This coronavirus vaccine would be two breakthroughs in one

IIn January 2019, Robin Shattock, Head of the Department of Mucosal Infection and Immunity at Imperial College London, gave a presentation at the World Economic Forum in Davos in which he argued that in a world threatened by "Disease X" – a term that Used by the world health organization and epidemiologist to describe an unexpected and fast moving epidemic with no known treatment – we had to "completely rethink the way we make vaccines against outbreaks and pandemics".

In addition to clean water, vaccines are the public health advances that are shaping our increasingly dense, interconnected world. Still, vaccination deadlines are still measured in years or decades (a 2013 study found the average vaccine took 10.71 years from concept to completion). When an outbreak hits, the response is slow. You would have a situation where people would die and no way of getting a vaccine in a "reasonable time frame".

Shattock's group at Imperial is one of the few teams in the world working on an experimental type of vaccine called mRNA vaccines, in which simple synthetic messages written in genetic code trigger an immune response. These are theoretically faster to develop and cheaper to manufacture than traditional vaccines, and may be ready to respond to a threat in months rather than years.

When Shattock spoke, no one knew when the next pandemic would break out, and although there had been little pharmaceutical and government interest in mRNA vaccine technology, it was years away from being ready. "It didn't attract much attention back then," says Shattock. A year later, times have changed.

Covid-19 has proven Shattock's argument: The traditional way of making vaccines is not suitable for pandemic purposes. The coronavirus strategy pursued by most countries – a version of lockdown and social distancing under the dictates of smoothing the curve – was developed for pandemic flu in the mid-2000s and is only intended to bring an outbreak to manageable levels. The disease is unlikely to be eradicated. Only a vaccine can do that.

Bruce Gellin, former director of the US Department of Health's National Vaccine Program and currently at the Sabin Vaccine Institute, explains, "The idea was that you could crouch down for a vaccine to arrive." It takes about six months to get a vaccine against a new one Produce flu strain. In the case of an unknown disease, the timeline can extend to years. "We crouch and wait for a vaccine we can't make," he says.

In the midst of the global coronavirus pandemic, waiting the normal time for a vaccine seems unbearable. While this is relatively unproven – only a handful of mRNA vaccines have ever been included in clinical trials, and none have been used publicly – mRNA vaccines have been selected as candidates to solve the problem. Not just to stop the pandemic, but to do it quickly.

In January, Shattock said, he was not sure whether his laboratory could even get funding to work on coronavirus. Since then, laboratories working on mRNA vaccines have been inundated with public money and support: the UK government has donated £ 41 million to Shattock's team since April, and US company Moderna, which is the first to announce an mRNA vaccine candidate for coronavirus, was promised $ 483 million (£ 390 million) by 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 to test the vaccines.

Five mRNA vaccines for Covid-19 are already in clinical trials, including Imperial's, and at least 20 more are in development. "We basically had nothing in January," says Shattock. "It is amazing, unprecedented to have already taken human trials."

Charles Cooney, a professor of chemical engineering at MIT, says he has "never seen anything like it". The pandemic, he says, is an immense incentive to "advance new science".

If a successful coronavirus vaccine emerges from any of these laboratories in the next few months, it will be one of the great scientific achievements of our time, which will not only represent a victory over the current virus, but a real advance in the way we make vaccines.

Robin Shattock (left) and research fellow Leon McFarlane in the laboratory at Imperial College London

Imperial College London / Thomas Angus

T.The basic idea of ​​producing a new type of vaccine with mRNA is more than 30 years old and arose as a little-appreciated offshoot of the genomic revolution of the late 80s and 90s. At the time, scientists were studying human genome sequencing efforts and the ability to quickly and inexpensively synthesize DNA and RNA, the molecules that store and transport genetic information in our cells, and envisioned a new frontier in precision medicine, where they could program genetic messages and send them directly to the machinery of our body.

