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Will the coronavirus help mRNA and DNA vaccines prove their worth?

As gene-based vaccines are being designed and tested at unprecedented speeds to fight COVID-19, scientists wonder if this will be the technology’s make-or-break moment.

by Ryan Cross
April 3, 2020 | A version of this story appeared in Volume 98, Issue 14


A photo of a lab at Translate Bio.
Credit: Translate Bio
Translate Bio is working with Sanofi Pasteur on an mRNA vaccine for COVID-19

Joseph Kim first heard about a mysterious pneumonia spreading in Wuhan, China, while watching the college bowl games on New Year’s Day. It was barely a blip in the news.

A week later, when Kim was back at work at Inovio Pharmaceuticals, where he is CEO, he learned that Chinese scientists had identified a never-before-seen coronavirus as the cause of the illness. It was a potentially frightening finding. From thousands of cataloged coronaviruses, only six were previously known to infect humans. Four of them just cause colds. The other two are responsible for much deadlier diseases: the infamous severe acute respiratory syndrome (SARS) and the even more lethal Middle East respiratory syndrome (MERS).

Kim was attuned to the gravity of the emerging outbreak. His company was wrapping up a small clinical trial to test the safety of a MERS vaccine—one of very few in development—and preparing for a larger study to begin in the Middle East this summer. The trials were funded by the Coalition for Epidemic Preparedness Innovations (CEPI), a nonprofit vaccine foundation founded in 2017 in the wake of the West Africa Ebola epidemic.

In early January, CEPI approached Kim with a proposition. “They wanted to see if we would be interested in developing a vaccine against this new coronavirus,” Kim says. “And of course we said yes.”

A photo of Inovio Pharmaceuticals CEO Joseph Kim.
Credit: Inovio Pharmaceuticals
Inovio Pharmaceuticals CEO Joseph Kim, whose company is developing a DNA vaccine for COVID-19

On Saturday, Jan. 11—Friday, Jan. 10, in the US—Chinese scientists posted the first sequences of the novel coronavirus’s RNA genome online. That same day, the Chinese state media agency reported the first known death caused by the coronavirus in Wuhan. Although they had no idea a pandemic was coming, Inovio’s scientists didn’t hesitate to download the viral sequences and use them to begin designing a DNA vaccine over the weekend.

“It took less than 3 hours to complete,” Kim says. “And we started the preclinical development process on day 1.” On April 6, Inovio began a clinical trial of its vaccine.

Amazingly, Inovio is trailing two other companies that already started testing their own vaccines in clinical trials in March. All hope their experimental vaccines will prevent COVID-19, the respiratory disease caused by the novel coronavirus, known as SARS-CoV-2. Moderna is studying its messenger RNA (mRNA) vaccine in the US, and CanSino Biologics has begun a trial of its adenoviral vector vaccine in China.

Moderna, CanSino, and Inovio were able to pull that off so quickly because they all specialize in gene-based vaccines. Unlike traditional vaccines, which require the laborious production of actual viruses or viral proteins, gene-based vaccines are made from DNA or mRNA. And companies like Inovio can design them on a computer in a matter of hours. “That’s the beauty of these vaccines,” Kim says.

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“They have been described as the vaccines of the future,” says Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center. “However, they have not yet been pressure tested,” he adds. There are no approved mRNA or DNA vaccines, and neither has ever been tested in a large-scale clinical trial for an infectious disease. “The COVID crisis is a great opportunity for those technologies to be pushed.”

More than a dozen drug companies developing gene-based vaccines have joined the blitzkrieg against the virus. They are moving new technologies from the computer into the clinic at an unprecedented rate, and normally distinct phases of a drug program—preclinical animal models, clinical testing, and manufacturing—are happening all at once. “It is like building an airplane while you are flying,” Kim says.

Biotech companies have been touting mRNA and DNA vaccines as the ideal technologies for rapidly fighting new pathogens, and the coronavirus pandemic may be their best chance yet to prove their worth. “It will be the first time that they will be tested in so many people,” says Wim Tiest, a former vaccine developer at GlaxoSmithKline who is now leading a COVID-19 program at the Belgian mRNA vaccine company eTheRNA Immunotherapies. The stakes have never been higher, because if these technologies fail, the whole world will be watching.

