The United States may be within months of a profound turning point in the country’s fight against the coronavirus: the first working vaccine.
Demonstrating that a new vaccine was safe and effective in less than a year would shatter the record for speed, the result of seven-day work weeks for scientists and billions of dollars of investment by the government. Provided enough people can get one, the vaccine may slow a pandemic that has already killed a million people worldwide.
It’s tempting to look at the first vaccine as President Trump does: an on-off switch that will bring back life as we know it. “As soon as it’s given the go-ahead, we will get it out, defeat the virus,” he said at a September news conference. But vaccine experts say we should prepare instead for a perplexing, frustrating year.
The first vaccines may provide only moderate protection, low enough to make it prudent to keep wearing a mask. By next spring or summer, there may be several of these so-so vaccines, without a clear sense of how to choose from among them. Because of this array of options, makers of a superior vaccine in early stages of development may struggle to finish clinical testing. And some vaccines may be abruptly withdrawn from the market because they turn out not to be safe.
“It has not yet dawned on hardly anybody the amount of complexity and chaos and confusion that will happen in a few short months,” said Dr. Gregory Poland, the director of the Vaccine Research Group at the Mayo Clinic.
Some of this confusion is inevitable, but some is the result of how coronavirus vaccine trials were designed: Each company is running its own trial, comparing its jab with a placebo. But it didn’t have to be this way.
In the spring, when government scientists began discussing how to invest in vaccine research, some wanted to test a number of vaccines all at once, against each other — what’s known as a master protocol.
Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, was in favor of the idea. But these mega-trials pose a business risk for any given vaccine maker because they reveal how a vaccine stacks up against its competitors.
Instead, the government offered to bankroll large vaccine trials if companies agreed to some common ground rules and shared some data. The companies were still allowed to run the trials on their own.
“You have to have the total cooperation of the pharmaceutical companies to get involved in a master protocol,” Dr. Fauci said. “That — I don’t know what the right word is — didn’t turn out to be feasible.”
The vaccine vetting system wasn’t set up for this logjam. Typically, scientists take several years to prepare a vaccine before testing it on people. Early safety trials, known as Phase 1 and 2, may take several years.
If all goes well — and it typically doesn’t — then Phase 3, the final stage, can begin, comparing thousands of people who receive a vaccine with thousands who are given a placebo. It may take three more years to get these results. Only then — a decade or more after the research has begun — will a vaccine manufacturer build a factory to make the products.
When the coronavirus began to spread early this year, vaccine researchers around the world knew we could not afford to wait that long. The World Health Organization organized a group of experts to start what came to be known as the Solidarity Vaccines Trial. Several vaccines would be given at random to one large group of volunteers, while a smaller group would receive a placebo.
All of the vaccines would be tested against the same placebo group, and all of the volunteers would be living in the same circumstances. “You have a fully valid comparison, not only of each of those vaccines against placebo, but against each other,” said Thomas Fleming, a biostatistician at the University of Washington and a member of the Solidarity Vaccines Trial group.
It took nine months to get off the ground, but that trial will start later in October with a small study in Latin America.
Around the same time that the W.H.O. was hatching plans for its mega-trial, U.S. government officials were discussing how they could best invest in — and speed up — vaccine trials. Some researchers, including Dr. Fauci, advocated a design much like the W.H.O.’s.
But Moncef Slaoui, the chief adviser of Operation Warp Speed, the multiagency effort to hasten the development of coronavirus vaccines and treatments, said in a statement that such a trial would have been impractical. “If OWS had tested all vaccines under one master protocol, the operation would have had to wait months before starting and recruit 200,000 volunteers at the same time.”
In the end, the government opted for what it described as a “harmonized approach.” It would allow vaccine makers to run their own trials, but only if they used protocols that followed certain guidelines and let the National Institutes of Health test all of their volunteers in the same way. In exchange for following these rules, the companies would get to tap into to the N.I.H.’s large network of clinical testing sites, and receive major financial support for their trials. Through this program, the government has promised $10 billion to vaccine makers to date.
So far, AstraZeneca, Johnson & Johnson and Moderna have begun trials in the network. Novavax and Sanofi are expected to start their own Phase 3 studies in the next couple of months. But Pfizer, one of the front-runners, never joined the network, opting to run trials completely on its own.
