For two decades, a new vaccine technology has been slowly approaching prime time. Now, can it stop a pandemic?
Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.
For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.
“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.
Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.
An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.
Lidia Oostvogels“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.
Oostvogels is the infectious disease chief for CureVac. Alongside Moderna, the German biotech has become one of the most high-profile companies working on a new kind of vaccines made out of mRNA, the same code our cells use to make proteins. It was a bold approach, conceived decades ago in labs on both sides of the Atlantic, and in recent years researchers have shown the first data suggesting it can work in humans.
As much of Big Pharma sat out the early days of the epidemic, CureVac and Moderna rose to the center of an international effort to build a vaccine that could stop a virus that’s now infected more than 70,000 people and killed more than 1,700. They were two of the four efforts backed by the Coalition for Epidemic Preparedness Initiative, a global fund launched three years ago to prevent a pandemic, and they raced to develop a vaccine faster than anyone had before.
“The promise, the potential of messenger RNA is very exciting,” CEPI’s programs and technology R&D chief Nick Jackson told Endpoints.
But experts, including Jackson, caution the tech hasn’t yet been proven. In fact, if the Covid-19 outbreak reaches the pandemic stage — and the future is very much still up in the air — our best hope of inoculation will likely rest with a technology that has only ever been tested in a few hundred healthy volunteers. If Covid-19 peters out like SARS and MERS, then Fauci will have had his test run; he’ll know if the world and this new science can respond.
“These technologies have not been put through Phase III,” GlaxoSmithKline CMO Thomas Breuing told Endpoints. “I have great hopes, I think it will revolutionize how vaccines are produced in the future, but it’s still early.”
The first vaccines were crude things; folk medicines strapped to the engine of an industrial revolution. For centuries, mothers rubbed smallpox into the arms of their kids to inoculate them. An English doctor learned what farmers knew, that milkmaids didn’t get smallpox, and tried injecting cowpox into kids instead of the human version. American Home Products, later known as Wyeth, eventually used a factory to mass-produce his serum. The last US outbreak was in 1902.
Advancement came rapidly. Louis Pasteur traced infections to viruses and bacteria and showed how those microbes could be attenuated, or weakened, and then injected into humans to prevent an infection: Soon rabies, anthrax and measles could be stopped. Later scientists learned how to give patients just a few parts of a microbe, rather than a living one, and have the body still build an immune defense. Typhoid, bubonic plague and, most famously, polio were newly preventable.
And then at some point in the latter half of the 20th century, something changed. Development, at least in how vaccines were built, halted.
Kizzmekia Corbett“The general way we make vaccines has not changed in decades,” Kizzmekia Corbett, the scientific lead at the NIH’s vaccine lab, told Endpoints.
It’s not that researchers stopped discovering new ways of preventing infection. GSK poured millions into virus-like particles — a near-replica of a virus but without genetic code — and J&J spent heavily on adenoviruses, a benign microbe that can be engineered to carry proteins from the dangerous one. But few of the vaccine candidates made it through the clinic.
“I’m not actually sure why that is,” Harvard virologist and epidemiologist Michael Joseph Mina told Endpoints. “It could be because the vast majority of pathogens we want to vaccinate against, we already have vaccines for. They were years in the making but they now exist.”
That’s good news for humanity. By some estimates, people in developed countries live over 3 decades longer on average because of these vaccines. But it leaves questions as to how quickly countries could respond in emergency situations, such as a novel virus outbreak. The old methods take longer. It took researchers over a year to come up with vaccine candidates for the SARS outbreak in 2003. Even a new kind of the familiar flu virus, like the H1n1 outbreak in 2009, presents problems. Many companies still use eggs to grow the viruses needed for flu vaccines, an idea pioneered in the 1960s.
“First you have to get the eggs from chickens,” Mina said. “I mean, like, really?”