A pressure test for new vaccines

Biotech companies, pharma firms, universities, and government agencies are all rushing to start clinical trials of newly created gene-based vaccines for COVID-19.

Technology  |  Phase I clinical trial

Moderna and National Institutes of Health
mRNA vaccine | Began in March 2020

CanSino Biologics
Adenoviral vector vaccine | Began in March 2020

BioNTech, Shanghai Fosun Pharmaceutical, and Pfizer
mRNA vaccine | April 2020

Inovio Pharmaceuticals and Wistar Institute
DNA vaccine | April 2020

University of Oxford
Adenoviral vector vaccine | April 2020

mRNA vaccine | By early summer

Imperial College London
mRNA vaccine | Early summer

Arcturus Therapeutics and Duke-NUS Medical School
mRNA vaccine | Second half of 2020

Johnson & Johnson and Biomedical Advanced Research and Development Authority
Adenoviral vector vaccine | By September

Adenoviral vector vaccine | Q3 2020

Translate Bio and Sanofi Pasteur
mRNA vaccine | By end of 2020

eTheRNA Immunotherapies
mRNA vaccine | 2021

Karolinska Institute
DNA vaccine | 2021

University of Pennsylvania and Duke Human Vaccine Institute
mRNA vaccine | Unknown

Sources: Companies, interviews

Need for speed

Although vaccines have evolved over the past century, their goal has remained the same: trick the body into thinking it is infected with a virus, give the immune system time to safely study the decoy, and when the real deal strikes, hope that your immune cells took good notes. For many years, scientists used dead or weakened viruses for the job, grown in chicken eggs. Some vaccine makers have shifted to using vats of genetically engineered cells to produce particular viral proteins; this approach helps the immune system study the most important part of the virus.

Gene-based vaccines go a step further and simply encode a chosen viral protein in DNA or mRNA. These genetic instructions temporarily turn some of our cells into factories for making parts of viruses. Those decoys can’t infect us, but they offer our immune systems some target practice.

These experimental COVID-19 vaccines take three strategies for ultimately delivering a piece of genetic code—either mRNA or DNA—that tells cells to start making viral proteins. Inovio and its research partner, the Wistar Institute, are outspoken proponents of DNA vaccines, in which circular pieces of DNA are shuttled into cells. Moderna is the most advanced of at least 10 teams making mRNA vaccines, which are typically injections of mRNA-stuffed lipid nanoparticles. And CanSino is at the front of a pack of several groups developing adenoviral vector vaccines, which use a common cold virus to shuttle DNA into cells.

Although these technologies are experimental, none are exactly new. Scientists have been tinkering with DNA vaccines, mRNA vaccines, and adenoviral vector vaccines for decades, but they were plagued with challenges. Finding ways to physically get genetic material into cells was one problem. Inovio overcame this by building an injection and electroporation device. And mRNA companies are refining lipid nanoparticles to shuttle the bulky mRNA molecules into cells. Another issue for mRNA vaccines was the molecules’ inherent instability, solved by making chemical modifications to the mRNA bases. Some of the first adenoviruses used were toxic in humans, and scientists have found safer viruses to use for adenoviral vector vaccines.

Now, after years of improvements, gene-based vaccine developers say their technology is ready for prime time. Proponents of the technology have long said that once they found a process for designing and making a DNA or mRNA vaccine, it should be relatively straightforward, and quicker, to make those kinds of vaccines over and over again. For each new vaccine, the manufacturing process remains the same. All that changes is the genetic sequence. The principle applies to adenoviral vectors too, in which different DNA sequences can be inserted into the same adenovirus shell.

Inovio has put theory into practice. It got its first taste of epidemic-speed vaccine development during the 2014 Ebola outbreak, taking 18 months to design a vaccine and administer it to the first human in a clinical trial. It cut that design-to-dose time down to 9 months during the MERS epidemic and 7 months during the Zika epidemic. “All of those experiences made us a lot better,” Kim says. “You could say those were the spring training.”

