Inside the science: Companies racing to develop a COVID-19 vaccine

A safe return to normal life without a widely available COVID-19 vaccine is looking more difficult.

Whichever company brings a vaccine to market first, it hopefully won’t be the last. Oxford University Pool via AP

Even as some states move to ease the lockdowns that have cost tens of millions of jobs and tipped the economy into recession, a safe return to normal life without a widely available COVID-19 vaccine is looking more difficult.

In South Korea and Germany, countries that were among the most effective at controlling initial outbreaks of COVID-19, rollbacks of lockdowns have been stymied by new flare-ups. As long as the virus lurks in people’s throats and on elevator panels, doorknobs, and subway-car poles, it is hard to see how the American economy can fully reopen.

More than 100 different programs are now under way seeking to develop a COVID-19 vaccine. Most will fail. Understanding which ones among the pack have the best shot at working well enough, and being distributed widely enough, to rein in the coronavirus is crucial to predicting what social and economic life could be like over the next few years.

As such, progress and setbacks in the vaccine race will drive the prices of stocks far beyond the pharmaceutical sector. The hair-trigger sensitivity of investors to COVID-19 developments was illustrated one day in April, when the S&P 500 climbed 2.7 per cent after Gilead Sciences announced that its antiviral remdesivir had benefited COVID-19 patients in a trial, even though the benefit was quite small. Over the coming year, news of steps toward a vaccine will move markets, perhaps even more than is rational.

For now, it is too early for investors to pick winners and losers among the programs. Only animal data is available so far, and only for some of the programs. What’s more, many of the major players, including GlaxoSmithKline, Johnson & Johnson, and AstraZeneca, say they will not seek a profit on any COVID-19 vaccine during the pandemic.

But the vaccine race does offer an opportunity for investors to make a call on the future of the global vaccine business.

Vaccines drive substantial, reliable revenue streams for companies like Sanofi, which sold $US2.1bn ($3.2bn) of flu vaccines alone in 2019, and GlaxoSmithKline, which sold $US2.4bn of its shingles vaccine that year. Those with the first widely available COVID-19 vaccines will prove the superiority of their science, manufacturing, and technology on a global stage.

Experimental products

For an established company like Pfizer, which has spent the past few years rebuilding its research and development operation, it would be the strongest-possible proof that its strategy is working. For the biotech Moderna, it would help validate the company’s long list of experimental products, all of which rely on the same relatively unproven technology as its COVID-19 vaccine.

There are, however, serious risks. Shares of smaller biotechs like Moderna, Novavax, and Inovio Pharmaceuticals have surged on enthusiasm for their COVID-19 vaccine programs, despite the companies having no marketed products. Those stocks face steep drops if their COVID-19 vaccines fall through. COVID-19 vaccine programs generally follow one of two broad strategies. Some have picked new, relatively unproven vaccine technologies that promise extraordinary speed.

Call them the hares: They include Moderna and Pfizer, which say they could have a small number of doses available for emergency workers and high-risk groups as early as this fall. J&J, which is also using a newer technology, is aiming for early next year.

Others are using more proven methods that will be slower to come to market. The giant tortoise here is the collaboration between Sanofi and GlaxoSmithKline. The partnership is employing a well-established technology that Sanofi uses in a flu vaccine, but a product won’t be ready until next summer.

“The greatest likelihood of success is applying known and proven technologies,” says Dr Geoffrey Porges, a senior analyst at SVB Leerink. “They’ve been demonstrated to be safe; they’ve been shown to be effective in other diseases. And those are both pretty big validations.”

Although the programs using newer technologies may have more to prove, they are powerful wildcards. A difference of nine months could mean hundreds of thousands of lives.

Not all experts are certain that a COVID-19 vaccine can be ready soon. For all the hundreds of millions of vaccine doses administered each year in the US, the Food and Drug Administration has approved only about 85 different vaccines out of thousands of pharmaceuticals. And of the known infectious diseases around the world, only 25 are considered to be vaccine-preventable. The bar for approval is high. Vaccines take a decade of testing on average. The world doesn’t have that long to wait.

The Hares

Vaccines work by showing the body’s immune system a safe version of a specific pathogen, or a piece of that pathogen, so that the body’s natural defences can be ready to fight off the real thing.

The fastest COVID-19 vaccine programs are trying to make pieces of SARS-CoV-2, the virus that causes COVID-19, inside of your body, rather than in the lab. Moderna, Pfizer, and others do that with a molecule called messenger RNA, which normally brings instructions from a cell’s DNA to its protein factories.

Johnson & Johnson, and an Oxford University program collaborating with AstraZeneca, are doing it with a nonreplicating virus similar to the cause of the common cold, which transports SARS-CoV-2 DNA into your cells.

In both cases, your cells then create certain proteins found on the virus, teaching your immune system to fight the virus. The techniques have been under development for years and, in some cases, manufactured on a large scale. But the FDA has yet to approve a single vaccine based on them.

Messenger RNA approaches appear to promise the quickest results. Excitement over Moderna’s experimental vaccine has lifted the biotech company’s shares some 220% this year. Moderna dosed its first patient in a Phase 1 safety trial on March 16, and says it expects to begin a 600-subject Phase 2 trial soon, and a Phase 3 study early this summer.

Moderna expects to submit the vaccine for FDA approval in 2021, but its CEO, Stéphane Bancel, has said that if there is positive data this summer, the company could seek emergency-use authorisation to distribute it in the fall.

Good risk-reward

“If we can be helpful, we of course want to be helpful,” Bancel told Barron’s in mid-April. “It would be something that the FDA would have to define very clearly — who they think there is a good risk-reward ratio to potentially be exposed to the vaccine.”

