(Reuters) - In the race to develop a vaccine to end the COVID-19 pandemic, governments, charities and Big Pharma firms are sinking billions of dollars into bets with extraordinarily low odds of success.

FILE PHOTO: Small bottles labeled with a "Vaccine COVID-19" sticker and a medical syringe are seen in this illustration taken taken April 10, 2020. REUTERS/Dado Ruvic/Illustration

They’re fast-tracking the testing and regulatory review of vaccines with no guarantee they will prove effective. They’re building and re-tooling plants for vaccines with slim chances of being approved. They’re placing orders for vaccines that, in the end, are unlikely to be produced.

It’s the new pandemic paradigm, focused on speed and fraught with risks.

“The crisis in the world is so big that each of us will have to take maximum risk now to put this disease to a stop," said Paul Stoffels, chief scientific officer at Johnson & Johnson JNJ.N, which has partnered with the U.S. government on a $1 billion investment to speed development and production of its still-unproven vaccine. “If it fails,” Stoffels told Reuters, “it will be bad.”

Historically, just 6% of vaccine candidates end up making it to market, often after a years-long process that doesn’t draw big investments until testing shows a product is likely to work. But the traditional rules of drug and vaccine development are being tossed aside in the face of a virus that has infected 2.7 million people, killed more than 192,000 and devastated the global economy. With COVID-19, the goal is to have a vaccine identified, tested and available on a scale of hundreds of millions of doses in just 12 to 18 months.

Drug companies and the governments and investors that finance them are boosting their “at-risk” spending in unprecedented ways. The overriding consensus among more than 30 drug company executives, government health officials and pandemic-response experts interviewed by Reuters is that the risks are necessary to ensure not only that a vaccine for the new coronavirus is developed quickly, but that it is ready to distribute as soon as it’s approved.

Investments from governments, global health groups and philanthropies have been aimed primarily at the most promising of the more than 100 vaccine candidates in development worldwide. But only a handful of those have advanced to human trials, the real indicator of safety and efficacy - and the stage where most vaccines wash out.

Even among the more encouraging prospects, very few are likely to succeed. It’s possible more than one will work; it’s possible none will.

For companies in the race, there are some likely benefits: It's a proving ground for vaccine technologies and a chance to burnish reputations and boost shares. While some large companies, including Johnson & Johnson and GlaxoSmithKline Plc GSK.L, have said they plan to make the vaccine available at cost - at least at first - they may reap profits down the road if seasonal vaccination is needed and countries invest in stockpiles.

But finding a vaccine that works does little good without the ability to produce and distribute it. That means building manufacturing plants now.

“We want to make investments up front, at risk, even before we know the vaccines work, to be able to (immediately) manufacture them at a scale of tens or hundreds of millions of doses,” said Richard Hatchett, a physician who managed U.S. pandemic flu policy under former President George W. Bush and returned to advise the Obama White House during the 2009 swine flu pandemic.

Hatchett now heads the Coalition for Epidemic Preparedness Innovations (CEPI), a vaccine-development consortium supported by private donors as well as the United Kingdom, Canada, Belgium, Norway, Switzerland, Germany and the Netherlands. The organization has raised more than $915 million of the $2 billion it anticipates spending to accelerate testing and build specialized production plants for at least three coronavirus vaccine candidates.

In the United States, the Biomedical Advanced Research and Development Authority (BARDA), a federal agency that funds disease-fighting technology, has announced investments of nearly $1 billion to support coronavirus vaccine development and the scale-up of manufacturing for promising candidates.

One underlying fear, shared by everyone Reuters interviewed, is that even if a vaccine does prove effective, there won’t be enough to go around.

Having reserves ready worldwide to immediately inoculate critical populations - health care workers, the elderly, people made vulnerable by medical conditions - would stamp out the pandemic faster and reignite economies, Hatchett said. The alternative, he said, is a replay of past pandemics, including the H1N1 influenza outbreak of 2009, with wealthy countries hoarding the vaccines.

If that happens, pandemic experts warn, infection hot spots will continue to pop up, each with the potential to create a new wave of illness.

FULL SPEED AHEAD

The scale of the coronavirus vaccine race has no historical parallels. CEPI has identified at least 115 ongoing vaccine initiatives worldwide. And the race is shattering norms of speed and safety in drug and vaccine development.

Some developers are running safety and efficacy trials in tandem, instead of sequentially, as is typical, and short-cutting traditional testing protocols. Others are working with regulators in multiple countries simultaneously, looking for the quickest path to market.

