Novavax On The Verge of Making History?

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The small vaccinemaker that faced an existential threat is slated to receive up to $2 billion from the U.S. government and a nonprofit organization to develop and manufacture a coronavirus vaccine, says an article published in ScienceMag.

A turnover like no one imagined

Eighteen months ago, a small vaccine maker here called Novavax faced an existential threat: delisting by the NASDAQ stock index. On the heels of a second failed vaccine trial in less than 3 years, the firm’s shares had plunged to less than $1 for 30 straight days, triggering a warning by NASDAQ. Frantic to conserve cash, the company sold its two Maryland manufacturing facilities, slicing its payroll by more than 100 employees. By January, it employed only 166 people.

“Good ideas. Bad management. … The company will probably die soon,” a former Novavax manager wrote on Glassdoor.com in October 2019.

What a difference a year—and a pandemic—make. Today, Novavax is slated to receive up to $2 billion from the U.S. government and a nonprofit organization to develop and manufacture a coronavirus vaccine. The company’s stock closed at $80.71 per share on 30 October, it has hired more than 300 new employees, and this month it plans to launch a pivotal clinical trial of its coronavirus vaccine in the United States and Mexico. Made by moth cells harnessed to crank out the virus’ spike protein—which the pathogen uses to invade human cells—Novavax’s vaccine outshone major competitors on key measures in monkey and early human tests.

One of the firsts to receive funding

The company is one of just seven vaccine makers to win funding so far from Operation Warp Speed, the giant multiagency U.S. government effort aiming to quickly produce at least 300 million doses of COVID-19 vaccines. 

“They are incredibly well positioned,” says Andrew Ward, a structural biologist at Scripps Research. Ward, who receives no payments from the company but owns some stock, led a team that last month published a paper in Science describing the structure of Novavax’s tailormade spike protein, the heart of its vaccine. He was impressed by its stability and conformation, as well as the vigorous antibody responses it has elicited in humans and animals. “They have the know-how,” he says. “And they obviously, as we confirmed, make a good product.”

Challenges ahead

Most significantly, the company has an Achilles’ heel. Novavax must rely mostly on contract manufacturers to meet its ambitious goal for 2021: producing enough vaccine to give 1 billion people two shots each. 

If manufacturing problems crop up—and the company last week said manufacturing delays had slowed the launch of its late-stage North American trial—competing vaccines may surge ahead. “That’s concerning,” says David Maris, a veteran drug industry analyst, and managing director at Phalanx Investment Partners. 

Where small companies such as Novavax are concerned, he adds, “people do want to believe in fairy tales.”

The company’s scientists started to work “with a frenetic pace,” Glenn says. Some of their competitors were already a lap ahead, working on their own vaccines. 

“There’s no question [that we’re] behind” several companies that also won Warp Speed funds, Glenn said on the morning of 24 September, the day Novavax launched its first phase III trial, of 15,000 volunteers in the United Kingdom.

Competitors

Most of Novavax’s key competitors—Moderna, Pfizer, Johnson & Johnson subsidiary Janssen, and AstraZeneca—had launched phase III trials by then. 

To make their vaccines, all four of those firms use new technologies based on genetic material that directs protein production, rather than delivering proteins directly. 

Those platforms rely on DNA loaded in disabled viruses or on messenger RNA to carry genetic instructions for building the spike protein. Cells within a vaccinated person then churn out the protein, alerting the immune system.

Developers of protein vaccines must develop their own version of the spike protein—one that closely mimics the naturally occurring spike and is stable enough to retain its immunological punch during manufacturing, packaging, and distribution. 

Most such vaccines include an additional compound called an adjuvant to help stimulate a strong, protective immune response. Those extra steps make protein vaccines slower to develop than those that deliver genetic instructions.

Novavax is the only one to have launched a phase III trial. 

Of the other firms, the huge vaccine maker Sanofi Pasteur is likely Novavax’s biggest rival. It “is going to be a formidable competition to the Novavax vaccine,” says Vijay Samant, a former head of vaccine manufacturing at Merck and now a consultant to vaccine companies. (Novavax is not a client.) 

But Novavax scientists say they’re ready for the competition. “We’ve been getting ready for this our whole lives,” says Gale Smith, Novavax’s chief scientist.

The heart of a new vaccine

To make their vaccine, Novavax scientists first used a baculovirus to insert the gene for the SARS-CoV-2 spike protein into moth cells, which produced the spikes on their cell membranes. 

Scientists then harvested the spike proteins and mixed them with a synthetic soaplike particle in which the spikes embed. A compound derived from trees serves as an immune-boosting adjuvant.

In North Carolina, countless baculoviruses loaded with the gene for the coronavirus spike protein are invading moth cells in 2000-liter bioreactors. 

