In January 2019, Robin Shattock, head of mucosal infection and immunity at Imperial College London, gave a talk to the World Economic Forum in Davos in which he argued that in a world under threat by “Disease X” – a term used by the World Health Organization and epidemiologists to describe an unanticipated and fast-moving epidemic with no known treatment – we needed to “completely reimagine the way we make vaccines for outbreaks and pandemics.”
Alongside clean water, he said, vaccines are the public health advance that underwrite our increasingly dense, interconnected world. And yet, vaccine timelines are still measured in years or decades (a study in 2013 found the average vaccine took 10.71 years from conception to completion). If an outbreak struck, the response would be slow. You would have a situation where people were dying, and no way to deliver a vaccine in a “meaningful timeframe”.
Shattock’s group at Imperial is one of a handful of teams worldwide working on an experimental type of vaccine called mRNA vaccines, which use simple synthetic messages written in genetic code to incite an immune response. These are theoretically faster to develop and cheaper to manufacture than traditional vaccines, and are potentially ready to respond to a threat in months rather than years.
When Shattock spoke, no one knew when the next pandemic would strike, and while there had been some minor pharmaceutical and government interest in mRNA vaccine technology, it was still years away from being ready. “It didn’t make a very big splash then,” Shattock says. A year later, times have changed.
Covid-19 has proved Shattock’s point: the traditional way to make vaccines is not fit for pandemic purpose. The coronavirus strategy adopted by most countries – some version of lockdown and social distancing under the imperative to “flatten the curve” – was developed for flu pandemics in the mid-2000s, and is only intended to push an outbreak down to a manageable level. It is unlikely to eradicate the disease; only a vaccine can do that.
As Bruce Gellin, former director of the National Vaccine Program at the US Department of Health and currently at the Sabin Vaccine institute, explains, “The idea was you could hunker down til a vaccine arrived.” It takes about six months to make a vaccine for a new flu strain; for an unknown disease, the timeline can stretch to years. “We’re hunkered down waiting for a vaccine we don’t know how to make,” he says.
Amid the global coronavirus pandemic, waiting the normal length of time for a vaccine seems unbearable. And so, despite being relatively unproven – only a handful of mRNA vaccines have ever entered clinical trials, and none have progressed to public use – mRNA vaccines have been seized on as a candidate to solve the problem. Not only to stop the pandemic, but to do it quickly.
In January, Shattock says, he wasn’t sure if his lab could even get funding to work on coronavirus. Since then, labs working on mRNA vaccines have been flooded with public money and support: the UK government has committed £41 million to Shattock’s team since April, and US company Moderna, the first to announce an mRNA vaccine candidate for coronavirus, has been promised $483 million (£390 million) from the US government’s Biomedical Advanced Research and Development Authority. Some members of the public even tried calling the Imperial lab directly, offering to donate money or volunteer themselves to test the vaccines.
Five mRNA vaccines for Covid-19 are already in clinical trials, including Imperial’s, and there are at least another 20 in development. “We had basically nothing in January,” Shattock says. “To be in human trials already is amazing, unprecedented.”
Charles Cooney, professor of chemical engineering at MIT, says he’s “never seen anything like it”. The pandemic, he says, provides an immense pull to “bring new science forward”.
If a successful coronavirus vaccine does emerge from one of these labs in the next few months, it will be one of the great scientific achievements of our time, representing not just a victory over the current virus, but a real step forward in the way we make vaccines.
The basic idea of using mRNA to make a new type of vaccine is over 30 years old, and arose as a little-appreciated offshoot of the genomic revolution of the late 80s and 90s. At that time scientists looked at efforts to sequence the human genome and the ability to quickly and cheaply synthesize DNA and RNA, the molecules that store and carry genetic information within our cells, and imagined a new frontier of precision medicine where they could program genetic messages and send them directly to the machinery of our bodies.
Traditionally, vaccines are made of either a killed or inactivated virus, or recombinant protein. These show the body an entire virus, or a piece of it, for future recognition. They trigger the production of antibodies that can then be activated if your body comes into contact with the real virus in the future.