In the 1990s, as the earliest forms of gene sequencing and gene editing became feasible, a new idea emerged that promised to rethink the entire field: DNA vaccines. The earlier forms of vaccines tried to get virus proteins harmlessly into the body, where immune cells would then learn to recognize them and build defenses to neutralize them. But what if instead of viruses or virus proteins, you gave patients only the genetic code for the virus proteins? A person’s cells would take up the DNA and make the virus’s proteins, and then the body’s immune cells would see and build defenses against them, as they would from an attenuated virus. You could build vaccines faster and code for antigens that had been difficult to create by other means.
After a mouse paper in 1993, an NIH official said: “this technique has conceptually raised the field of vaccine research to another level.”
In the years since, however, those efforts have struggled to take off and may have been eclipsed by another technology. As recently as the last major global epidemic, Zika in 2016, DNA technology was at the center of the hunt for a vaccine. Now Moderna is working in lockstep with NIH and CureVac has its own funded effort. Their rise has caught the eye of Joseph Kim, CEO of Inovio, the DNA-based vaccine biotech that got a Zika candidate into the clinic in 2016 and is now developing a Covid-19 candidate.
“It’s a healthy competition,” Kim, whose company also got a $9 million grant from CEPI to build a Covid-19 vaccine, told Endpoints. “I don’t mind going mano a mano.”
Talented, nerdy and brash, Katalin Karikó liked to brag over the Xerox machine at the University of Pennsylvania Medical School offices. She boasted the way you might at a bar: About her work on RNA, for instance, a field still in infancy. Or about her daughter, who would become a two-time Gold Medal-winning Olympic rower.
Origin stories are dangerous in science. Few breakthroughs are as we remember: Edison didn’t really invent the light bulb and even Darwin had his predecessors. Ideas swell on a continuum, not in steps. But if mRNA vaccines began anywhere, they began in two places: In Germany in 2000, when Curevac was found, and two years before at Penn, when Karikó saw a new hire approaching as she copied a journal article: immunologist Drew Weissman.
“So I waited,” Karikó told Endpoints. Then she said to him, “You are a new guy, and you know what? I am Kate, I do RNA, I can do anything.”
Weissman was less intimidated than intrigued. The two talked. Karikó had done her early RNA work on HIV and AIDS at the height of the epidemic, when she and others toyed with the idea of using it to make “the perfect vaccine.” Weissman had come from Fauci’s NIH lab to Penn to build an antiviral program, but was struggling to use plasmids — little circles of DNA — to deliver them.
“So I said, ‘Oh I can make RNA,’ and he said, ‘OK I will try it,'” Karikó said. “So that’s how it happened.”
Drew Weissman and Katy Karikó
Click on the image to see the full-sized version
Messenger RNA often gets cast as a sidekick to DNA, a courier who takes orders from its nucleic cousin and delivers them for the rest of the cell to execute: Build this enzyme, that ribosome. But messenger RNA also contains the code for every protein, and in theory, you can use them, like DNA vaccines, to hijack the cell’s machinery and coax the body to make its own antigens.
The advantage of RNA, as the vaccine world has come around to, is that you can simply inject it into a cell and the ribosomes floating in the cytoplasm will pick it up and start making the proteins. DNA vaccines need to reach the nucleus, where DNA is housed.
It’s “a little bit more difficult from a molecular biology perspective compared to mRNA,” said CEPI’s Nick Jackson, who previously worked on vaccines for Sanofi and Pfizer.
There were many questions, though: Could you make an RNA that was stable? Could you deliver it without causing severe side effects that had long deterred others from trying to build such drugs? After a shot, would patients become immune to the RNA itself? CureVac launched in 2000 after a German scientist found injecting plain mRNA led tissues to express proteins, but for years it was the only major company in the space; big pharma showed little interest.
“It was a question of who was brave enough,” Phillip Sharp, an MIT professor who won the 2016 Nobel Prize in Medicine for his work on messenger RNA and co-founded Alnylam, told Endpoints. “To picture it and to organize it.”
Noubar Afeyan wasn’t trying to stop a pandemic when he started building a new company in 2010. The CEO of one of biotech’s largest VCs, then called Flagship Ventures, he was looking for a new way of making drugs. And, at a time when gene and cell therapy looked infeasible, he got a pitch from Derrick Rossi, a Harvard professor who worked on stem cells.
