The United States may be within months of a deep turning point in the country’s fight against the coronavirus: the first vaccine in effect.
Demonstrating that a new vaccine is safe and effective in less than a year will break the speed record, the result of seven days of work for scientists and billions of dollars in government investment. Provided enough people can get it, the vaccine could slow the pandemic, which 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 life back to what we know. “As soon as it is given the green, we will take it out, we will defeat the virus,”
The first vaccines can only provide moderate protection, low enough that it is prudent to continue wearing a mask. Until next spring or summer, there may be several of these vaccines, without a clear sense of how to choose between them. Because of this set of options, early vaccine manufacturers in the early stages of development may struggle to complete clinical testing. And some vaccines may be suddenly withdrawn from the market because they are unsafe.
“He has not yet realized the complexity, chaos and confusion that will occur in a few short months,” said Dr. Gregory Poland, director of the Mayo Clinic’s Vaccine Research Group.
Part of this confusion is inevitable, but some is the result of the way coronavirus vaccination attempts are designed: Each company conducts its own trial, comparing its stroke to a placebo. But it didn’t have to be that way.
In the spring, when government scientists began discussing how to invest in vaccine research, some wanted to test a number of vaccines at once, against each other – what is known as a master protocol.
Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, supported the idea. But these mega-trials pose a business risk for any vaccine manufacturer, as they reveal how the vaccine accumulates against its competitors.
Instead, the government has offered to fund large-scale vaccine trials if companies agree to some common ground rules and share some data. The companies still had the right to conduct the tests themselves.
“You have to have the full cooperation of the pharmaceutical companies to get involved in the main protocol,” said Dr. Fauci. “That – I don’t know which is the right word – didn’t turn out to be feasible.”
The vaccine verification system is not designed for this lodge. It usually takes scientists several years to prepare a vaccine before testing it on humans. Early safety tests, known as Phase 1 and 2, can take several years.
If all goes well – and it usually doesn’t – then Phase 3, the final stage, can begin by comparing thousands of people who receive the vaccine to thousands who receive a placebo. It may take another three years to obtain these results. Only then – a decade or more after the study began – will the vaccine manufacturer build a factory to produce the products.
When the coronavirus began to spread earlier this year, vaccine researchers around the world knew we couldn’t afford to wait that long. The World Health Organization is organizing a group of experts to launch what has become known as the Solidarity Vaccine Test. Several vaccines will be given randomly to a large group of volunteers, while a smaller group will receive a placebo.
All vaccines will be tested against the same placebo group and all volunteers will live under the same circumstances. “You have a perfectly valid comparison not only to each of these placebo vaccines, but also to each other,” said Thomas Fleming, a biostatist at the University of Washington and a member of the Solidarity Vaccines test group.
It took nine months, but the process will begin later in October with a small study in Latin America.
At about the same time that the WHO was devising plans for its mega-trial, U.S. government officials were discussing how best to invest in – and accelerate – vaccine trials. Some researchers, including Dr. Fauci, have advocated a design similar to that of the WHO.
But Moncef Slavey, chief adviser to Operation Warp Speed, a multi-agency effort to accelerate the development of coronavirus vaccines and treatments, said in a statement that such a test would be impractical. “If OWS had tested all vaccines under one main protocol, the operation would have had to wait months before starting and recruiting 200,000 volunteers at a time.”
In the end, the government chose what it described as a “harmonized approach.” This will allow vaccine manufacturers to conduct their own trials, but only if they use protocols that follow certain guidelines and allow National Institutes of Health to test all their volunteers in the same way. In return for complying with these rules, the companies would touch on the large network of NIH clinical trials and receive significant financial support for their research. Through this program, the government has promised $ 10 billion to vaccine manufacturers to date.
So far, AstraZeneca, Johnson & Johnson and Moderna have begun testing online. Novavax and Sanofi are expected to begin their own phase 3 studies over the next few months. But Pfizer, one of the leading players, never joined the network, deciding to conduct tests 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 permit for its vaccine, potentially for only one group of high-risk people. The company can then quickly switch to applying for a license, making it widely available.
