First, a Vaccine Approval. Then 'Chaos and Confusion.'
The United States could reach a profound turning point in the country's fight against the coronavirus within a few months: the first working vaccine.
Evidence that a new vaccine was safe and effective in less than a year would destroy the speed record, the result of seven days of work for scientists and billions of dollars in government investment. Provided enough people can get one, the vaccine can slow a pandemic that has killed 1 million people worldwide.
It's tempting to look at the first vaccine like President Donald Trump: an on-off switch that brings back life as we know it. "As soon as the clearance is given, we will take it out and defeat the virus," he said at a press conference in September. But vaccine experts say we should prepare for a confusing, frustrating year instead.
The first few vaccines may offer only modest protection, low enough to make mask wearing prudent. By next spring or summer there may be several of these mediocre vaccines without a clear idea of how to choose between them. Because of this multitude of options, manufacturers of a superior vaccine in the early stages of development may have difficulty completing clinical trials. And some vaccines may be withdrawn from the market abruptly because they turn out not to be safe.
"Hardly anyone has realized how complex, chaotic and confusing it will be in a few months," said Dr. Gregory Poland, Director of the Vaccine Research Group at Mayo Clinic.
Part of this confusion is inevitable, another part is the result of coronavirus vaccine trial design: each company conducts its own trial comparing its sting to a placebo. But it didn't have to be like that.
In the spring, when government scientists were discussing how to invest in vaccine research, some wanted to test a number of vaccines against each other at the same time - a so-called masters protocol.
Dr. Anthony S. Fauci, director of the National Institute for Allergies and Infectious Diseases, endorsed the idea. However, these mega-studies pose a business risk for a particular vaccine manufacturer as they show how a vaccine holds up against its competitors.
Instead, the government offered to fund large vaccine trials if the companies agreed to some common ground rules and shared some data. The companies were still allowed to carry out the tests themselves.
"You have to have total collaboration from the drug companies to get involved in a master protocol," said Fauci. "That - I don't know what the right word is - has not proven feasible."
The vaccine review system has not been set up for this jam. It usually takes scientists several years to manufacture a vaccine before testing it in humans. Early security attempts, known as Phase 1 and 2, can take several years.
If all goes well - and usually doesn't - phase 3, the final phase, can begin and compare thousands of people who are given a vaccine to 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 begins - will a vaccine manufacturer build a factory to manufacture the products.
When the coronavirus spread earlier this year, vaccine researchers around the world knew we couldn't afford to wait that long. The World Health Organization organized a group of experts to start the so-called solidarity vaccine process. A large group of volunteers would be given multiple vaccines at random, while a smaller group would be given a placebo.
All vaccines would be tested against the same placebo group and all volunteers would live in the same circumstances. "You have a completely valid comparison, not just for each of these vaccines against placebo, but against each other," said Thomas Fleming, biostatistician at the University of Washington and a member of the Solidarity Vaccines Trial Group.
It took nine months to begin the process, but that process will begin later in October with a small study in Latin America.
Around the same time the WHO was preparing plans for its mega-trial, US government officials were discussing how best to invest in and speed up vaccination trials. Some researchers, including Fauci, advocated a design very similar to that of the WHO.
But Moncef Slaoui, chief advisor to Operation Warp Speed, the multiagency attempt to expedite coronavirus vaccine and treatment development, said in a statement that such an attempt would have been impractical. "If OWS had tested all of the vaccines under a master protocol, the operation would have had to wait months before starting and recruiting 200,000 volunteers at a time."
In the end, the government opted for a "harmonized approach". This would allow vaccine manufacturers to conduct their own studies, but only if they use protocols that follow certain guidelines and the National Institutes of Health have all of their volunteers tested the same way. In return for complying with these rules, companies could take advantage of the NIH's large network of clinical testing sites and receive substantial financial support for their studies. Through this program, the government has so far promised vaccine manufacturers $ 10 billion.
So far, AstraZeneca, Johnson & Johnson and Moderna have started trials in the network. Novavax and Sanofi are expected to start their own phase 3 studies in the next few months. However, Pfizer, one of the frontrunners, never joined the network and chose to conduct trials entirely on its own.
