Manufacturing enough Covid-19 vaccine is a logistical nightmare
In the southwestern corner of Michigan, a vast industrial site filled with row upon row of freezers is about to become one of the most important locations in the battle against Covid-19. Soon, these freezers will be filled with millions of doses of vaccine and from there they’ll be distributed as part of the largest global vaccination drive in recent history. In Puurs, Belgium, a similar facility will produce and store doses destined for the UK and elsewhere in Europe.
Both of these facilities belong to Pfizer, the US pharmaceutical firm that was the first to announce that its vaccine, developed with the German company BioNTech, had shown positive results in its final round of human trials. On November 9, Pfizer and BioNTech presented preliminary evidence that their vaccine was over 90 per cent effective. Nine days later the companies announced that full results from the trial showed that their vaccine prevented 95 per cent of cases of Covid-19. Moderna, another US-based pharmaceutical firm making a Covid-19 vaccine also announced that an interim analysis had found that its vaccine is nearly 95 per cent effective.
It’s now looking likely that these two vaccines will be the first to be approved for use in the US and Europe. (Two other vaccines, one from China’s CanSinoBIO and the either from Russia’s Ministry of Health have already been approved for limited use in those countries before the conclusion of clinical trials.) Aside from these four, there are eight other vaccines that are currently in Phase 3 trials – very large studies which determine how good a vaccine is at protecting against the coronavirus. What once seemed a far-off-prospect – an effective coronavirus vaccine – is now on the verge of becoming a reality.
But that doesn’t mean that we’ll all be lining up to get our vaccines by next summer, or even by the end of 2021. Now the vaccine challenge is moving into another decisive phase: the herculean effort of manufacturing billions of doses of vaccine, distributing them all over the world and injecting them into everyone that needs one.
The two leading vaccines from Pfizer/BioNTech and Moderna are both based on very similar technology. They’re what are known as messenger RNA (mRNA) vaccines, and they work by inserting a small amount of genetic material inside the body’s cells that causes those cells to manufacture a tiny protein that in turn stimulates an immune response against the coronavirus. In this case, the genetic material (mRNA) contained within these two vaccines codes for the production of the spike protein that the virus that causes Covid-19 uses to get inside our cells and wreak all kinds of havoc. But since the mRNA just codes for the spike protein on its own and not the rest of the virus, it’s enough to train your immune system to recognise the virus without making you severely ill.
This type of vaccine has a big advantage when it comes to scaling up vaccine production, explains Norbert Pardi, an assistant professor at the University of Pennsylvania who studies mRNA therapeutics. The key components are relatively simple, and putting them together to make the vaccine doesn’t take too long either. Although we don’t know exactly how Pfizer and Moderna make their vaccines, producing an mRNA vaccine in the lab is relatively straightforward. You make copies of your mRNA by mixing together an enzyme, a stretch of DNA and lots of nucleotide bases, which are the fundamental building blocks of mRNA. After waiting a couple of hours, you can purify the mRNA and package it into little vessels called lipid nanoparticles that help it get into our cells without being destroyed by the body’s enzymes.
Obviously when it comes to producing the vaccine for real, this will have to happen on a much bigger scale than in the lab. Both the Moderna and Pfizer vaccines require two doses several weeks apart, so vaccinating everyone in the world would require more than 15 billion vaccine doses, and that doesn’t allow for vaccine vials that are spoiled, broken or end up lost in the back of a freezer somewhere. While the precise figure might be quite a lot lower as you don’t have to vaccinate everyone in order to stop the transmission of disease, the general premise is simple: we need to produce lots and lots of doses of vaccine, and fast.
Here, the mRNA vaccines have another advantage. Because they are made in a relatively simple way, we won’t have to build huge, fancy factories in order to make them. This kind of vaccine could easily be produced in 2,000 litre bioreactors that are common in the industry, says Andrey Zarur, CEO of GreenLight Biosciences, a company that makes its own RNA therapeutics. It also takes less of an mRNA vaccine to produce an immune response – since it relies on the body manufacturing the virus proteins – which means you can get more doses out of the same volume of liquid. Zarur estimates that a 2,000 litre bioreactor might yield 100 times more vaccine than a similar volume of more conventional vaccines, which sometimes have to be grown in chicken eggs.
