needed to:
- streamline the process and undertake various stages of development at the same time
- fund as many vaccine candidates as possible using a range of different approaches and technologies
- have trials running at a number of locations around the world
- build manufacturing capacity to be able to meet demand.
So, how is the global research community developing potential vaccines for COVID-19 and how are we part of this accelerated pipeline?
Understanding the virus
Our first challenge was understanding this new virus. We were given a sample of virus from the Peter Doherty Institute. We cultivated the virus, growing it to levels allowing us to understand its genomic sequence and its characteristics.
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Sequencing of the virus
Researchers identified the structure of proteins that make up the virus. Since then our researchers have been able look at the first 181 published genome sequences of the virus to understand how changes in the virus affect its behaviour and impact. The team confirmed the virus is evolving into a number of distinct clusters in different parts of the world.
Growing the virus
To undertake research with a virus, you need to be able to isolate it and grow it so you have enough to undertake the work. Thanks to the Peter Doherty Institute, our Dangerous Pathogens Team, was able secure the first strain of SARS-CoV-2 isolated outside of China. They were then able to grow sufficient stocks for the next phases of work.
"Since SARS, we have new techniques to understand what is going on inside the virus and at a molecular level, and also more technology to understand what is going on, on the surface of the virus. However, it’s important to find out how it behaves in biological systems."
Dr Rob Grenfell
Vaccine development
As of early May, more than 120 vaccine candidates are reported in be in development.
The University of Queensland (UQ) is one of the teams we are working with. In less than a month from starting work on a COVID-19 vaccine, the team was able to create a vaccine candidate in the laboratory, based on their years of work developing their patented ‘molecular clamp’ technology.+
Vaccine manufacture
The researchers at our state-of-the-art biologics production facility in Melbourne move into action to start producing and scaling-up the University of Queensland (UQ)’s vaccine candidate.++
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Engineer mammalian cell line to produce the antigen
Our partners at UQ bioengineered mammalian cells to contain the DNA that codes for the antigen, which is the protein that is the basis of the vaccine.
Cells produce the protein
The antigen protein is secreted out from the cells and is captured from the media using an antibody developed by UQ as part of their vaccine platform.
The antigen protein is secreted out from the cells and is captured from the media using an antibody developed by UQ as part of their vaccine platform.
The cells grow well and produce the antigen at scales of 100 millilitres. The challenge for the team is to scale from lab to clinical scale. This takes moving from simple flasks to a state-of-the-art bioreactor, keeping the cells growing well and producing the protein – and all in line with best practice manufacturing standards. This will be used in laboratory and animal studies to ensure the safety of the vaccine.
Purify the vaccine to high standards to make eligible for animal and human trials
The antigen is then purified to the stringent requirements of a vaccine using a multi-step process developed by the protein purification team designed to remove the bioengineered cell proteins, DNA and other contaminants.
Prepare vials
Once the purified antigen has passed the quality checks, it will be filled into vials for first-in-human clinical trial.
Combined with an adjuvant
An adjuvant is added to the vaccine to enhance the body's immune response to the antigen.
Commercial manufacture and supply
If the vaccine has passed all the trials, and has been approved, a commercial manufacturer will need to optimise the methods developed by UQ, CSIRO and other partners to produce the vaccine at commercial manufacturing scale. This will involve transferring the technology from our scientists to the manufacturer.
Pre-clinical trials
At the pre-clinical stage researchers are looking to see if the vaccine works in biological models to provide a guide as to what the responses may be in humans. These are also used to see how effective the vaccine is at preventing the disease and allows researchers to adapt the vaccine.
We’re looking at does the vaccine produce antibodies, does it protect against illness, what dose is necessary, and what type of administration of the vaccine is effective?
In late March, we commenced pre-clinical trials for two COVID-19 vaccine candidates - one from Oxford University and the other from Inovio Pharmaceuticals.
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Development of biological model
Our previous work identified the ferret as a suitable model in which to study the course of infection and the animal’s response to the virus. This model allows us to check the vaccine is safe and to make a comparison between vaccinated and unvaccinated animals.
Vaccination of biological models
We vaccinate animals by different routes, with different vaccines and also give some animals two doses, to see if this improves the level of protection provided.
Challenge of biological models
After a period, we challenge the vaccinated animals and perform a similar study, comparing the results with the unvaccinated animals.
Quantification of vaccine efficacy
We compare the results obtained from the different groups, some with no vaccine, some with one dose and others with two doses, looking for absence or reduced levels of infection and re-excretion of virus and also the level of antibody and the response of other parts of the immune system.
Our high containment facility
This work is being done at our secure Australian Centre for Disease Preparedness (formerly the Australian Animal Health Laboratory) high-containment facility. The research is helping to determine the characteristics of the current virus – a key step in developing a new vaccine.
Clinical trials
This step is where many promising potential vaccines fail. Through these three phases the vaccine needs to show it’s safe, leads to a strong immune response and provides effective protection against the virus.
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Phase one human trials
Involving healthy volunteers, these trials are to test the vaccine safety. In a normal situation, human trials only follow after the preclinical trials. However, a number of manufacturers are already undertaking Phase one human trials in parallel to preclinical. Safety and effectiveness are still paramount and it is unlikely Phase two human trials will start until the preclinical trials have been completed. Both Oxford and Inovio started Phase one human trials in April, running parallel with our preclinical trials. If it makes it through, the vaccine manufacturing is scaled up for the next phase.
Phase two human trials
Involving several hundred people, usually in an area affected, looks at how effective the vaccine is. If it makes it through, large-scale manufacture starts for the next phase.
Phase three human trials
Involving several thousand people, Phase three trials look at how effective the vaccine is.
Approvals
If regulators have approved similar products before, approval can be accelerated – although this is not likely for a COVID-19 vaccine. Each country also has its own regulations and approval processes.
Along the way, if any of these vaccine candidates are shown to be unsafe or ineffective, researchers must return to the drawing board or in this case the lab to tweak their existing candidate or develop a new one. There are no guarantees of success and why vaccine development can be a long and uncertain process.
+ The UQ project is supported by CEPI, Queensland and Federal Governments and philanthropic donors.
++ Manufacturing is made possible by a network of capabilities under the NCRIS funded National Biologics Facility including at CSIRO and UQ.