Some call it “happy soup”.
Take a streak of modified Covid-19 protein DNA, mix it with cells from a Chinese hamster’s ovary, and place the combination in two state-of-the-art 2000 L bioreactors at a sprawling science facility on the northern fringes of Melbourne .
The result? A broth that, when purified and combined with an immune booster, could help end the Covid-19 crisis as we know it.
For months, much hope rested on vaccine technology developed by the University of Queensland, which produced a version of the virus unable to use its crown – or corona – spikes to attach to target cells inside the human body.
But if the hopes come true and the UQ vaccine turns out to be safe and effective, what to do next? How will Australia manufacture it on the dizzying scale needed to get the country out of the crisis?
How the vaccine works
The Guardian received a unique insight into the operations of CSL, the company responsible for making 100 million doses of the UQ vaccine and tens of millions of doses of the AstraZeneca vaccine, one of the world’s other high hopes.
Production will take place at CSL’s biotech manufacturing facility in Broadmeadows, a lab run by a soft-spoken, bespectacled scientist named Phil Elliott.
Elliott and his team are already making the UQ vaccine to help with clinical trials and to ensure it’s available for distribution throughout Australia and New Zealand as soon as possible, once found to be safe.
“If the trials continue to be successful and provide the results we all hope for, we will have manufactured enough equipment to provide the people of Australia and New Zealand with access to vaccine candidates for administration,” says Elliott. “The team is very happy to be able to say that they have been involved in what is an activity of global significance.”
The infection process relies on the virus using advanced proteins on its outer surface to attach to human ACE2 receptors – a protein on the surface of many cells, including in organs and on languages.
Once attached, the peak transforms and unfolds, hooking onto the cell and crushing the viral particle and cell together, forming a channel through which a chain of viral genetic material can pass into the human cell.
When the body’s immune system kicks in to fight the virus, much of its effort goes towards this spike protein.
UQ effectively took the genetic sequence for Covid-19, isolated the section that codes for the spike protein, and changed that sequence to include a clamp that locks three spike proteins together in the form they exist in before trying to bind to human cells.
The result? The body receives the entire immune response without any infection and is vaccinated against future Covid-19 infection.
The UQ vaccine manufacturing process begins when CSL receives DNA that encodes the modified spike proteins.
The DNA is then introduced into mammalian cells – most often a cell line originally derived from the ovary of a single Chinese hamster – and placed in the bioreactors at the CSL facility.
It starts small.
Mammalian cells making the spike protein are grown in small volumes of about 50 ml. Then 100 ml and 200 ml.
And so on, until you start getting the quantities you need to produce a vaccine.
“Ultimately, you need to scale up the growth of these [Chinese hamster ovary] cells at a very large volume so that you can produce sufficient quantities, ”says CSL Chief Scientist Andrew Nash.
“So in our case you end up in a 2,000 liter bioreactor.”
The cells grow continuously for about 12 days, while producing the spike protein so crucial for the UQ vaccine.
Once the 2000 L reactor is full, it is harvested and purified.
The goal here is simple: to separate the spike protein from mammalian cells and any other unwanted by-products and debris to get the best vaccine possible.
“The more purified you can make the protein antigen you want to use in the vaccine, the more likely you are to get an immune response directed to that protein,” says Nash. “And the less likely you are to have side effects associated with cell debris or unwanted by-products of this bioreactive process. “
The process is completed by combining the purified spike proteins with an adjuvant, an agent that strengthens the immune system, officially known as MF59.
This is a crucial step for people with weaker immune systems – the elderly, for example – to make sure they are protected against viral infection. The same adjuvant has been used safely for many years in influenza vaccines.
The challenge is the urgency
The process is not unusual for CSL. Making the UQ vaccine – a type of recombinant protein vaccine – isn’t something CSL hasn’t done before.
The scale of production required, although immense, is also well within CSL’s capacity.
CSL estimates that it can produce 100 million doses of a Covid-19 vaccine by the end of next year. About 51 million will go to Australia and an additional 51 million will go to developing countries under an agreement with the Coalition for Epidemic Preparedness Innovations, a global body that seeks to ensure equitable distribution of vaccines.
The challenge in all of this, however, is the urgency.
The vaccine development process has been compressed by taking measurements that would generally be linear and running them in parallel.
This means, for example, the intensification of manufacturing while vaccines are still in the testing phase.
“The main issue for us was that the facilities are being used for our own R&D processes and we have a very active portfolio and pipeline of projects,” says Nash. “The challenge is to find a way to make vaccine manufacturing part of our regular business. Given the circumstances of the pandemic, we put aside our usual activities and found ways to manufacture the vaccine. “
The manufacture of a vaccine at the trial stage is rare, simply because of the risks of making such a huge investment in an unproven vaccine.
Professor Paul Griffin, director of infectious diseases at Mater Health Services and associate professor of medicine at the University of Queensland, says vaccine manufacturing typically does not begin until after phase three clinical trials are completed.
“It’s a huge investment in this scaling process that CSL would be involved in, because it often takes a lot of time, and a lot of money in terms of infrastructure and expertise and other things,” so normally this is not considered until phase three, ”he said. “And of course, not all vaccines that make it to phase three trials will be successful.
“So you are potentially spending hundreds of millions of dollars to ramp up the manufacture of something that might not work.
“It’s a huge investment, but you know of one that is certainly worth it right now, given the importance of the vaccine.”
Peter Collignon, infectious disease expert at Australian National University, says vaccine manufacturing requires a huge amount of infrastructure and expertise, like only CSL in Australia.
The speed of the vaccine development process has raised concerns among the general public.
Reluctance over vaccines appears to be a potentially significant barrier to adoption of any Covid-19 vaccine, which Prime Minister Scott Morrison wants to distribute to 95% of the population.
But Nash and Griffin say there’s no reason to worry about the speed of the process.
“The audience is very focused on what’s going on right now,” Nash says. “While there is a lot of pressure to find something as quickly as possible, I think everyone resists the temptation to cut corners when it comes to safety, because at the end of the day, it’s not there. than anyone wants to be. “
Griffin says many of the fast-track steps are between clinical trials.
“So what we’ve done to really speed up the process is basically take a lot of steps between clinical trials that often take so long, and it’s those steps that are often responsible for the really big delays that we often have developed. that type of product, ”Griffin says. “But what’s important is that we haven’t actually shortened any of the key steps. “
It is still unclear when and if a Covid-19 vaccine might be available.
If this proves to be safe and effective and CSL manufactures the millions of doses needed, the next step is distribution, a process fraught with pitfalls.
This is an issue the federal government must take into account.
In the meantime, Nash and his team are working around the clock to make sure the vaccine is available.
“If you take it as an individual episode, the pandemic, people within CSL realize that this is really important and all the extra work that needs to be done is definitely worth it,” he says. “Working for a company, CSL works a lot on rare diseases, and we understand our patients and their issues very well, and I think that’s often a very motivating factor for our scientists and our product developers. It’s just an urgent extension of that. ”