Derrick Rossi“We had done animal studies showing mRNA could express literally hundreds of proteins,” Rossi told Endpoints, describing his presentation.
The word “vaccine” never appeared in Rossi’s slides. He had a grand goal, explaining how, by expressing any protein, these nucleotides could be turned into a treatment for a vast array of illnesses. Afeyan bit.
“We were interested in patients being their own protein factories,” Afeyan told Endpoints.
(Rossi said his work was partially inspired by Karikó and Weissman’s, which Moderna would ultimately license for $74 million, although Afeyan said they didn’t use them.)
For three years of stealth mode, those who knew Rossi or his work speculated it was a stem cell company.
Then Moderna launched and it wasn’t brave; it was audacious. In a couple of years, it grew to the most valuable private biotech in the world. It had over 100 programs, was estimated to hold $1.5 billion in cash reserves, and spoke boldly about changing how drugs were made.
Messenger RNA isn’t only valuable for stopping infectious diseases like coronavirus. Its nimbleness and precision make it a good medium for potential HIV and universal flu vaccines, and the same principles could be applied to make antibody drugs. They were ideal forms of cancer vaccines — an old idea researchers had long struggled to make work — because you could sequence a patient’s tumor and edit a vaccine to build precise antigens against it. Rare genetic diseases in which patients are missing or have a mistyped gene could be treated by bits of mRNA that told the cells to build working copies of the protein.
CureVac also recognized the potential, as did BioNTech, which quietly launched with similar mRNA aims in 2008 and now employs Karikó as a senior vice president. (BioNTech quietly announced in an SEC filing that they were investigating Covid-19 vaccines, but declined to comment further on the effort.)
Those applications, though, took time. Moderna wasn’t sure how to administer multiple doses without the cells becoming resistant to RNA, or how to get it into all cell types. Skeptics questioned Moderna’s meteoric valuation as data failed to appear. They grew louder as some top scientists left the company.
It was also Flagship’s long-running strategy to develop tech step-by-step, Afeyan said.
“We mapped out the space and basically asked, what was the minimal thing we could do?” Afeyan, who serves as chairman of Moderna, said.
Noubar Afeyan, Flagship CEOWell-understood — just express enough of one protein — and requiring only a single dose, vaccines provided an easy test. In 2016, Moderna announced two vaccine trials. Then an opportunity arose in crisis. As the Zika virus outbreak continued to spread across South and Central America in 2016, Moderna began hunting for a vaccine. They teamed with the Bill & Melinda Gates Foundation and the NIH. The result was a vaccine candidate still going through trials and Moderna’s first peer-reviewed publication, the first in several swaths of data that have quieted criticism around the company.
“Moderna is the most serious biotech effort” for mRNA vaccines, Sharp said. “Basically when Moderna started was when mRNA vaccines became really discussed.”
It also helped lead to another NIH collaboration in 2017, on Middle East Respiratory Syndrome, a close cousin of Covid-19. CEPI was founded the same year. Then, this past September, Moderna released results from a Phase I trial on CMV. Four months later, CureVac announced results from its rabies trial.
There had been improvements since Moderna’s launch. Researchers knew better how to make a stable mRNA molecule and how to encase it in lipid nanoparticles — infinitesimally small balls of fat, to be slightly less than scientific — in order to get it into the cell. The field had broadly switched over to a form of the vaccine Karikó and Weissman helped pioneer that doesn’t cause an innate immune response to the molecule. Building personalized cancer vaccines had also given them experience in designing vaccines rapidly.
The studies were both small, designed to show safety more than efficacy, but they both pointed one way: An mRNA vaccine could work.
“The technology is there,” CureVac CEO Daniel Menichella told Endpoints.
mRNA vaccines are sophisticated things: Ancient biology tied to the 21st century’s biotech revolution. You begin with a virus’ genetic code, and if you have that, you can theoretically design a candidate in hours.