The resulting uncertainty makes it especially risky to invest in manufacturing facilities for a given candidate, since different types of vaccines can require very distinct production lines.

Many of the candidates attracting the most investment rely on proven vaccine approaches being adapted by Big Pharma companies with regulatory and production acumen. Some funders are gambling on smaller biotech companies and academic labs, which may have promising technologies but little to no experience getting a drug or vaccine approved and produced at scale.

BARDA, the U.S. R&D agency, is one of the biggest vaccine funders, with some $5 billion to spend. The agency plans to invest in five vaccine candidates, focusing mostly on projects from experienced drug makers.

“Each is coming with a lot of prior experience,” said Rick Bright, who until this month was BARDA’s director. “They all know how to scale up.”

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In one of its biggest bets, BARDA is pouring nearly $500 million into a J&J effort.

J&J’s coronavirus vaccine candidate uses a cold virus, rendered harmless, to deliver genes derived from the spiky, crown-shaped proteins on the surface of the new coronavirus, prompting an immune response.

J&J is using the same technology to develop vaccines for other viruses, including Ebola. While none has completed testing and won full U.S. approval, trials so far in tens of thousands of people have produced data showing the basic approach is safe, which could speed regulatory approval for the new coronavirus vaccine. But it’s far from a sure bet: Animal test data, due this summer, will give the first hint of the vaccine’s effectiveness and human trials will begin in September.

“By end of the year, we’ll know whether it protects humans,” said Stoffels, J&J’s chief science officer.

In China, CanSino Biologics Inc 6185.HK has vaccine technology similar to the one being used by J&J. CanSino is further along with its testing, having announced this month that its candidate had cleared initial safety trials in humans and was set to advance to the next stage.

Sanofi SA SASY.PA, the world’s largest vaccine maker, has attracted BARDA money for another proven approach, based on its approved Flublok flu shot. Sanofi uses insect cells instead of the traditional chicken eggs to grow the genetically altered virus proteins used to spur an immune response.

Not all the vaccine projects getting attention have a Big Pharma pedigree.

Moderna Inc MRNA.O, a biotech firm based in Cambridge, Massachusetts, was the first in the United States to begin human trials when it began testing its vaccine last month. Working with the U.S. National Institutes of Health, the company received seed money from CEPI, and this month, BARDA kicked in $483 million to support the vaccine’s development and help scale up manufacturing. That includes hiring 150 skilled workers to eventually produce vaccine around the clock.

Moderna’s vaccine uses genetic material called messenger RNA (mRNA) to instruct cells in the body to make specific coronavirus proteins that then produce an immune response.

No mRNA vaccine has ever been approved for public use, but the technology is drawing interest, in part because it makes a vaccine easier to design and produce in vast quantities.

“The end game is millions of doses," Tal Zaks, Moderna's chief medical officer, told Reuters. The company hopes to have an approved vaccine available as early as March 2021, and possibly before then for healthcare workers. German vaccine makers CureVac and BioNTech SE 22UAy.FBNTX.O, which is partnering with Pfizer Inc PFE.N, are preparing to begin trials with similar mRNA-based vaccine candidates. So is Lexington, Massachusetts-based Translate Bio Inc TBIO.O, which is working with Sanofi.

EXTRAORDINARY SHORTCUTS

Even for vaccine hopefuls already in human tests, it will be months before there’s conclusive evidence on safety and effectiveness - something funders are keenly aware of.

The rush has prompted scientists to consider previously unthinkable shortcuts.

Normally, vaccines would need to undergo clinical trials involving thousands of people before widespread inoculation is allowed. But after testing a prospective vaccine in a smaller group to ensure it is not toxic, Swiss researchers seek to “immunize a lot of the Swiss population in the next six months and then produce for a world market,” Dr Martin Bachmann, head of immunology at Inselspital, the University Hospital of Bern, said this week.

A spokesman for Swissmedic, the country’s drug regulator, said it was in contact with Bachmann’s group and would not allow trials until the agency is assured that safety risks are addressed.

The Swiss vaccine employs virus-like particles to provoke an immune response, an approach that theoretically is considered safer because it does not directly expose people to the actual coronavirus. So far, it has only been tested in mice.

Dr. Gregory Poland, a vaccine researcher at the Mayo Clinic in Rochester, Minnesota, is among those worried about the risks of injecting a large group of people with a vaccine that has only been through minimal testing in humans.

“I don’t see how this is possible,” he told Reuters, referring to Inselspital’s plan.

