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Novavax’s vaccine is made of tiny particles studded with the coronavirus spike protein plus honeycomblike molecules, derived from plants, that stimulate the immune system.

A.KITTERMAN AND V. ALTOUNIAN/SCIENCE

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Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

GAITHERSBURG, MARYLAND—Eighteen months ago, a small vaccinemaker 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.

The company is one of just seven vaccinemakers 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. But most Warp Speedbacked companies are giant pharmaceutical firms, and most have already launched late-stage clinical trials in the United States. Tiny Novavax is rushing to keep pace with its larger rivals because companies that win the first approvals from regulators will have big market advantages. Still, some observers say Novavax’s technology gives it an edge.

“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.”

Novavax scientist Nita Patel (left) examines a plate measuring antibodies in vaccinated monkeys; other staffers gauge how the vaccine’s protein binds to human cells.

ALYSSA SCHUKAR

But other people are skeptical. They note that Novavax has focused on making vaccines for more than 20 years but has never brought one to market, and that its senior executives have sold tens of millions of dollars of company stock since its share price began to soar this summer.

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 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.”

On 10 January, researchers in China 彩神下载app安卓版published the genome sequence of the virus ravaging the city of Wuhan. Three days later, Gregory Glenn, president of R&D at Novavax, asked his staff to order from a supplier the gene for the virus’ spike protein.

Glenn and other Novavax scientists had spent years developing “protein subunit” vaccines, so named because they employ a protein (or part of one) from the targeted virus, plus an immune-boosting compound called an adjuvant, to provoke an immune response. The company hadn’t had a commercial success—its vaccine against a serious respiratory illness failed in clinical trials. But it had produced a promising flu vaccine aimed at older adults, which was nearing the end of a pivotal trial. The company had also created protein subunit vaccines against two close cousins of the pandemic virus—the coronaviruses that cause severe acute respiratory syndrome and Middle East respiratory syndrome, using those viruses’ spike proteins. Those vaccines hadn’t made it to market, but Novavax had plenty of experience with the coronavirus family. Glenn believed it was his company’s moment.

The gene for the spike protein was slow to arrive, however. Finally, at 6 a.m. on 3 February, a vice president from the supplier hand-delivered a red-capped vial bearing the gene to Novavax’s beige brick building here. The virus still hadn’t been officially named—the vial was labeled “Cov/Wuhan”—but Novavax was now out of the gate and in the race to tame it.

The company’s scientists started to work “with 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.

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.

But protein-based vaccines also have a long track record of effectiveness, in contrast with the newer, largely unproven approaches. The successful hepatitis B vaccine licensed in 1986 and recommended for all U.S. babies in their first day of life is a protein subunit vaccine. So are a flu vaccine approved in 2013 and the human papillomavirus vaccines that have sent rates of cervical cancer plunging since the first ones were licensed in the 2000s.

Perhaps because the technology is tried and true, scores of other companies are also racing to develop protein subunit vaccines. Novavax is the only one to have launched a phase III trial. Of the other firms, the huge vaccinemaker Sanofi Pasteur is likely Novavax’s biggest rival. It “is going to be 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.) Sanofi Pasteur has deep pockets, infrastructure, and experience, and markets vaccines against 19 infectious diseases.

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.

Once the pandemic coronavirus gene arrived in Gaithersburg, Maryland, on 3 February, the company spent weeks making more than 20 versions of the spike protein, aiming for a product as immunologically potent as possible. The winner was the most stable antibody-inducing protein, one that mimicked the energy-packed state of the spike just before it fuses with the host cell membrane.

In March, a team led by Nita Patel, a senior director in the vaccine development department (see sidebar, below), confirmed in lab tests that the engineered protein bound tightly to its human cell-surface receptor. The results strongly suggested antibodies to Novavax’s protein would interfere with the virus’ own spike protein as it tried to fuse with cells.

Patel’s boss, Smith, next enlisted Ward to verify the protein’s structure and stability with electron microscopy. Other tests showed the Novavax spike is stable for many weeks at 2°C to 8°C—a key advantage over the Moderna and Pfizer vaccines, which need to be stored at 20°C and 70°C, respectively, and once thawed, last only days in the refrigerator.

Now, the challenge was to make the protein in the vast quantities that the world would need. Novavax had a system to do that, co-invented by Smith decades earlier and since used by the company to develop its other vaccine candidates: moth cells.

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.