Traditionally, vaccines are made from either a killed or inactivated virus, or from recombinant protein. These show the body an entire virus or a piece of it for future detection. They trigger the production of antibodies which can then be activated when 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 parts but no function, like a deadly viper preserved in formaldehyde. Jeffrey Almond, former head of discovery research at Sanofi Pasteur and current Martin Fellow at Oxford University, explains: “Grow it in cells, kill it with formalin, put it in your arm. It's not the fancyest, but chewing gum works. "Recombinant protein uses only a single viral protein that was grown in a laboratory.

In both cases, growing viruses or proteins in vitro – in a laboratory – can be a delicate process, like making a complex machine in an unfamiliar factory. Optimizing and tinkering can take months. Almond recalls that it took four years for the viral protein used in the hepatitis B vaccine to be stably produced. For more than 20 years, scientists have been trying to optimize the growth of the HIV envelope protein.

Most researchers in the early genome era worked on DNA and attempted to cure genetic diseases by sending in a permanently healthy synthetic DNA copy of a gene that was defective from birth to replace it. The Hungarian biochemist Katalin Karikó was fascinated by messenger RNA (mRNA), which carries the messages encoded in DNA in our cells and lasts only a few hours or days. “You could program it, but it would be basically like a drug. The effect would wear off, ”she says.

The problem, however, has been that RNA made outside of the body can be deadly and upset the immune system, regardless of what message was attempted. Drew Weissman, Karikó's former supervisor at the University of Pennsylvania, recalls that she would bring him new mRNA for testing. "You would shoot 30 micrograms of RNA into a mouse and it would die," he says. That happened all the time; The mice that did not die were either sick or had no therapeutic effect. There was no way I could try it on humans.

Karikó solved the problem in 2004 after research showed that certain receptors in the immune system were sensitive to uridine, a molecule that serves as one of the “letters” of the genetic code of RNA. This was likely intended to capture viral RNA, but it also tagged their synthetic mRNA. She replaced uridine in the code with an analog, a molecule that would read the same thing, but the shape of which would not trigger the immune system. The trick worked, the mice were alive, and Karikó remembers thinking: "Now we can use it for anything."

The therapeutic potential was evident. What Karikó unlocked was the ability to send a simple RNA message to a cell instructing it to make the desired protein itself – and stop the laborious process of growing a protein or virus in the laboratory. "They're sending a message to the human body to make the vaccine right inside the person's body," explains John Tregoning, an immunologist at Imperial College.

Karikó, Weissman and colleagues published their results in 2005, but “people weren't interested,” she says.

"The field hasn't really opened up at all," says Weissman. "We spoke to anyone who would listen, but pharma doesn't really like early-stage research."

And so mRNA vaccines went slowly. Its most obvious use was in responding to pandemic threats quickly, but that wasn't really Big Pharma's business. Several pharmaceutical executives told me that historically global health and pandemics are "on the verge", which is a "shame". Almond says they made progress in Sanofi with a vaccine against the original Sars outbreak, but after a year "the disease was gone and there was no more phone call for the vaccine." There was simply no business case for breakouts. Pharmaceutical companies were interested in stable, long-term blockbusters, not the chaotic business of leading a new vaccine technology through the growing pain. It was up to academic researchers and small biotech companies to work out the details.

There have been some successes. Moderna was founded in Boston, Massachusetts in 2010 by a group of MIT and Harvard professors who recognized the commercial potential of mRNA and raised enough money for investors to get multiple candidates into trials. Karikó joined the German company BioNTech in 2014, which tests several mRNA drugs. Both companies primarily apply the technology to cancer, which is usually a more lucrative area.

Moderna and Weissman's laboratory separately developed potential Zika virus vaccines in 2017 – Moderna is currently in Phase 1 studies, which are in the timeline ahead of Covid studies – and international organizations interested in fighting epidemics, like the Coalition of Epidemic Preparedness Innovations (CEPI) and The Gates Foundation began funding mRNA vaccine projects. Around the same time, Big Pharma began licensing Pfizer and Sanofi through smaller developers of mRNA vaccines.

