Elegant but unproven, RNA experiments leap to the front in coronavirus vaccine race - will they work

London: In the global race to beat back the coronavirus pandemic, scientists in Britain, Germany, China and the United States are pushing to develop, and possibly manufacture, millions of doses of vaccine in a completely new way.

This promising - but unproven - new generation of vaccine technologies is based on deploying a tiny snip of genetic code called messenger RNA to trigger the immune system. It has never before been approved for use.

But almost overnight, these cutting-edge RNA vaccine efforts have leaped forward as top candidates to fight covid-19. Some developers plan to have tens of millions of doses ready by the end of the year.

Elegant in theory, efficacious in the laboratory but untested in the real world, the possible RNA vaccines are especially attractive because they might be cheaper, easier and faster to manufacture on a massive scale - at least one team boasts it could partner with producers in developing countries to provide millions of vials for as little as $5 a pop.

More than 150 possible vaccines are now being developed by multinational pharmaceutical companies, academic groups and government laboratories around the world, many using traditional protocols used to make flu and other vaccines for decades.

At least 17 teams are now testing their potential vaccines in humans - and at least five of these are betting on RNA vaccines.

The RNA group has been among the first out of the gate because they can be rapidly designed on computers, using just the genetic sequence of the coronavirus that was shared online in early January.

The stakes, and risks, are enormous.

"This is the greatest science experiment in vaccinology that's ever been done," said Andrew Ward, a structural biologist at the Scripps Research Institutein La Jolla, Calif. "It's literally testing all the different technologies, and it's going to be cool to see how this all shakes out."

The RNA vaccines under study come from a small laboratory at Imperial College London, from the People's Liberation Army Academy of Military Sciences in China, from three large pharmaceutical companies - Pfizer, Moderna and CureVac - and their partners.

They're competing alongside groups pursing a slew of other methods, including the use of inactivated or killed virus or bits of the virus - a traditional strategy used against seasonal flu and other pathogens. Others harness harmless viruses to ferry distinctive pieces of the coronavirus machinery into cells.

Though never deployed in humans outside of clinical trials, the RNA research is being backed by hundreds of millions of dollars in investment, fueled by the urgency to crack the covid code. Each team is seeking the prize of being first to a vaccine, while guaranteeing their own populations will get early access.

It's a high-wire, high-price gamble on 21st century, computer-aided medicine.

Among the first to begin human trials is a self-amplifying RNA vaccine developed by the British professor Robin Shattock, 57, who in his college days, at North East Surrey College of Technology, wasn't very good at math or science and thought maybe he'd like to be a rock star instead.

Within days of the virus emerging in Wuhan, China, and the genetic sequence of the coronavirus being published, Shattock and his small team at Imperial College London went to work.

In January, February and March, Shattock couldn't get his telephone calls answered by top British officials. He spent days of precious lab time applying and cajoling for funding to move his vaccine forward, allies said.

Then Britain's Health Secretary, Matt Hancock, decided to back Shattock and his vaccine, and $50 million poured in.

In the past week, at an anonymous clinic in west London that cannot be named for security reasons, the first nine volunteers got a jab from the Imperial College vaccine.

"They seem to have responded well," Shattock said.

Another 300 volunteers will receive the dose over the summer. Imperial College hopes to launch a 6,000-person trial in October.

"We think that just around the corner there will be a sea change in the way that vaccines are developed and manufactured," Shattock told The Washington Post. "I think we'rejust on the cusp of that."

If all goes well, a U.S. trial of the first potential RNA vaccine will enter the crucial third phase to measure how well it protects against infection and sickness this month. It's the gold standard of double-blind controlled studies involving thousands of volunteers in multiple countries. half get the candidate vaccine and half get a placebo.

All vaccines share a common aim: to teach the immune system to recognize and neutralize the coronavirus. Newer approaches use genetic material such as RNA or DNA to turn the body's own cells into miniature vaccine factories.

Some of the possible vaccines are breaking speed records.

Scientists were able to use the genetic sequence shared by researchers in China on Jan. 10 to design possible vaccines on a computer before the coronavirus causing a mysterious pneumonia even had a name.

The Imperial College researchers took just two weeks to identify the bit of genetic material they wanted to deploy to attempt to trigger an immune response.

The leading American effort, an RNA vaccine being developed by the Massachusetts biotechnology company Moderna, went from a genetic sequence on a computer screen to a shot in the arm of a person in an unprecedented 66 days.

Leaders of Inovio Pharmaceuticals, a Pennsylvania company working on a possible vaccine that uses DNA, have said it took three hours to design.

The idea of deploying RNA to fight infectious disease and cancer has tantalized scientists for years. But they have yet to move beyond the experimental stage.

Each vaccine technology has advantages and trade-offs - the speed and flexibility of the RNA platform balanced against the lack of experience in using them in large human populations.

Vaccines that might take longer to make could offer a stronger immune response.

The usefulness of some vaccines could be limited in the developing world if they require extensive refrigeration. Questions remain about how long any of the potential vaccines might be effective, and whether people might need booster shots.

"No one thinks there's going to be a single silver bullet," said Deborah Fuller, a microbiologist at the University of Washington.

That's because multiple treatments might be needed to meet the number of doses required around the world - and it's likely that vaccines will have different profiles.

The fastest to be developed might not be the most effective. One might work better in older people than younger, or vice versa.

"As a collective team they're going to be able to battle this pandemic together," Fuller said.

The RNA technology now being tested in human volunteers is promising, but questions remain about safety, whether it works and how long it might last.

"I don't think we know," said Peter Jay Hotez, dean of National School of Tropical Medicine at Baylor College of Medicine. "It's a brand new technology, and we've not really had large numbers of (vaccinated) people walking around for years."

Pharmaceutical giant Pfizer and the German firm BioNTech are testing four RNA vaccine candidates in a clinical trial. The Pfizer candidate uses a modified strand of RNA that codes for the spike found protein on the surface of the coronavirus, with a tweak to its genetic code to increase its ability to trigger an immune response.

Such modifications "try to get the right balance between stimulating the innate immune response, but not stimulating it so much you shut down the RNA's ability" to create the spike protein, said William Gruber, senior vice president of Pfizer Vaccine Clinical Research.

The Pfizer results, shared in a preprint article that has not been peer-reviewed, showed that an RNA-based formula was safe at low doses and triggered a stronger immune reaction in people who were vaccinated than in those recovering from a natural infection. Pfizer plans to test at least one of its possible RNA vaccines in a 30,000-person clinical trial by the end of the July, pending regulatory approval.

The hoped-for RNAvaccines being tested by some of the groups means a smaller dose could potentially be extremely potent - which could mean people might need only a single dose.

The technology could also decrease the amount of genetic material needed in the future vaccine, making manufacturing more efficient.

Shattock said one liter of his RNA reaction - about four cups' worth - can make at least 2 million doses of possible vaccine.Other vaccine models require thousands of liters to make the same number of doses.

One of Pfizer's candidates is a self-amplifying RNA vaccine.

"Once you inject it into a human being, it gets taken up by a cell and it's like its own factory - it amplifies itself in the cell," Kathrin Jansen, head of vaccine research and development at Pfizer, said in May, when human trials began. "One copy goes in and the factory starts kicking in and making more and more copies."

If the self-amplifying RNA vaccine is successful, Jansen said, it could allow the company to use a much smaller dose - and radically change the company's predictions about how much vaccine it could manufacture next year.

Pfizer has not chosen which of its four vaccines it will scale up, but has said that next year it will manufacture 1.2 billion doses.