None of those vaccines have been approved yet. When the Ebola and Zika epidemics—thankfully—sputtered out, the funding waned, and so did Inovio’s programs. It’s a familiar story for vaccine developers and one of the reasons that CEPI was founded. But Inovio’s MERS program, which is now funded by CEPI, helped accelerate the company’s SARS-COV-2 vaccine.

The genetic instructions in CanSino’s, Inovio’s, and Moderna’s vaccines all teach cells how to make coronavirus spike proteins—the characteristic knobs that project from the virus’s surface. These spikes bind to particular proteins on the surfaces of human cells, initiating their infiltration. During the SARS and MERS epidemics, scientists found that people who recovered from the viruses had made antibodies targeting the viral spike proteins.

You will be able to really see how well these platforms can perform under the heavy pressure of a pandemic.
Joseph Kim, CEO of Inovio Pharmaceuticals

Inovio was able to quickly identify the SARS-CoV-2 spike protein gene and use that as the starting point for its DNA vaccine design.

Moderna also benefited from experience working on MERS, for which it had an ongoing vaccine collaboration with the US National Institutes of Health (NIH). By Feb. 7, Moderna had manufactured, filled, and finished the first vials of the vaccine for human testing. That night, the company started its quality-control and sterility testing of the lot. On March 2, the US Food and Drug Administration gave Moderna and the NIH, its clinical partner, a green light to begin its Phase I study in humans. Two weeks later, on March 16, a volunteer in Seattle received the first shot.

“Our ability to respond quickly to this pandemic is directly related to the work that was done for prior pandemics, particularly SARS and MERS,” Beth Israel’s Barouch says. “Everything from basic science to clinical science is progressing at a pace faster than ever before.”

In addition to working on DNA and mRNA vaccines, Barouch is collaborating with Johnson & Johnson and the US Biomedical Advanced Research and Development Authority (BARDA) to develop adenoviral vector vaccines that will be ready for clinical testing by September. Although J&J has developed experimental vaccines for other viral diseases, including Ebola, HIV, and Zika, with this technology, none of them are approved yet. CanSino’s Ebola vaccine is the only approved adenoviral vector vaccine, but even that comes with the caveat that China’s FDA, now known as the National Medical Products Administration, granted approval after a Phase II study rather than after the larger Phase III study typically required.


Companies are putting vaccines based on newer technologies into human tests at an unprecedented speed, but even in the best-case scenario, in which they are safe and clearly effective, they still won’t be widely available for at least a year—likely longer.

Citing “significant technological hurdles” and “historical precedent,” drug industry analysts at Mizuho Securities concluded at the end of March that expectations for a commercial COVID-19 vaccine in 18 months are “overly optimistic.”

One significant hurdle is the lack of data on how well these new technologies work. DNA and mRNA vaccines have been tested in a minuscule number of people compared with more traditional approaches, which are given to hundreds of millions of people every year. Inovio says that more than 2,000 people have received its experimental DNA vaccines, and Moderna has tested its mRNA therapies and vaccines in more than 1,000 individuals.

And some of the variables affecting the vaccines’ outcomes are out of companies’ control, such as how long the pandemic lasts. If it ends before Phase III clinical trials are completed, a commercial product may never materialize. The speed at which companies are moving and the corners that regulatory agencies are letting drug companies cut suggest a serious effort to avoid that outcome.

The coronavirus is fostering a blurry overlap of normally distinct stages of drug discovery and development. A virtual meeting in March helmed by the US FDA and the European Medicines Agency concluded that during the pandemic, companies will not have to prove that their vaccines work in animals before beginning human studies. Moderna, for example, began its preclinical animal studies while its vaccine was being shipped to the NIH, which is running the clinical trial. Other companies may follow suit.

“We would be interested in doing that,” says Ronald Renaud, CEO of Translate Bio, which is developing an mRNA vaccine with Sanofi Pasteur. “For a pandemic situation, it is much different than it is for a nonpandemic development, so we are in an uncharted territory here.”