However, the field remained a minor issue due to the lack of substantial funding for traditional vaccine projects. Since Karikó's discovery in 2004, there have been only 12 clinical trials for mRNA vaccines against infectious diseases prior to Covid. In contrast, according to a current industry report, 171 vaccination attempts were completed in 2018 alone and over 600 in the last four years.

A centrifuge spins the vaccine solution into microneedle shapes

Jason Koxvold

F.With Covid-19, the traditional pharmaceutical industry didn't have an immediate answer. What was missing was what is known in the emerging disease vaccine world as a platform: a system into which you can plug any new viral gene target and quickly make a vaccine candidate.

Shattock's group at Imperial had a platform. "We worked on Marburg virus, rabies, Ebola, HIV, what you call it," says Paul McKay, a lead researcher in the lab. The idea has always been that their system could quickly adapt to any virus. When news broke from 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 a lot of plug-and-play with the genetic code, swap Ebola for coronavirus and off you go," he says.

Chinese researchers had already put the genetic sequence of the new coronavirus online. It took only a few days to choose a target – a gene for the spike protein known from SARS and MERS research to elicit an antibody response – and a week to order a synthetic copy of the gene, made by a German biotech company compiled from the Chinese sequence 7p per genetic letter.

There was another week of tinkering with the sequence in the lab before sending it off again, this time to Vancouver to a company that specializes in suspending mRNA in tiny globules of fat for use on its journey through the body shield. It was a potential cure that was spreading around the world at the same time as the virus itself. The compound vaccine was used in animal studies on February 13th. The first human trials began on June 15th in London.

But for those who work on site, the pace was set by Moderna. It took her vaccine just 42 days to go from a sequence of genes on a computer on January 18 to the first human-approved test dose on February 24. Anthony Fauci, director of the National Institute for Allergies and Infectious Diseases, called it a world record. "Nothing has ever happened that fast," he told the Wall Street Journal. Moderna's official clinical trial began on March 16. (Moderna was able to skip animal testing as their similar products had already been used in human studies for other diseases, slowing the work of other vaccine manufacturers by at least 6-8 weeks.)

While mRNA vaccines were the first to come out of the blocks, the field has expanded significantly since January. The WHO is currently pursuing over 200 vaccine candidates, 15 of which are already in clinical trials. Among the other front runners are several old-school killed or inactivated viral vaccines developed in China, as well as vaccines that transfer the coronavirus spike protein to a harmless carrier virus, another promising and relatively quick approach – Chinese biotech company CanSino Biologics and the Oxford University have vaccines based on this technology in studies. Virtually every lab or company that could potentially adapt its existing system for coronavirus has something in the works. "It's a combination of urgency and opportunism," says Almond. "Everyone wants to jump in and try out their approach."

Traditional recombinant protein vaccine makers are on a slower path – most expect to see them enrolled in clinical trials later this year or in 2021. However, with around 50 in development, they're still making up most of the effort. And they're not necessarily concerned that new technology will overtake them. "We want one of the newer vaccines to hit the market very quickly. In that case, we'd be pleasantly surprised," said Louis Falo, professor of medicine at the University of Pittsburgh. Falo and Andrea Gambotto are working on a protein-based vaccine, and while they're not yet in studies, they still like their chances.

Back in 2003, Gambotto published one of the original studies showing that the SARS spike protein elicits a strong immune response in monkeys and helps solidify it as a target for all subsequent coronaviruses. The group's new purified coronavirus spike protein is currently awaiting approval from the FDA to participate in studies. The lab has been busy turning coronaviruses on and off for almost 20 years and is confident that the established record of using proven vaccine technology will prevail.

“Production and validation take a little longer with protein. Everyone is a new animal, ”says Gambotto. But Falo says, “Most of the vaccines in the world are based on proteins. Many of the vaccines that are being talked about now don't have that track record. "

And being first isn't necessarily enough: a more effective or easier to make vaccine could overtake the front runner in the same way that Sabin's cheap, swallowable polio vaccine overtook Salk's original injectable vaccine in the 1960s.