Killed or inactive is exactly what it sounds like: a virus with all of the parts but none of the function, like a deadly viper preserved in formaldehyde. As Jeffrey Almond, the former Head of Discovery Research for Sanofi Pasteur, and current Martin Fellow, Oxford University, explains: “Grow it in cells, kill it with formalin, stick it in your arm. It’s not the fanciest, but by gum it works.” Recombinant protein uses just a single viral protein grown in a lab.
In both cases, growing viruses or proteins in vitro – in a laboratory – can be a finicky process, like producing a complex machine in an unfamiliar factory. It may take months of optimisation and tinkering. Almond recalls that the viral protein used in the Hepatitis B vaccine took four years to produce in a stable manner. Scientists have been trying to optimize growing the HIV envelope protein for more than 20 years.
Most researchers in the early genomic era worked on DNA, trying to cure genetic diseases by sending in a permanent healthy synthetic DNA copy of a gene that had been faulty from birth to replace it. Hungarian biochemist Katalin Karikó, however, was fascinated by messenger RNA (mRNA), which carries the messages encoded in DNA around our cells, and only lasts a few hours or days. “You could program it, but it would basically be like a drug. The effect would wear off,” she says.
The problem, though, was that RNA made outside the body could be deadly, making the immune system go haywire no matter what message was tried. Drew Weissman, Karikó’s former colleague at the University of Pennsylvania, recalls that she would bring him new mRNA to test. “You would shoot 30 micrograms of RNA into a mouse and it would die,” he says. This happened all the time; the mice that didn’t die were either sick or showed no therapeutic effect. There was no chance of trying it in humans.
Karikó cracked the problem in 2004, after seeing research that showed certain immune system receptors were sensitive to Uridine, a molecule that serves as one of the “letters” of RNA’s genetic code. This was probably meant to catch viral RNA, but it was tagging her synthetic mRNA as well. She replaced Uridine in the code with an analog, a molecule that would read the same but whose shape wouldn’t trigger the immune system. The trick worked, the mice lived, and Karikó recalls thinking, “Now we can use it for everything.”
The therapeutic potential was obvious. What Karikó unlocked was the ability to send a simple RNA message to a cell that would instruct it to make the protein she wanted itself – cutting out the painstaking process of growing a protein or virus in the lab. “You’re making a message to the human body to make the vaccine directly inside the body of the person,” explains John Tregoning, an immunologist at Imperial College.
Karikó, Weissman and colleagues published their results in 2005, but “people were not interested,” she says.
“The field didn't really open up at all,” Weissman says. “We talked to everyone who would listen to us, but pharma doesn’t really like early-stage research.”
And so mRNA vaccines progressed slowly. Their most obvious application was as a quick response to pandemic threats, but that wasn’t really the business of big pharma. Several pharmaceutical executives told me that historically global health and pandemics were on “the fringe”, which was a “shame”. Almond says that at Sanofi they made progress on a vaccine for the original Sars outbreak, but after a year “the disease had gone away and there wasn’t a call for the vaccine anymore.” There just wasn’t a business case for outbreaks. Pharma companies were interested in stable, long-term blockbusters, not the messy business of taking a new vaccine technology through its growing pains. It fell to academic researchers and small biotechs to hammer out the details.
There were some successes. Moderna was founded in 2010 in Boston, Massachusetts, by a group of MIT and Harvard professors who saw the commercial potential in mRNA, quickly raising enough investor money to put multiple candidates into trials. Karikó joined German company BioNTech in 2014, which has several mRNA medicines under review. Both companies are mainly applying the technology to cancer, generally a more lucrative area.
Moderna and Weissman’s lab separately developed potential Zika virus vaccines in 2017 – Moderna’s is currently in phase 1 clinical trials, stuck in the pre-Covid trial timeline – and international organisations interested in combating epidemics, like the Coalition of Epidemic Preparedness Innovations (CEPI) and the Gates Foundation, began funding mRNA vaccine projects. Big Pharma began inking deals around the same time, with Pfizer and Sanofi licensing technology from smaller mRNA vaccine developers.