The moth cells then express the coronavirus spikes on their cell membranes. Scientists harvest the proteins and mix them with a delivery vehicle: synthetic particles, on average 30 to 40 nanometers across. 

Each “nanoparticle” ends up studded with up to 14 spike proteins. The finished particles are only slightly smaller than the coronavirus itself, helping the immune system “see” them as a danger, Smith says. Then Novavax adds its adjuvant, based on saponin, a compound found in soap bark trees that stimulates the immune system. 

The Harsh reality

To crank up production in the spring, Novavax had to cope with a harsh reality. “What we didn’t have—what we’d lost by downsizing last year—is taking [the vaccine] right over to a manufacturing facility,” Glenn says. 

“We could have been much earlier if we had that strategic asset.” Instead, the company “had to beg” he says, turning to Gaithersburg-based contract manufacturer Emergent BioSolutions to produce a vaccine for the first human trials. It was “not ideal,” Glenn says. “We’re sprinters … [but] it’s hard to get someone else to sprint.”

A vital piece of good news came on 24 March, boosting the company’s search for cash. The phase III clinical trial of Novavax’s flu vaccine in older adults, also made using the moth cell system, returned excellent results. For Novavax, which was now asking funders for major dollars for its pandemic coronavirus vaccine, the proof of its capabilities came at a fortuitous time.

Three days later, senior Novavax scientists met with decision-makers from a key funder—the nonprofit, international Coalition for Epidemic Preparedness Innovations (CEPI)—in a crucial Zoom call. 

Six weeks later, CEPI awarded Novavax up to $384 million for trials and manufacturing of its vaccine.

By late May, Novavax had launched its first human safety trial in 131 volunteers in Australia and used the CEPI funding to buy, for $167 million in cash, a state-of-the-art vaccine manufacturing facility in the Czech Republic that the company said would deliver more than 1 billion doses in 2021. 

And in early July, Operation Warp Speed granted the company up to $1.6 billion, with $800 million available immediately, for a phase III clinical trial and for manufacturing 100 million doses of vaccine.

Australian Trial was successful 

In early August, the big investors in the tiny company won an initial vindication when Novavax announced strong results from the Australian trial. 

After two injections, “the antibody responses in the Novavax paper were markedly stronger than any of the other vaccines that have been reported,” and participants had experienced no severe adverse events, says Moore, who recently published a Journal of Virology review of the leading vaccine candidates. 

Moore says he intends to volunteer for a Novavax trial if eligible. “I’m going, ‘Yes, I’ll have that [vaccine].’”

“It’s the only vaccine I’ve seen out of all the candidates that are further down the pipeline that actually had no viral replication in the nasal swabs of vaccinated animals,” says Angela Rasmussen, a virologist at Columbia University. 

That’s important, she says, because stopping viral replication in the nose can reduce the spread of infection among people who may be unaware they are sick. But she cautions that monkeys are not people. 

“We can’t really conclude that this vaccine is going to be better in practice until we have some reliable safety and efficacy data in people.”

That’s why researchers will be eager to see results from Novavax’s phase III trials. In the one in progress in the United Kingdom, volunteers get either placebo or vaccine in two injections, 21 days apart. 

Researchers will evaluate whether vaccinated volunteers have fewer symptomatic coronavirus infections than placebo recipients. They’ll also keep monitoring safety, including any reactions to the adjuvant, because this will be the first time huge numbers of younger people with vigorous immune systems receive it.

Sales figures

Novavax says it will release the contract next week as part of its quarterly financial reporting.

Novavax leaders continued their sales in September, with four senior managers selling shares worth a combined $18.9 million. “Pretty much all the value I have is in Novavax,” says Glenn, who pocketed $6.2 million (before taxes) in August and sold shares worth $4.9 million in September. “A year ago it was worth nothing.” CEO Stanley Erck, who sold $4.5 million in stock in September, did not respond to requests for comment.

Even if Novavax’s phase III trials succeed, vaccine watchers say the company’s biggest vulnerability will remain: the manufacturing process. “I think the vaccine is going to be efficacious,” Samant says. “But you put that 2 billion–dose task in front of a small company, it’s a huge uphill task.”

Sale of vaccines

Novavax counters that the company’s manufacturing partners are deeply experienced in making vaccines at scale. 

For instance, the Serum Institute of India, a veteran vaccine maker that is the world’s largest, is helping Novavax expand production at the 14,000-square-meter Czech facility, plus manufacturing an additional billion doses itself, in India, for low- and middle-income countries. 

That brings the total doses the company now says it can manufacture in 2021 to 2 billion, the promised number.

The fact that world-class manufacturers such as the Serum Institute “didn’t even blink before wanting to work with them and helping them scale up” speaks highly of the company,” Mamtani says.

“It’s going to be a dark horse,” he predicts. “A dark horse helping us to get out of this darkness.”

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Source: ScienceMag

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