If Pfizer's results are positive, many experts expect the company to seek emergency approval from the Food and Drug Administration for its vaccine, possibly only for a group of high-risk people. The company could then quickly apply for a license and make it widely available.
Approval of a vaccine depends on how much protection the vaccine offers in the Phase 3 study - what scientists call its effectiveness. In June, the FDA set a target of 50% effectiveness for a coronavirus vaccine.
However, the effectiveness of a study does not necessarily have to be the same as its effectiveness in the real world. This is because, like any statistical study, phase 3 studies have error rates. A vaccine that meets FDA guidelines may be more than 50% effective or less effective. It might turn out to be only 35% effective.
Whether it's Pfizer or another company, this initial vaccine approval could hamper ongoing trials by its competitors. Some volunteers, unsure whether they received an experimental vaccine or a placebo, might opt out of an ongoing study to get the approved vaccine, slowing research. John Shiver, Sanofi's global director of vaccine research and development, agreed that this scenario could affect the company's vaccine study.
It could be worse with vaccines in earlier stages of testing. These products may need to demonstrate that they are better than the newly approved vaccine. The difference between two vaccines is less than that between a vaccine and a placebo. As a result, these attempts may have to be larger and take longer. The high cost can be more than many small startups working on innovative vaccines can afford.
"That basically prevents the development of better vaccines," said Dr. Naor Bar-Zeev, a vaccine expert at Johns Hopkins University Medical School. "Given the massive investment by taxpayers, the public should make better demands."
The FDA guidelines open up the possibility of testing future vaccines against an approved one, but do not give a clear indication of whether the agency would change the requirements for testing. "We cannot speculate about what might or might not happen in the future," said an FDA spokeswoman.
Slaoui of Operation Warp Speed said in a statement that studies that had not yet started or had just started recruiting volunteers would be limited to groups that were not eligible to receive the approved vaccine once a vaccine was approved has been. Since the first wave of vaccinations is likely to go to healthcare workers or other risk groups, this policy could mean that these groups are not allowed to participate in new clinical trials.
American consumers may have several coronavirus vaccines to choose from by spring or summer. But that choice will be difficult. For example, a vaccine that showed 50% effectiveness in one study might actually be more protective than a vaccine that showed 60% effectiveness in another study.
"I can see people reading a lot about subtle differences that might just be a statistical coincidence," said Natalie Dean, biostatistician at the University of Florida.
Speaking to reporters on Friday, Paul Mango, an official with the Department of Health and Human Services, said Operation Warp Speed is on track to get up to 700 million doses of various vaccines by March or April - enough to he said, for "all Americans who want to get it." It was up to the Vaccine Advisory Board of the Centers for Disease Control and Prevention who would receive which vaccine. "They will show us which vaccine is best for which class of Americans," he said.
However, the advisory board has no plan for it yet, and Dr. Grace Lee, a professor of pediatrics at Stanford University School of Medicine and a member of that committee, warned that it would be difficult to find one. "This is difficult to do with the uncertainty surrounding COVID vaccines," she said.
Even moderately effective vaccines will be of great help in reducing cases of COVID-19 - but only if enough people take them and only if they realize they could still get sick. "For some of these vaccines we still have to use a mask," said Poland of the Mayo Clinic.
The NIH's harmonized approach to all Phase 3 studies that will receive funding from Operation Warp Speed should yield some scientific evidence. For example, it is possible that in all studies a molecular signature in the blood of a vaccinated person shows that they are protected. Future attempts might just look for these signatures instead of waiting for people to get sick.
However, there is no guarantee that such a clear signature will result. And there will be more uncertainty as regulators continue to look for rare but dangerous side effects with approved vaccines.
"You will have random events," said Bar-Zeev. For example, a group of elderly people might have a stroke shortly after being vaccinated, which begs the question of whether the vaccine is the culprit. "It is very likely that some vaccines will be withdrawn."
The only way to tackle this chaotic year, according to Poland, is for scientists to speak honestly about how vaccines are tested and for people to know what lies ahead. "As long as you frame something in advance, people do better," he said.
This article originally appeared in the New York Times.
© 2020 The New York Times Company
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