The imperial group relies on the unique quality of their system. His vaccines use "self-amplifying RNA". The mRNA sequence contains instructions for a second protein, a tiny molecular machine that cells use to make the spike protein more efficiently. This should produce a stronger antibody response in the body and thus provide better immune protection. But it also means that vaccine doses could be lower – much lower. "Probably 100 to 150 times less material is needed," says Shattock.

“We tested up to 0.01 micrograms in mice and still got a great response. In humans, the highest dose we test is 1 microgram. Moderna makes 25 to 200, 250. They think these big shots are the best, ”explains McKay. It's not about scientific bragging rights, but about the cost of producing the vaccine, if any. "We can keep it simple 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 deep pocket countries line up to buy it, we can make vaccines available to low-income countries," Shattock says.

For vaccine professionals, this is a primary concern: once the praise for being there first has faded, the question will be how to get a vaccine to the billions of people who need it.

PhD postdoc Stephen Balmart working on the microneedle array at the University of Pittsburgh

Jason Koxvold

M.Manufacturing is the big second stage in the race for a coronavirus vaccine. If we only focus on laboratory science, we are envisioning a finish line way too early. "Make no mistake, everyone is always missing the manufacturing part," says Darren Dasburg, former vice president of global strategy at AstraZeneca, who is now retired. “In general, when you make a successful new molecule is great, but you have to make a hundred million of it. With Covid, maybe billions. "

Vaccine manufacturing has traditionally been more like an industrial process in a factory than a simple, clean laboratory. The world's most popular vaccine, the annual flu vaccine, is grown in fertilized hen's eggs obtained from huge laying facilities – "like big, sterile IKEAs," where the chickens eat irradiated food to prevent disease, Mike Austin, production manager at Cobra Biologics in Liverpool explains. "I think only Tesco processes more eggs here than the vaccine manufacturers," he says. The eggs are injected with live flu, which is later harvested to make the vaccine. By the time the process was automated in the early 2000s, all eggs were hand injected and harvested by hundreds of workers in each facility.

Making a flu vaccine is a particularly idiosyncratic process, but most traditional vaccines are something called "biologics," a virus or protein that needs to be grown in living cells – egg or otherwise – which is almost always difficult, messy, and special . "When you make a biologic, you generally need a new factory for each one," says Almond. "This is the problem with Covid. There is no factory for coronavirus. If it was a new flu it would be different. However, since it is a brand new type of virus, we are starting from scratch."

In theory, mRNA vaccines are faster and cheaper to make than a traditional vaccine – and potentially deliver hundreds of millions of doses at a fraction of the cost. But it has never been tried on the scale of coronavirus requirements. Like the University of Leeds, virologist Nicola Stonehouse explains, vaccinating the coronaviruses for essentially the entire world would "roughly double" the current global manufacturing capacity for traditional vaccines that has been built over decades.

The promise of mRNA vaccines is that they will reduce all of this to the size and scale of a regular laboratory. "You don't need huge campuses, facilities and factories. We can manufacture millions of doses in a small space," says Frank DeRosa, technical director of Translate Bio, a biotechnology company that is working with pharmaceutical giant Sanofi on a future mRNA vaccine against coronavirus is working.

However, there are only a handful of manufacturers in the world who can produce more than a few grams of medicinal RNA at a time. "It's hard," says DeRosa, who won't continue with the company's own process. "It is unstable, it not only rises cleanly to larger quantities." But any facility can produce impressive volumes. Translate is promoting the possibility of producing two 250g batches per month – between 50 and 200 million vaccines depending on the dose. Lonza Bioscience, a partnership with Moderna, promises one billion doses per year from just two manufacturing sites. In contrast, China's National Biotec Group recently announced that it has completed the world's largest vaccine factory for a traditional killed vaccine that can produce 100 million doses annually.

