Everything Must Go Right for Big Pharma’s Bet on a Fast Vaccine

(Bloomberg Businessweek) -- Much about the coronavirus has defied belief—the speed at which it has spread around the world, the insidious way it penetrates the lungs, the unexpected impact it’s having on young people in some parts of the world while sparing them elsewhere. The most effective way to stop it would be to vaccinate the global population. For that to happen in the next year or so, an almost equally implausible set of circumstances has to occur: flawless scientific execution, breakneck trials, and a military-style manufacturing mobilization unlike any the pharmaceutical industry has put in place before. Normally it takes 10 or 15 years of careful lab work and meticulous testing to bring a totally new vaccine to market. For the coronavirus, the drug industry hopes to compress this time frame by tenfold.

This may sound like mission impossible, but Big Pharma wouldn’t be working this hard if it didn’t think it had a shot at pulling it off. Already, Cambridge, Mass.-based biotech Moderna Inc., a company that’s never launched a product, has started human trials of a vaccine harnessing a brand-new type of RNA technology to protect against coronavirus. Drug giant Pfizer Inc., with German partner BioNTech SE, is working on a vaccine with a similar new technology, while Johnson & Johnson is building off a template for its experimental Zika and Ebola vaccines. French drugmaker Sanofi is adapting technology used for manufacturing its flu shots to see if it will protect against the coronavirus.

All told, more than two dozen coronavirus vaccines are already in early stages of testing. “There is no precedent for the speed at which we are moving,” says Clement Lewin, an associate vice president at Sanofi. In his two and a half decades of work on vaccines, “I can’t think of a parallel.”

It’s a sentiment echoed throughout the halls of pharma and biotech as leaders of some of the world’s biggest companies race to rewrite the rules in a bid to slow or stop the coronavirus. To accomplish this, they’re going to need to radically change the way drug development works. This for a vaccine that J&J, for one, is promising it won’t even make a cent from. From a public-health perspective, a vaccine can’t come soon enough: More than 1 million people have been infected with the coronavirus globally, with hot spots such as New York and Seattle building field hospitals to accommodate sick patients.

The mere hope of a vaccine has generated so much excitement that shares in drug giants such as Pfizer and Johnson & Johnson have shot up in recent weeks, with one-day spikes of 6% and 8%, respectively, rare moves for large companies that normally aren’t prone to big swings. Moderna is up more than 75% year-to-date. This could easily be a vaccine bubble. The time frame the U.S. government has given out, of having a shot within 12 to 18 months, has drawn skepticism from many vaccine experts. “You would have to have everything go perfectly to get there,” says Seth Berkley, chief executive officer of the nonprofit Gavi, the Vaccine Alliance, which helps developing countries finance and distribute vaccines. “The most important thing is to have people understand that science is miraculous and can make things happen but it isn’t going to happen tomorrow.”

Still, the first steps are happening remarkably quickly. To understand the buzz around Moderna, one must understand how much it’s accomplished in just a few short months. On Jan. 11, when few in the West were paying attention to the virus, Chinese scientists posted the genetic sequence of the new coronavirus that was spreading in Wuhan. Researchers at Moderna took note. They’d been pioneering a novel vaccine technology for another coronavirus disease and went to work on devising a vaccine against the new one. By late February, when President Trump was still downplaying the risk of coronavirus, Moderna’s scientists had already delivered the first batch of candidate vaccines to researchers at the U.S. National Institutes of Health. When the coronavirus was starting to explode in the U.S. in mid-March, the first healthy patient received a dose in a small, government-sponsored safety trial.

The technology being used by Moderna, Pfizer, and several others relies on the body’s own cells to produce viral proteins. Moderna’s vaccine consists of genetic material that codes for the spike protein on the surface of the coronavirus. (Those red bumps in the ubiquitous coronavirus image that’s emblazoned in your brain by now.) Once injected into the body, the RNA slips into human cells and tells them to produce the viral proteins. “When you inject a person in the arm with our vaccine, what you are really injecting is instructions for their body to make thousands of copies of proteins from the surface of the virus,” says Stephen Hoge, president of Moderna. If the vaccine works, those proteins will then trigger the body to generate protective antibodies against the virus.

In practical terms, the RNA technology can move faster into trials because, unlike traditional vaccines, it doesn’t involve brewing batches of protein or inactivated viral particles in living cells, a bespoke process that can take months to ramp up. Some flu vaccines are still made in chicken eggs. If the RNA technology sounds exotic and unproven, that’s because it is. There isn’t an approved RNA vaccine yet for any disease, nor are there existing plants already making these vaccines in enormous quantities.

In additional to betting on new technologies to speed the process, companies are throwing caution to the wind by performing numerous testing steps in parallel. Pfizer, working in a partnership with the German group BioNTech, hopes to get an experimental RNA vaccine into humans later this month. Pfizer is taking a novel approach to improve its odds: Instead of testing the single vaccine candidate it thinks will work best, it’s planning to move into human trials with four different options simultaneously, to see which of those is the most successful before taking the studies to bigger populations. Vaccine makers normally do three stages of human trials, moving sequentially from small safety studies to bigger and bigger efficacy trials. But Pfizer is considering an all-encompassing trial that would grow larger over time as results flow in. And the company hopes to share incoming trial data with regulators in real time for quicker decision-making about how to proceed. “We are proposing to basically change the way we do development as a result of this crisis,” says Kathrin Jansen, head of vaccine research and development at Pfizer.