LESSONS UNLEARNED?

The war on COVID-19 is haunted by lessons from the fight against another virus a decade ago.

In the spring of 2009, the H1N1 swine flu virus emerged in the United States and Mexico and spread worldwide. Within weeks, the World Health Organization(WHO) declared it the first pandemic since 1968.

Wealthier governments that had provisional contracts with vaccine makers immediately exercised them, “effectively monopolizing the global vaccine supply,” according to Hatchett and numerous official reports. The U.S. alone ordered 250 million doses, and Australia, Brazil, France, Italy, New Zealand, Norway, Switzerland and Britain all had vaccine.

Under pressure from the WHO, those countries ultimately committed to share 10% of their stockpiles with poorer nations. But due to production and distribution snarls, only about 77 million doses were shipped – far less than needed – and only after the disease had peaked in many regions.

If an effective vaccine emerges for the new coronavirus, a replay is possible, experts in pandemic preparedness say. None of the global health authorities consulted by Reuters believes there will be sufficient supplies to satisfy the immediate demand. Governments will be under tremendous pressure to immunize their own citizenry and get life back to normal, so hoarding remains a serious risk.

Ronald St. John, a physician who has held government posts on infectious disease control in the United States and Canada, expects a similar scenario with vaccines.

“There is going to be a lot of self-interest in terms of the production,” he said.

BARDA explicitly gives preference to vaccine projects promising U.S. production capacity.

“We’re asking the American taxpayer to give a lot” to the vaccine effort, so it’s important to ensure U.S. access to any successful vaccine, said Bright, BARDA’s recent chief.

But he added that BARDA also is encouraging the companies it backs to build manufacturing capacity outside the United States, “so we can have a global supply all at once.”

Many governments are pouring money into vaccine initiatives with expectations that they will be first in line if a viable vaccine emerges.

Arcturus Therapeutics Holdings Inc ARCT.O, a San Diego biotech, is receiving up to $10 million from the Singapore government to develop its mRNA-based coronavirus vaccine candidate in partnership with the Duke-National University of Singapore Medical School. If the vaccine is approved, Singapore gets first access, said Arcturus CEO Joseph Payne. Everything after that, he said, goes to “whoever pays for it.”

“Arcturus is not responsible for the ethics of distribution - governments are - but in order for governments to get the vaccine, they need to pay for it,” Payne said. “The country that will win is the country that stockpiles multiple vaccines at risk.”

The company raised $80.5 million this week from a common stock public offering.

In China, a major global producer of vaccines, the government is backing several coronavirus vaccine projects, raising the prospect it will inoculate its 1.4 billion people first. One government-backed effort, by Sinovac Biotech Ltd. SVA.O, is already testing vaccine candidates in humans and awaiting initial data..

Sinovac got 60 million yuan ($8.4 million) in low-rate credit lines through a discount loan program supported by China’s central bank. Government officials quickly made land available for the company to build production plants, including a factory meant to produce up to 100 million doses a year of its coronavirus vaccine.

Sinovac would not discuss how much public money is being invested. The relevant government agencies declined requests for comment.

On Friday, the World Health Organization announced a “landmark collaboration” across the international community to raise $8 billion to accelerate the coronavirus vaccine development and ensure equitable access worldwide to any successful vaccine. Countries across Europe, Asia, Africa, the Middle East and the Americas announced their participation, but the United States and China, two of the world’s biggest pharma forces, did not.

“There will be no U.S. official participation,” a spokesman for the U.S. mission in Geneva told Reuters, adding that the U.S. supports “global cooperation to develop a vaccine.”

Broader questions about U.S. policy on international vaccine distribution are still under consideration within the Trump administration, according to a member of the White House coronavirus task force who spoke to Reuters on condition of anonymity. The official noted that the U.S. Department of State and the U.S. Agency for International Development are spending nearly $500 million to assist with the COVID-19 response internationally.

A WHO spokeswoman said Friday’s announcement was the beginning of a global collaboration and “we would welcome more countries coming on board.” China did not respond to a request for comment.

People involved in the global vaccine race told Reuters that the greatest incentive for countries to promise to share coronavirus vaccines may be the uncertainty around which ones will work.

Since no country can be sure the candidates it backs will prove successful, committing to sharing with other nations can help assure they’ll have an initial supply to inoculate health care workers and other critical populations.

“That’s enlightened self-interest, as well as a global public good,” said Jeremy Farrar, an infectious disease expert and director of the Wellcome Trust global health charity.