Moderna plans to test its mRNA vaccine in 45 healthy volunteers in its Phase I trial, underway in Seattle and Atlanta. Moderna CEO Stéphane Bancel recently said the firm expects to have data on the vaccine’s safety this spring and immunogenicity data—which would determine whether antibodies in the blood samples from the volunteers actually neutralize the virus—by early summer.


Immunogenicity data are an early sign of whether the vaccine is working, but Moderna is not waiting before planning its next steps. In a webinar hosted by MIT Sloan School of Management professor Andrew Lo on April 1, Bancel said that Moderna is already manufacturing mRNA for vaccines in its potential Phase II study, which could begin enrolling hundreds of people this spring, as well as its potential Phase III study, which could enroll thousands of people as early as late summer or early fall. In a US Securities and Exchange Commission filing the week before, Bancel also indicated that Moderna may request special permission to give people like doctors and nurses access to its vaccine this fall, before a formal approval.

It’s an audacious plan for a company—and technology—that has yet to put a drug on the market.

“I really hope that Moderna’s vaccine works very well, because if it doesn’t, it will be a disaster for mRNA vaccines,” says Norbert Pardi, who is developing an mRNA vaccine for SARS-CoV-2 at the University of Pennsylvania. “A great success would be very good for the whole field.”

It is the greatest demand for a pharmaceutical product ever, way more demand than the iPhone
Joseph Payne, CEO of Arcturus Therapeutics

Growing pains

If any of the DNA or mRNA vaccines are successful, their makers will face a new challenge: manufacturing massive quantities of them.

Makers of both technologies insist that their products are easier to make than traditional vaccines. Inovio produces DNA plasmids in vats of rapidly dividing bacteria, a standard biofermentation process. It isolates and purifies the DNA before using it in a vaccine. mRNA vaccine companies use a cell-free, enzymatic reaction to make their mRNA, which is then encapsulated in a lipid nanoparticle.

All groups are banking on government or nonprofit agencies to fund massive manufacturing scale-ups if their vaccines prove to be effective. BARDA has already committed to help with Moderna’s manufacturing in Phase II and III studies, and the US Department of Defense is funding $11.9 million worth of manufacturing for Inovio’s upcoming trials. J&J and BARDA together are committing more than $1 billion to develop the pharma firm’s adenoviral vector vaccine.

No company currently has the capacity to make enough vaccine for the entire US, let alone the world. That’s one reason why some smaller mRNA vaccine companies, like Arcturus Therapeutics, aren’t worried about being the first to have a vaccine.

“There are billions of people that would like access to a vaccine. It is the greatest demand for a pharmaceutical product ever, way more demand than the iPhone,” says Joseph Payne, CEO of Arcturus, a company with a grant to develop mRNA vaccines for Singapore, a country of about 5.8 million people. “Even if we all succeed, it will be very challenging to satisfy the demand in the near term.”

Beyond the practical challenges of making these new vaccines, gene-based vaccines carry the same risks as all the other vaccines. There’s a rare, but real, chance that a vaccine can actually boost a viral infection rather than prevent it. And although SARS-CoV-2 has mutated relatively slowly so far—especially compared with other RNA viruses like HIV and influenza—there’s always a possibility that an effective vaccine could suddenly be rendered useless if the virus evolves in just the right way.

Yet despite the challenges, several companies see a silver lining in the pandemic: an opportunity to test their therapies in the clinic, and potentially put them on the market, far faster than they would have otherwise. “You will be able to really see how well these platforms can perform under the heavy pressure of a pandemic,” Kim says. “So for us, this is a time to shine.”


This story was updated on April 6, 2020, to correct the attribution in the pull quote. Arcturus CEO Joseph Payne, not Translate Bio CEO Ron Renaud, said, "It is the greatest demand for a pharmaceutical product ever, way more demand than the iPhone."

This story was revised on April 9, 2020, for clarity and to add information on the start of Inovio's clinical study.


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