RNA vaccine technology isn’t without its risks. Less is known about its efficacy, and while there’s a decent amount of early-stage safety data showing the technology should be safe, there are concerns some RNA vaccines could induce unwanted immune responses. Another issue that all Covid-19 vaccines will have to avoid is a troublesome complication called “disease enhancement,” hints of which were seen in animal tests of vaccines for SARS, another coronavirus disease.

And as the battle against HIV shows, there’s no guarantee a vaccine is possible. Some of the approaches touted now are likely to fizzle, either because of side effects or lack of efficacy. But coronavirus experts are guardedly hopeful that with so many of the best and brightest pharmaceutical minds working on the problem, at least one vaccine will work.

Another challenge for any coronavirus vaccine would be scaling up production. Say it works. There would then be the need to meet the global demand for inoculations. Pfizer has started making plans to invest in manufacturing capacity both in the U.S. and abroad. Moderna says it already has the ability to produce millions of doses of bulk vaccine per month at a factory that was gearing up to produce a different vaccine. But for a development-stage company with no marketed products, it will be a tall order. Moderna is talking to potential partners to get that off the ground, but it didn’t name names.

And as ambitious as “millions” of vaccines sounds, it’s only a fraction of what the demand for a Covid-19 vaccine could be. While not precisely comparable to the situation now, a 2018 planning road map for a pandemic influenza vaccine, put out by the U.S. Centers for Disease Control and Prevention, shows the enormity of demand for such a vaccine.

First in line would be millions of doctors, nurses, and other first responders as well as infants, toddlers, and pregnant women. That’s 26 million people in the U.S. alone. Next in line would be millions of other essential personnel plus children with preexisting conditions. After that would be broader groups of higher-risk patients, including 41 million adults over age 65 and 38 million younger adults with preexisting conditions. Add all together, and you get well north of 100 million Americans who would be high-priority candidates to get a vaccine.

And that’s just the U.S. It doesn’t include hundreds of millions more in China, Europe, India, and elsewhere, all of whom will be clamoring for inoculations. The real question isn’t just proving whether a vaccine works, “but how quickly can you ramp up manufacturing to meet global need,” says Mark Feinberg, a former Merck & Co. vaccine executive who now leads the International AIDS Vaccine Initiative.

“There aren’t a lot of drugs in the industry that are filled at these scales, period,” says Moderna’s Hoge. “Even large pharma companies don’t usually operate on this kind of a scale. No one entity or one company” will be able to do it on their own, he says.

While drug giants such as J&J and Sanofi may not be able to get into trials as fast as Moderna, their proven manufacturing capabilities do give them an edge in scaling up to hundreds of millions of doses should their vaccines work. Sanofi says the coronavirus vaccine it’s working on uses the same technology already used in one of its licensed flu vaccines, making it easier to produce in large quantities. Sanofi hopes to begin human trials of its first vaccine, which uses the protein technology of its Flublok flu vaccine, by fall. Its U.S. manufacturing plants have capacity for 100 million to 600 million doses a year, depending on the amount of vaccine that ends up being needed for each shot, says Lewin, the associate vice president. Sanofi isn’t stopping there: The company also hopes to begin trials on a second vaccine that uses RNA technology similar to Moderna’s by yearend.

J&J is relying on an old playbook, working off a vaccine platform the company used for experimental vaccines for several diseases including Ebola, Zika, and RSV, a respiratory illness that can be particularly problematic for young children. It’s an inactivated cold virus with a piece of the coronavirus spike protein on it to generate an immune response. J&J started by evaluating 10 different approaches to the coronavirus before selecting one on March 30, a development that sent its shares up 8%.

The drugmaker has seen its ability to do this type of epidemic vaccine research wax and wane; diseases such as Ebola and Zika petered out while it was studying experimental shots, slowing the pace of research. But the company managed to continue the work by using the vaccine in outbreaks prior to official approval. It’s ready for this possible outcome, too. “We have clinical trial capacity around the world in 80 countries, and we will be prepared to move around the world to where an outbreak is. If it is Brazil, we will be there. If it’s in Africa, we’ll be there. China, we’ll be there,” says Paul Stoffels, J&J’s chief scientific officer.

It would be ideal for the coronavirus to taper off to the point that all of these vaccine trials would grind to a halt. But top industry officials aren’t counting on this outcome, given that the curve of patients and deaths is only increasing. “It’s really scary. Most likely we need a vaccine to put a stop to the epidemic, and that’s where we go full bore with the input of a lot of scientific expertise from inside and outside but also a lot of discussions with governments around the world,” Stoffels says. “It’s at least an insurance that at a certain point we can put a stop to this virus.”
 
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