If Pfizer’s results turn out well, many experts expect the company to ask the Food and Drug Administration for an emergency authorization of its vaccine, potentially for just one group of high-risk people. The company might then swiftly move to apply for a license, making it widely available.
The authorization of a vaccine will depend on how much protection the vaccine provides in the Phase 3 trial — what scientists refer to as its efficacy. In June, the F.D.A. set 50 percent efficacy as the target for a coronavirus vaccine.
But the efficacy in a trial may not necessarily match its effectiveness out in the real world. That’s because, like any statistical study, Phase 3 trials have margins of error. A vaccine that met the F.D.A.’s guidelines might actually be more than 50 percent effective, or might be less so. It might well turn out to be only 35 percent effective.
Whether it goes to Pfizer or another company, that first vaccine authorization could hamper ongoing trials of its competitors. Some volunteers, unsure of whether they had been given an experimental vaccine or a placebo, could drop out of an ongoing trial to get the authorized vaccine, slowing down the research. John Shiver, Sanofi’s global head of vaccine research and development, agreed that this scenario might play out for the company’s vaccine trial.
Things could be even worse for vaccines in earlier stages of testing. Those products might have to prove that they are better than the newly approved vaccine. The difference between two vaccines will be smaller than between a vaccine and a placebo. As a result, these trials may have to be bigger and run longer. The steep cost may be more than many of the small start-ups working on innovative vaccines can afford.
“That basically prevents the development of better vaccines,” said Dr. Naor Bar-Zeev, a vaccine expert at the Johns Hopkins University School of Medicine. “Given the massive taxpayer investment, the public should demand better.”
The F.D.A.’s guidelines raise the possibility of testing future vaccines against an authorized one, but they don’t give a clear sense of whether the agency would change the requirements for testing. “We cannot speculate on what may or may not happen in the future,” an F.D.A. spokeswoman said.
Dr. Slaoui of Operation Warp Speed said in a statement that once a vaccine is authorized, trials that had not yet started or had just begun recruiting volunteers would be restricted to groups that were not approved to receive the authorized vaccine. Because the first wave of vaccines is likely to go to health care workers or other high-risk groups, this policy could mean these groups would not be allowed to be part of new clinical trials.
By spring or summer, there may well be several coronavirus vaccines for American consumers to choose from. But that choice will be tough. A vaccine that showed 50 percent efficacy in one trial, for example, might actually be more protective than one showing 60 percent efficacy in a different trial.
“I can see people reading a lot into even minor differences that could just be statistical chance,” said Natalie Dean, a biostatistician at the University of Florida.
In a phone call with reporters on Friday, Paul Mango, an official at the Department of Health and Human Services, said that Operation Warp Speed was on track to have up to 700 million doses of various vaccines by March or April — enough, he said, for “all Americans who wish to get it.” As for who would get which vaccine, he said that would be left up to the Centers for Disease Control and Prevention’s vaccine advisory committee. “They will guide us as to which vaccine is most appropriate for which class of Americans,” he said.
But the advisory committee doesn’t have a plan for that yet, and Dr. Grace Lee, a professor of pediatrics at Stanford University School of Medicine and a member of that committee, warned it would have a hard time coming up with one. “It’s tough to do, given all the uncertainty with Covid vaccines,” she said.
Even moderately effective vaccines will be a huge help in reducing the cases of Covid-19 — but only if enough people take them, and only if they realize they could still get sick. “We’ll have to continue to use a mask for some of these vaccines,” said Dr. Poland of the Mayo Clinic.
The N.I.H.’s harmonized approach for all Phase 3 trials getting Operation Warp Speed funding is likely to bring some scientific insights. It’s possible, for example, that across all trials, some molecular signature in a vaccinated person’s blood would show that they were protected. Future trials could simply look for those signatures rather than wait for people to get sick.
There’s no guarantee that such a clear signature will emerge, however. And more uncertainty will come about as regulators continue to look for rare but dangerous side effects in authorized vaccines.
“You’re going to have random events,” Dr. Bar-Zeev said. For example, a group of older people could all have strokes shortly after being vaccinated, raising the question of whether the vaccine was the culprit. “It’s very possible that some vaccines will be withdrawn.”
The only way to manage this chaotic year, Dr. Poland said, is for scientists to talk honestly about how vaccines are tested, and for people to learn what lies ahead. “As long as you frame something in advance, people do better with it,” he said.
Sharon LaFraniere contributed reporting.