This is all great news, but the novelty of mRNA vaccines – no vaccine of this kind has ever been approved yet – presents a problem too. We’ve never had to make so much of this kind of vaccine at scale before, so there aren’t the supply chains in place to make it happen as fast as we might need. “The process [labs] have was really never designed to be an industrial, global scale process,” says Zarur. Vaccine manufacturers may struggle to get their hands on the raw materials, such as nucleotides, that go into the vaccines. “People are working hard to come up with ways to de-bottleneck those supply chains, but the reality is that the long term solution is to have industrial processes developed,” he says.
In April, the Gates foundation pledged to build seven factories that could each manufacture a different vaccine, but producing and distributing enough vaccines is still going to take a long time. There just isn’t the spare factory capacity hanging around waiting to be used to create billions of doses of vaccines in a year or two. “If you’re a maker of nucleotides, would you go out and risk building a 100 million dollar plant to make nucleotides for a vaccine that may or may never be approved?” says Zarur. “That’s where the governments of this world needed to have better coordination and needed to take this pandemic situation more seriously.”
So how many doses will we be able to produce in the short term? Pfizer has said it could produce up to 50 million doses by the end of 2020, and a further 1.3 billion doses in 2021. Moderna has its sights set on 20 million by the end of the year and between 500 million and one billion in 2021. This is still a huge amount of vaccine, enough to vaccinate over one billion people by the end of 2021 if the companies do manage to hit these production figures.
Distributing all of these doses will present another headache. Because mRNA disintegrates fairly rapidly at high temperatures, the Pfizer vaccine must be stored at -80 degrees Celsius.
Transporting it to medical facilities requires a special box filled with dry ice that must be replenished every five days, up to a total of 15 days. According to USA Today, sales of dry ice are already spiking in anticipation of the need for ultra-cold storage. This presents a major headache for health centres, most of which don’t have freezers that can go to such low temperatures. (A typical freezer can go as low as -20C.) The challenge will be even greater in parts of the developing world, where even access to a normal vaccine fridge at between 2C and 8C is not guaranteed.
When it comes to distribution, it looks like the Moderna vaccine will be slightly easier to handle. It can remain stable at between 2C and 8C for up to 30 days and can be stored for up to six months at -20C. Unfortunately, Moderna’s production estimates are lower than those from Pfizer so while this may be the easiest vaccine to transport, it might not be the most readily available in the short term.
Even with these technological hurdles, the trickiest part of delivering a coronavirus vaccine might be the very final part: getting it in people’s arms. “The massive problem that I think is going to take a lot of work is simply rolling out vaccination because of the infection control problem, and because we don’t have that many healthcare staff to start with and because everybody’s completely stretched,” says Al Edwards, an associate professor at the University of Reading’s Pharmacy Research Division. Delivering mass vaccination programmes require the coordination of millions of people, who must receive two doses of the vaccine three weeks apart. It’s a logistical challenge at the best of times, but in the middle of a pandemic it’s a nightmare.
According to a report in The Guardian the vaccination programme in the UK will involve district nurses, high street chemists, retired doctors and GPs alongside other staff who will be given a small amount of training. In England, the NHS has told healthcare workers that some clinics may be open from 8am to 8pm seven days a week in order to deliver the required vaccinations.
Despite these challenges, it’s looking increasingly likely that during 2021, vaccines will start being delivered to people who need them, starting with the most vulnerable, and people who work in healthcare. While it’s unlikely that most of us will have had a vaccine by the end of 2021, there is reason for cautious optimism here. And as more vaccines reach the end of Phase 3 trials, there’s a good chance that we’ll increase our production capacity as different vaccines with alternative production methods become available. In the end, it’s likely to be a patchwork of different vaccines that gets us towards that precious herd immunity threshold, says Zarur. “The fact that we have multiple approaches to a vaccine is incredibly powerful.”
Matt Reynolds is WIRED’s science editor. He tweets from @mattsreynolds1
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