There are practical constraints on that, though, and as the new coronavirus swelled from a worrying story Tal Zaks read about in the Wall Street Journal to an infection that spilled through China and threatened to leak beyond, the NIH–Moderna response team found themselves in a waiting game. For over two years, they had worked on building a vaccine for MERS, a coronavirus that by all indications was quite similar to the new coronavirus. They could use it as a template, quickly swap in genetic code from the new virus, and send it off to Moderna for manufacturing. But first, they needed that code.
The novel coronavirus Covid-19 spread through February 18 (Edward Parker, The Vaccine Centre, London School of Hygiene & Tropical Medicine )
Click on the image to see the full-sized version
“There’s only so much you can do,” Kizzmekia Corbett, the NIH vaccine researcher, said. “The antigen was essentially designed in our head, all we needed was the sequence from China.”
The sequence appeared on a public database on January 11, around two weeks after the outbreak became public knowledge. It was a seminal date for labs watching the epidemic, including Moderna and CureVac.
The NIH lab took their MERS vaccine and removed the genetic code for the existing crown-like spike proteins that give coronaviruses their name. Coronaviruses use these proteins to infect cells, making them prominent targets for vaccines. They substituted in code for the novel coronavirus’s spike proteins and fired off the whole code in four days later in an email to Moderna.
In Massachusetts, Moderna started making both the vaccine and the research materials needed to study it, including the reagents researchers need to test if it’s causing an immune response, with aims of starting a clinical trial within 3 months of launching the program, a goal set by the NIH. They’ve planned for rapid development before, but never had to execute on this timescale.
“It’s a test of what we can do,” Zaks said.
Research on a potential vaccine began shortly after Lidia Oostvogels returned to CureVac’s headquarters in Tübingen, Germany, but the sequence meant they could begin designing their candidate. They ordered plasmid DNA, which is then induced to transcribe itself onto a strand of mRNA to create the vaccine. One researcher pulled out their own old MERS program from which they can build the virus. They worked more slowly than the NIH and Moderna.
“If everything goes really, very, very quickly and it’s like an easy one, it can be a question of a few weeks,” Oostvogels said of finding a vaccine candidate.
Early work done, researchers then gathered around a table to plan how fast they could respond: Good candidates would be in the lab soon, they concluded, and preclinical testing would then take a few months.
Daniel MenichellaThey presented the plan to CEPI, who agreed to back it in full. Menichella, though, had already given a go-ahead. Since then, CureVac has settled on two vaccine candidates. They are not disclosing how they work, although they said they have ways of attacking the coronavirus outside of the crown-like spike proteins. They have started producing both for clinical testing, aiming to start a trial on the one that works best in early summer, a couple of months after the NIH target but far faster than a normal vaccine timeline.
“You can always stop a program,” Menichella said. “But if it’s going to be like this one has worked out, you want to get yourselves on it as quickly as you can.”
Last year, CEPI gave CureVac a grant for up to $34 million for a sci-fi-esque idea. Because mRNA nucleotides can essentially be “printed,” researchers had flirted with the idea of building facilities across the globe that could rapidly churn out a vaccine in the event of a new virus, or with a disease like the flu, respond to different strains in different regions by printing a vaccine to match. CureVac wanted to build it.
It was a bold plan and although, like with Moderna and Fauci’s proposed test, the outbreak would pre-empt the technology, it got at one of the key benefits public health leaders see in mRNA.
“It’s probably going to be very inexpensive” to manufacture, Drew Weissman, the mRNA pioneer, told Endpoints. “The Bill and Melinda Gates Foundation said a global vaccine has to get down to $1.50. Few very vaccines get down to that.”
Moderna and CureVac have each unveiled new facilities in the last couple of years to make mRNA vaccines on an industrial scale for the first time. CureVac uses a form of mRNA that triggers an immune response and allows the company to give doses as small as 1/1,000,000 of a gram and for its plant, they say, to churn out up to 1 million doses every two weeks.
Moderna’s doses are much larger but they can still make their vaccines in lots of less than 10 liters — a fraction of the thousands of liters required to house the living cells that make attenuated and inactive viruses. A flu manufacturing facility would require a chicken farm.