But the field was still a minor concern, lacking the large-scale funding that drives traditional vaccine projects. Since Karikó’s discovery in 2004 there have been only 12 clinical trials for mRNA vaccines against infectious diseases – before Covid. In contrast, according to a recent industry report, there were 171 vaccine trials completed in 2018 alone, and over 600 in the preceding four years.
Faced with Covid-19, the traditional pharmaceutical industry didn’t have an immediate answer. It lacked what is known in the emerging-disease vaccine world as a platform: a system you could plug any new viral gene target into and get a candidate vaccine produced quickly.
Shattock’s group at Imperial had a platform. “We were working on Marburg virus, Rabies, Ebola, HIV, you name it,” says Paul McKay, a senior researcher in the lab. The idea was always that their system could adapt quickly to any virus. When news emerged out of China about a new coronavirus, the team met several times to discuss whether it was “a big deal,” says Shattock. On January 19, they committed to making a vaccine. “It’s very much plug-and-play with the genetic code, swap out Ebola for coronavirus and you’re off,” he says.
Chinese researchers had already posted the genetic sequence of the new coronavirus online. It took just days to select a target – a gene for the spike protein, known from SARS and MERS research to provoke antibody response – and a week to order a synthetic copy of the gene, assembled from the Chinese sequence by a German biotech company for 7p per genetic letter.
There was another week of tinkering with the sequence in the lab before it was sent off again, this time to Vancouver to a company that specialises in suspending mRNA in tiny fat globules to shield it on its journey through the body. It was a potential cure whizzing across the world at the same time as the virus itself. The assembled vaccine entered animal testing on February 13. And the first human trials started in London on June 15.
But for those working in the field, the pace was set by Moderna. Their vaccine took just 42 days to go from a gene sequence on a computer on January 18, to the first human-approved test dose, on February 24. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, called it a world record. “Nothing has ever gone that fast,” he told the Wall Street Journal. Moderna’s official clinical trial started on March 16. (Moderna was able to skip animal safety testing because their similar products for other diseases had been used in human trials before, something that pushed other vaccine-makers’ work back at least 6-8 weeks.)
While mRNA vaccines were first off the blocks, the field has widened considerably since January. The WHO is tracking over 200 candidate vaccines in development, with 15 in clinical trials already. Among the other frontrunners are several old-school killed or inactivated virus vaccines being developed in China, and vaccines grafting the coronavirus spike protein onto a harmless carrier virus, another promising and relatively fast approach – Chinese biotech firm CanSino Biologics and the University of Oxford both have vaccines based on this technology in trials. Virtually every lab or company that could conceivably adapt their existing system for coronavirus has something in the works. “It’s some combination of urgency and opportunism,” Almond says. “Everybody wants to jump in and try their approach.”
Makers of traditional recombinant protein vaccines are on a slower track – most expect to enter clinical trials later this year or in 2021. But they still make up the bulk of the efforts, with about 50 in development. And they aren’t necessarily worried about upstart technologies outrunning them. “We’re rooting for one of the newer vaccines to hit the market very quickly – we would be pleasantly surprised if that occurs,” says Louis Falo, a professor of medicine at the University of Pittsburgh. Falo and Andrea Gambotto are working on a protein-based vaccine, and despite not being in trials yet, they still like their chances.
Back in 2003, Gambotto published one of the original studies showing the SARS spike protein provoked strong immune response in monkeys, helping solidify it as a target for all subsequent coronaviruses. The group’s new purified coronavirus spike protein is currently awaiting FDA approval to enter trials. The lab has worked on coronavirus on-and-off for nearly 20 years, and has a quiet confidence that its established record, working with a proven vaccine technology, will win out.
“The production, the validation, it takes a little longer with protein; each one is a new beast,” Gambotto says. But, Falo says, “Most of the vaccines in the world are protein-based. Lots of the vaccines people are talking about now don’t have that track record.”