Zoltán Kis, a biochemist at Imperial College who has been working on optimizing vaccine production for potential pandemic situations since 2018, says that one billion doses per year from a single facility is theoretically possible. There are problems with very large volumes, but the basic process is the same one that scientists use every day in the lab – a "fairly simple reaction mixture" of enzymes that copy your genetic template many times, and then several purification steps to everything but remove the RNA for injection. The hard part, he explains, might be getting the reaction materials yourself. "We have already seen the difficulty with PPE and other medical supplies whose limits don't work," he says. "We should expect the same with vaccines."

Some of the enzymes and reagents used have few manufacturers, but every item in the supply chain is vulnerable, no matter how prosaic. Dasburg, the former vice president of AstraZeneca, recalls that during the 2008 H5N1 avian flu panic, the US government “requested as much flu vaccine as possible”. However, they were unable to get a plastic top for their nasal inhalation model. "We could make millions of cans, but we had nothing to do," he says.

Kis and his colleagues have been working tirelessly since the beginning of the crisis to identify the tangled international network of services and suppliers behind the UK government-sponsored vaccine projects, call suppliers and identify possible breaks in the chain. Maria Papathanasiou, a chemical engineering professor who is also working on the project, says it is "very difficult to predict global capacity" and that it has not really happened yet. Nobody ever expected that the same vaccine would have to be made for everyone at once.

This type of planning could mean the difference between an all-out battle for enzymes, similar to what happened in countries seizing PPE supplies in the early days of the pandemic, and a smooth surge to billions of doses around the world. "We already know we can make enough vaccine for the UK," says Shattock. "It's different from providing billions of cans around the world. We don't want to wait years."

Tina Sumpter, PhD student prof. dermatology, researches the skin's immune response

Jason Koxvold

T.The scientists behind mRNA vaccines have already shown that they can reduce the time it takes to develop a vaccine. If they prove effective, they promise an equivalent revolution in production. Between these phases, however, lies the crucial test phase, which ultimately determines its success. We are entering a long summer season of clinical trials.

Moderna entered the third phase in July, and the Imperial group began the second phase around the same time. We'll likely take advantage of any early results – Moderna's share price nearly doubled in May when it was approved for Phase 2 trials and released positive results from just eight patients in its Phase 1 trial – but we will nothing solid know about the effectiveness of these vaccines at least until autumn.

After the constant buzz and the promise of early development, doubts arise. Even carefully crafted traditional vaccines keep failing. In a sense, expectation is a failure with vaccines. Everyone from pharma managers to Shattock and his team offered me a version of that warning: About 90 percent of vaccines fail in clinical trials. "A lot of promising things go into clinical trials and nothing comes out on the other side," says Stonehouse.

However, there are just as many reasons to maintain hope. The history of science is full of overlooked discoveries that are marginally changing the world after years.

Since the beginning of the Covid-19 crisis, we have had to grapple with some of the chaotic realities of science. Until now, we have rarely processed the incomplete or contradicting results of science in real time. We were used to hearing mostly about safety and success. That has all changed. As the clinical trials progress, we'll see something similar with vaccines. Some candidates will fail. And we're used to thinking of vaccines as binary – they're either protected or not – which has made a coronavirus vaccine act like a reset switch or time machine, allowing us to get back to normal life. However, a vaccine is just as likely to provide partial protection or work better for some people than for others.

"There is an expectation that a vaccine will stop this thing completely," says Gellin of the Sabin Institute. "When you look at vaccines overall, they don't always work that way. It might be partially effective, then we need to figure out why, improve it, do it again. This is probably an iterative improvement. The expectation is that you will get with all vaccines gets there in the race – a silver bullet. But that may not be the case. "

"There is currently a no-substance based public relations war going on about 'My vaccine is better than yours'." says Shattock. Everyone is impatient to see the experimental results, and the data, he says, will speak for itself. “This is the first shot we get in humans – we suspect we can improve that. Nobody will stop working. "

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Stephen Buranyi is a London-based science writer and former researcher in immunology

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