The authorization of a vaccine will depend on the degree of protection that the vaccine provides in phase 3 – what scientists call its effectiveness. In June, the FDA set a 50 percent efficacy target for a coronavirus vaccine.
But efficacy in a trial may not necessarily coincide with its effectiveness in the real world. This is the case, as in any statistical study, the Phase 3 experiments have errors. A vaccine that complies with FDA guidelines may actually be more than 50 percent effective or may be less effective. It may be only 35 percent effective.
Whether it’s Pfizer or another company, the first vaccine authorization could hamper competitors’ ongoing testing. Some volunteers, unsure whether they have been given an experimental vaccine or a placebo, may drop out of an ongoing trial to receive the authorized vaccine, delaying the tests. John Shiver, Sanofi’s global head of vaccine research and development, agreed that this scenario could be played out for the vaccine company’s trial.
Things can be even worse for vaccines in the earlier stages of testing. These products may need to be shown to be 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 need to be larger and last longer. Steep costs may be more than many small start-ups working with innovative vaccines can afford.
“This essentially prevents the development of better vaccines,” said Dr. Naor Bar-Zeev, a vaccine expert at Johns Hopkins University School of Medicine. “Given the huge investment of taxpayers, society needs to want better.”
The FDA guidelines raise the possibility of testing future vaccines against authorized ones, but they do not give a clear sense of whether the agency will change the testing requirements. “We can’t speculate on what may or may not happen in the future,” an FDA spokesman said.
Dr Slaoui of Operation Warp Speed said in a statement that once the vaccine is authorized, trials that have not yet begun or have just begun to recruit volunteers will be limited to groups that are not approved to receive the authorized vaccine. As the first wave of vaccines is likely to go to healthcare professionals or other high-risk groups, this policy may mean that these groups will not be allowed to be part of new clinical trials.
By spring or summer, there may be several coronavirus vaccines for American users to choose from. But this choice will be difficult. For example, a vaccine that shows 50 percent efficacy in one trial may actually be more protective than one that shows 60 percent efficacy in another study.
“I see people who read a lot about even minor differences, which could be just a statistical chance,” said Natalie Dean, a biostatist at the University of Florida.
In a phone call to reporters on Friday, Paul Mango, an employee of the Ministry of Health and Social Services, said that Operation Warp Speed was about to have up to 700 million doses of various vaccines by March or April – enough, he said. all Americans who want to get it. ”As for who gets which vaccine, he said it will be left to the advisory committee of the Centers for Disease Control and Prevention. “They will tell us which vaccine is best for which class of Americans,” he said.
But the advisory committee has no plan yet, and Dr. Grace Lee, a professor of pediatrics at Stanford University School of Medicine and a member of the committee, warned that it would be difficult to come up with one. “It’s hard to do, given all the uncertainty with Covid vaccines,” she said.
Even moderately effective vaccines will be a huge help in reducing the incidence of Covid-19 – but only if enough people take them and only if they realize that they can still get sick. “We will have to continue to use a mask for some of these vaccines,” said Dr. Poland of the Mayo Clinic.
The NIH’s harmonized approach to all Phase 3 trials receiving funding for Operation Warp Speed is likely to provide some scientific insights. It is possible, for example, that in all experiments, some molecular signature in the blood of a vaccinated person will indicate that he is protected. Future trials could simply look for these signatures instead of waiting for people to get sick.
However, there is no guarantee that such a clear signature will appear. And more uncertainty will arise as regulators continue to look for rare but dangerous side effects in permitted vaccines.
“You will have random events,” said Dr. Bar-Zeev. For example, a group of older people could have a stroke shortly after vaccination, raising the question of whether the vaccine is the culprit. “It is very possible that some vaccines will be withdrawn.”
The only way to deal with this chaotic year, Dr. Poland said, is for scientists to talk honestly about how vaccines are being tested and for people to know what’s next. “As long as you frame something in advance, people do better with it,” he said.
Sharon LaFraniere contributed to the report.