And being first isn’t necessarily enough: a more effective or easier-to-produce vaccine might supersede the front-runner in the same way Sabin’s cheap, swallowable polio vaccine lapped Salk’s original injection vaccine in the 1960s.
The Imperial group is betting on its system’s own unique quality. Its vaccines use “self-amplifying RNA”. Its mRNA sequence includes instructions for a second protein, a tiny molecular machine to help cells produce the spike protein more efficiently. This should provoke more antibody response from the body, and thus afford better immune protection. But it also means vaccine doses could be lower – much lower. “Probably around 100 to 150 times less material needed,” Shattock says.
“In mice we tested down to 0.01 micrograms and still got a great response. In humans the highest dose we’re testing is 1 microgram. Moderna is doing 25 up to 200, 250. They think those big shots are the best,” McKay explains. It isn’t scientific bragging rights at stake, but the cost of manufacturing the eventual vaccine. “We can keep it easy and cheap,” he says.
This part of the mission may ultimately be more important than being the first to develop a successful vaccine. “Even if a vaccine comes first and countries with deep pockets line up to buy it, we can still make vaccines accessible for low-income countries,” Shattock says.
For vaccine experts, this is a priority concern: once the plaudits of being first have faded, the question will be how to get a vaccine to the billions of people who need it.
Manufacturing is the great second leg of the race for a coronavirus vaccine. By concentrating on the laboratory science alone, we’re imagining a finish line far too early. “Make no mistake, everyone always misses the manufacturing part of it,” says Darren Dasburg, former VP of global strategy for AstraZeneca, now retired. “Generally if you come up with a successful new molecule, great, but you have to make a hundred million of them. With Covid, maybe billions.”
Vaccine manufacturing has traditionally looked more like an industrial process in a factory than a simple, clean laboratory. The most popular vaccine in the world, the yearly flu vaccine, is grown in fertilized hens eggs, procured from massive laying facilities – “like big, sterile IKEAs” where the chickens eat irradiated food to prevent disease, Mike Austin, head of production at Cobra Biologics in Liverpool, explains. “I believe only Tesco processes more eggs than the vaccine-makers here,” he says. The eggs are injected with live flu, which is later harvested to make the vaccine. Until the process was automated in the early 2000s, all the eggs were injected and harvested by hand by hundreds of workers at each facility.
Making flu vaccine is a particularly idiosyncratic process, but most traditional vaccines are what are called “biologics”, a virus or protein which must be grown in living cells – egg or otherwise – which is almost always difficult, messy and particular. “If you’re making a biologic, you generally need a new factory for each one,” Almond says. “This is the problem with Covid, there’s no factory for coronavirus. If it was a new flu, that would be different. But because it’s a brand new virus type, we're starting from scratch.”
In theory, mRNA vaccine manufacturing will be faster and cheaper than a traditional vaccine – potentially delivering hundreds of millions of doses at a fraction of the cost. But it has never been tried at the scale coronavirus demands. As the University of Leeds, virologist Nicola Stonehouse explains, vaccinating essentially the entire world for coronavirus would mean “roughly doubling” the current worldwide production capacity for traditional vaccines, which has been built up over decades.
The promise of mRNA vaccines is that they will collapse all that to the size and scale of a regular laboratory. “You don’t need huge campuses and facilities and factories to do this. We can make millions of doses in a small room,” says Frank DeRosa, chief technical officer for Translate Bio, a biotech that is working with the pharma giant Sanofi on a future mRNA vaccine for coronavirus.
But there are only a handful of producers in the world who can make more than a few grams of medical-grade RNA at a time. “It’s hard,” says DeRosa, who won’t elaborate further on the company’s proprietary process. “It’s unstable, it doesn’t just ramp up cleanly to larger amounts.” But each facility can turn out impressive volumes. Translate advertises the ability to make two 250g batches a month – anywhere from 50 to 200 million vaccines, depending on the dose. Lonza Bioscience, which has partnered with Moderna, promises a billion doses a year from just two manufacturing sites. In contrast, China’s National Biotec Group recently announced it had completed the world’s largest vaccine factory for a traditional killed vaccine, capable of producing 100 million doses annually.