“Moderna has manufacturing down to a science,” Corbett said.
But those facilities are built to build vaccines for millions of people. If the coronavirus spreads as far and for as long as some experts fear, it could require hundreds of millions or more vaccines. Fauci has been all but begging a Big Pharma to foot the bill, but it would be a massive one. The industry has built itself around the old model and Zaks said a new factory would have to be built.
In the meantime, the National Institutes of Health is relying on a company that has made batches of drugs for preclinical and Phase I success, and all but nothing beyond.
“We’ve done it on a small scale repeatedly. It’s quite different to actually scale up,” Zaks said. “We have yet to illustrate that and that requires time, and one of the things you don’t have in the setting of a pandemic is time.”
Michael Osterholm knows a thing or two about public health crises. He directs the Center for Infectious Disease Response and Prevention, ran the CDC for a part of the SARS outbreak and serves on both the National Science Advisory Board on Biosecurity and the World Economic Forum Working Group on Pandemics. And he sees more questions than answers in Moderna and CureVac’s programs.
Michael Osterholm“I congratulate them for taking on the effort, but I caution the world not to think this will have any impact on this particular situation,” Osterholm told Endpoints. “It’s not. These are years off.”
Fauci told Axios on Tuesday Covid-19 was “at the brink” of global pandemic. It may yet tail off come summer, but public health officials are growing increasingly concerned it could linger for years, becoming a regular infection, like the flu. And yet the questions that plagued vaccine development during the previous outbreaks are still present now, Osterholm said.
Chief among those is manufacturing, Osterholm said. Companies mobilized for past epidemics, such as SARS, only to be left footing the bill when the virus was contained and their drugs were useless. CEPI’s grants have curbed some of the burden for biotechs, but Fauci is still asking pharma companies to take a several-hundred million dollar risk in partnering on a vaccine.
It’s also not a given that the vaccines will work. Experts caution that mRNA, while promising, is largely untested. That first Zika vaccine from Moderna? It didn’t actually work once given to humans. They had to go back to the lab and make it stronger, and the results from the new vaccine are still forthcoming.
Asked how confident people should be an mRNA vaccine will work, given the early struggles the Zika vaccine faced, Zaks, though optimistic, said: “That’s a great question.”
CureVac’s Menichella points to their recent rabies trial as proof their technology can work, but their first rabies attempt was far from perfect: Only a fraction of patients responded and only when given with needle-free devices.
Peter Hotez“We have to see if it works or not,” Peter Hotez, a Baylor College of Medicine immunologist who designed a vaccine candidate for SARS and sees potential in mRNA, told Endpoints. “The problem is not a single nucleic acid vaccine has been approved.”
Hotez and most of the experts interviewed wish that governments would set up incentives to develop vaccines even after an epidemic. His SARS vaccine sat in a freezer for years, but had it gone through trials he said it could’ve been deployed when the outbreak began.
Corbett said if they had a general coronavirus vaccine approved, they could have quickly adjusted it to work on Covid-19 and launched a trial. Now Moderna and the NIH are pushing into a Phase I trial without full preclinical testing. It’s not unusual to shorten steps during outbreaks, but the timeline is particularly accelerated.
“It is risky,” Zaks said, but worth the risk.
The NIH hasn’t said its plan for what would happen after a Phase I, but CureVac and outside experts say the demands of preclinical testing and the time it takes to run the first and subsequent trials mean the best estimates are a vaccine available after 12 to 18 months — a vaccine, essentially not for an early outbreak but for a worst-case scenario.
“If this becomes the next pandemic, then we need be to able the protect the population,” Oostvogels said.
Still, Corbett sees hope in the speed with which they’ve been able to move thus far. A SARS vaccine took 20 months to reach people and a MERS vaccine took several years. Now, on the third coronavirus outbreak of the century, experts expect multiple vaccines to be in humans in less than than 6 months. If this is the test, they might be passing.
“I don’t think I could’ve hoped for anything better,” she said. “I wake up and think we’re living in a dream.”