The FDA can issue emergency-use authorisations during public health crises to allow the use of unapproved medical products. Gilead’s remdesivir received an authorisation in May.

Moderna says it aims to produce one billion doses of its vaccine a year, and will be able to produce millions of doses a month later this year.

Pfizer, too, is aiming for the fall. It says that its COVID-19 vaccine could be ready for emergency-use authorisation or accelerated approval by October. The company is developing its mRNA vaccine with BioNTech of Germany. While Moderna is testing a single vaccine candidate, Pfizer has bought four separate versions of its vaccine into clinical trials.

Pfizer’s chief scientific officer, Mikael Dolsten, says that by October, the company will have dosed up to 8000 people with the vaccine, and will have millions of doses ready for emergency use by frontline workers, or for high-risk people in hard-hit areas. The company says it will make hundreds of millions of doses in 2021.

Pfizer picked an mRNA-based vaccine because it wanted something ready if a second wave of COVID-19 hits this fall, Dolsten says. “The idea was, we cannot afford to not have a vaccine that could start being used at some extent … this fall, when we get a combination of a flu and a Covid comeback in some areas,” he says.

Dolsten acknowledges that no mRNA-based vaccine has ever been approved by regulators. But he says that companies like Moderna and BioNTech have been working on mRNA for years. And he argues that the flexibility and speed of the approach, and the ability to quickly tweak the vaccine if the virus mutates, make it a better option for a pandemic than the more traditional approach being used by Sanofi and GlaxoSmithKline.

Fast-moving enemy

“You need to use tools, weapons to fight an enemy that’s fast moving,” he says. “It doesn’t help you to come with a technology where you’re always a step behind.”

The Johnson & Johnson effort, meanwhile, though a bit slower than Pfizer’s, is perhaps the most proven of the faster COVID-19 vaccine programs. The technology, which employs an altered version of a cold virus called Ad26, was used in an experimental ebola vaccine that has been given to 50,000 people. The vaccine has yet to be approved by regulators, but crucially, J&J has manufactured two million doses of it, a key experience that the mRNA developers cannot boast.

Johnson & Johnson has also developed experimental Ad26 vaccines for zika, HIV, and respiratory syncytial virus. Overall, the company says it has dosed more than 65,000 people with experimental Ad26-based vaccines.

“There’s a fairly large database,” says Dr Dan Barouch, the scientist at the Ragon Institute who first constructed Ad26 vectors, and who is now collaborating with J&J on the COVID-19 vaccine. “Other leading [COVID-19] vaccine modalities certainly have less clinical experience, and less experience with large-scale clinical trials, than the Ad26 platform.”

Johnson & Johnson plans to begin Phase 1 trials of the COVID-19 vaccine by September. The company aims to be ready for emergency-use authorisation in early 2021, when it could have tens of millions of doses available for healthcare workers and possibly for high-risk individuals. J&J aims to have produced hundreds of millions of doses by the second quarter of 2021, and more than a billion by the end of that year.

Paul Stoffels, J&J’s chief scientific officer, says his team is now preparing for the Phase 3 trial, which could include 30,000 to 100,000 subjects before the end of the year. Stoffels says he isn’t concerned about competing with other programs looking to recruit subjects, given how widespread the virus is expected to be. But that sort of recruitment effort could be harder if a Pfizer or Moderna vaccine is available in the fall.

These vaccines remain a gamble. Other, similarly novel programs are under way from Inovio, the Oxford-AstraZeneca collaboration, and others. The good news is, if they flame out, the tortoise won’t be far behind.

The Tortoise

Sanofi and GlaxoSmithKline together sell nearly two billion vaccine doses a year. If any organisations in the world know how to get a lot of vaccine into a lot of bodies fast, it is these two.

Their alliance is built around the technology that Sanofi uses to make an influenza vaccine called Flublok. The technique involves using insect cells to grow proteins found on the surface of the target virus, and then injecting those proteins to induce an immune response in the body. Flublok is approved by the FDA, and at least 10 million doses have been sold.

“It’s an established technology that has been shown to be able to make vaccine very successfully,” says John Shiver, senior vice president of global vaccine R&D at Sanofi Pasteur, Sanofi’s vaccine arm. Before joining with GlaxoSmithKline, Sanofi worked on the COVID-19 vaccine with a US government office called the Biomedical Advanced Research and Development Authority, which funds vaccine development.

“They knew that our platform already worked and had been tested and validated, because we produce an influenza vaccine,” says Sanofi CEO Paul Hudson. “They came to us because they knew we would be a little bit slower than, say, mRNA, but that our probability of success was probably higher, and that we would be able to produce it in large volumes.”

Now, Sanofi and GlaxoSmithKline say they will start Phase 1 trials in the second half of this year, and would be ready to submit the vaccine for full approval by the middle of next year. Shiver says that 100 million to 600 million doses will be ready by then, depending on a variety of factors. “Inherently, it is an advantage to have a technology that has actually made product before,” Shiver says. “You do not quickly produce that type of manufacturing capability.”

Other companies are also working on vaccines that use similar approaches. Novavax plans to begin a Phase 1 trial this month of its COVID-19 vaccine and has received significant funding from the Coalition for Epidemic Preparedness Innovations. Novavax says that it is aiming for emergency-use authorisation by year end, by which time it says it could have 100 million doses ready.

Whichever company brings a vaccine to market first, it hopefully won’t be the last. The first might not be the best, and many executives and scientists involved in the race for a vaccine say that making enough of it to inoculate the world is beyond the capability of even the largest drugmaker.

“We do need multiple vaccines to move forward, because we don’t know at this point in time which are going to be the safest, the most effective, the most durable, and the most deployable,” Barouch says.

Barron’s