Zoltán Kis, a biochemical engineer at Imperial College who has been working on optimising vaccine production for possible pandemic situations since 2018, says a billion doses a year from a single facility is theoretically possible. There are hitches with very large volumes, but the basic process is the same as scientists use in the lab every day – “a fairly simple reaction mix” of enzymes that copy your genetic template many times, and then several purification steps to remove everything but the RNA for injection. The tough part, he explains, may be in sourcing the reaction materials themselves. “We’ve already seen the difficulty with PPE and other medical supplies with borders not working,” he says. “We should expect the same with vaccines.”
Some of the enzymes and reagents used have only a few manufacturers, but any item in the supply chain is vulnerable, no matter how prosaic. Dasburg, the former AstraZeneca VP, recalls that during the H5N1 bird flu panic of 2008 the US government requested “as much flu vaccine as you could make”. But they were unable to source a plastic top for their nasal inhaler model. “We could make millions of doses, but had nothing to put it in,” he says.
Kis and his colleagues have been working non-stop since the crisis began trying to map out the tangled international network of services and suppliers that are behind the vaccine projects supported by the UK government, calling suppliers and mapping out potential breaks in the chain. Maria Papathanasiou, a lecturer in chemical engineering also working on the project, says it is “very hard to predict the global capacity”, and that it hasn’t really been done before. No-one ever expected the need to make the same vaccine, for everyone, all at once.
It’s this kind of planning that could make the difference between an all-out fight for enzymes, similar to countries seizing PPE shipments in the early days of the pandemic, and a smooth ramp-up to billions of doses around the world. “We already know we could make enough vaccine for the UK,” Shattock says. “That’s different than providing billions of doses worldwide. We don’t want to wait years.”
The scientists behind mRNA vaccines have already shown they can cut the time required to develop a vaccine. If they prove effective, they promise an equivalent revolution in production. But between these stages is the all-important testing period that will ultimately determine their success. We are entering a long summer season of clinical trials.
Moderna entered phase three trials in July, and the Imperial group started phase two around the same time. We will likely seize on any and all early results – Moderna’s share price nearly doubled in May when it was approved for phase two trials, and released positive results from just eight patients in its phase one trial – but we won’t know anything solid about these vaccines’ efficacy until at least the autumn.
After the constant buzz and promise of early development, doubts begin to seep in. Even meticulously crafted traditional vaccines fail all the time. In a sense, the expectation with vaccines is failure. Everyone from pharma execs to Shattock and his team offered me some version of this warning: about 90 per cent of vaccines fail in clinical trials. “Lots of promising things go into clinical trials and nothing comes out the other side,” Stonehouse says.
But there are an equal number of reasons to keep hope. The history of science is full of overlooked discoveries transforming the world after years on the sidelines.
Since the Covid-19 crisis began, we have had to confront some of the messy realities of science. Previously, we rarely processed the incomplete or contradictory results of science done in real time; we were accustomed to hearing mainly about surety and success. That all changed. As clinical trials progress, we will see something similar with vaccines. Some candidates will fail. And we’re used to viewing vaccines being a binary – you’re either protected or you aren’t – which has led to the idea of a coronavirus vaccine being like a reset switch or a time machine, allowing us to return to normal life. But a vaccine is just as likely to provide partial protection, or work better in some people than others.
“There’s an expectation a vaccine will stop this thing totally,” says Gellin, of the Sabin Institute. “When you look at vaccines overall, they don’t always work that way. It could be partially effective, then we need to figure out why, improve it, do it again. It’s likely an iterative improvement. The expectation is with all the vaccines in the race, one will get there – a silver bullet. But that may not be the case.”
“There’s a PR war right now about ‘my vaccine is better than yours,’ based on no substance.” says Shattock. Everyone is impatient to see trial results, and the data, he says, will speak for itself. “This is the just the first shot we get into humans – we suspect we will be able to improve on that. Nobody is going to stop working.”
Updated 17.08.20, 10:50 GMT: Drew Weissman’s position has been clarified
This article was originally published by WIRED UK
