Think about a vaccine against Covid-19 like the venerable winter sport of curling. The giant granite stone sliding along the ice (the “sheet”) inexorably toward a target (the “house”) is President Donald Trump, sunny optimist, touting a vaccine “sometime in October.” That’s only two weeks away! Except the president has also shown no compunction against pressuring his nominally science-based advisers to give the thumbs-up to drugs that haven’t proven effective. (See, for example, the Food and Drug Administration’s authorizations of hydroxychloroquine and convalescent plasma.)
So trying to change the momentum of that ponderous chunk of stone are people with brooms frantically sweeping the path ahead of its arrival. Look! There’s Robert Redfield, director of the Centers for Disease Control and Prevention, telling everyone that masks are critical to slowing the disease’s spread and that a safe and effective vaccine just can’t be ready before 2021 (and getting crushed underneath the encroaching president-rock for his trouble). Brushing even more furiously are the heads of nine pharmaceutical companies, signatories to an unprecedented pledge that they won’t try to get one of those too-early authorizations from the government without good science. (They also bought a newspaper ad saying the same thing.) You can almost hear the whish-whish-whishing of the brooms—the whishful thinking, if you will—trying to alter the president’s course away from authorizing a vaccine that doesn’t exist or doesn’t work in an attempt to juice his chances at reelection in November. Because that might also blow up people’s belief in vaccines and science in general. That would be bad.
It might have already happened. A recent poll from the Pew Research Center says just 51 percent of Americans would definitely or probably get a Covid-19 vaccine if one were available today—down almost 20 points since May. Fully 49 percent of those polled said they would definitely or probably not get a vaccine. Claims from the president and his allies that one was imminent, combined with cautions from people like me that one was almost certainly not, have merged with a generalized cloud of anti-science rhetoric, vaccine hesitancy, and straight-up QAnon/antivaxxer crazypantsness to put us here, out on the end of the curling sheet, nowhere near the house. And the ice we are standing on is thin.
Here’s what’s going on: Three vaccine candidates are in large-scale, Phase III randomized clinical trials with tens of thousands of human volunteers. They’re from the pharmaceutical companies Pfizer, Moderna, and AstraZeneca. The Moderna and Pfizer vaccines use the genetic material mRNA to induce an immune response; the AstraZeneca vaccine, developed at the University of Oxford, uses the shell of an adenovirus to give people a protein found on the exterior of the SARS-CoV-2 virus (which causes Covid-19), also inducing an immune response. Getting to Phase III in half a year is astonishingly fast for huge drug trials, especially considering nobody even knew about the disease they want to vaccinate against as recently as November of 2019.
Science-watchers agree here that the key to a successful Covid-19 vaccine will be twofold. First, it’s gotta work, and not hurt people in the process. That’s harder than you’d think for a fast-tracked drug intended to be given to hundreds of millions of people. Those numbers quite literally leave a lot of room for error—and require carefully developed protocols for trials. But the second thing may be just as important—you need a communications strategy that explains exactly what the drug does and how it does it.
“I think by the end of the year, we should have enough data on the efficacy and safety for at least the two mRNA vaccines to know whether they seem to be working and if they’re not showing any big safety signal. As we move into the new year, we should potentially start releasing vaccines to the public,” says Peter Hotez, a vaccine expert and dean of the National School of Tropical Medicine at Baylor School of Medicine. The tricky bit there, he says, is under what regulatory auspices all that might happen. “Ideally, it would have been done through a full approval process or an expedited review. But because that can take 6 to 8 months, the thinking is, there are alternatives—like going through the expanded access program. But I think what’s likely is they will be released through an Expanded Use Authorization.”
That’s an FDA rule by which a drug that looks promising and seems safe can get expedited. But that system has never been applied to a large-scale vaccine, so nobody really knows the rules. And since it’s also what hydroxychloroquine and convalescent plasma got (and then, for hydroxychloroquine, lost), EUAs now look sketchy or compromised. “Normally we would trust the FDA, but we now know the FDA isn’t trustworthy, because we’ve seen too many times where it caved and was lacking independence from the Trump administration,” says Eric Topol, a professor of molecular medicine at the Scripps Research Institute who has been following Covid-19 research. “The companies started to address this trust gap by publishing that ad and having the written pledge. That was a good thing, but it doesn’t get us far enough.”
That’s why the two companies furthest along in their vaccine trials—Moderna and Pfizer—have now released the full protocols for their trials. A spokesperson for a third company, AstraZeneca, confirms that it’ll be releasing its protocol “shortly” as well. (Update! AstraZeneca posted its protocol Saturday, a few hours after we initially published this story.) Ordinarily those protocols wouldn’t be public until the results came out, and only data nerds would care. But these are not ordinary times. “The public health stakes are so high, we know there’s existing vaccine hesitancy, and we know there are concerns about the political context in which FDA is operating,” says Patti Zettler, a professor at Ohio State University’s Moritz College of Law and former associate chief counsel at the FDA. “I don’t have a legal opinion as to whether FDA is allowed to be more transparent right now, but it’s also true that companies can voluntarily be more transparent. The more that balanced, accurate, complete scientific information is shared, the better right now.”
(A spokesperson for the FDA declined to comment.)
The multiple pressures on the pharmaceutical companies working on vaccines make these extraordinary times even more extraordinary. Drug companies basically never try to push back against getting expedient approval of their products, because they’re for-profit businesses trying to sell stuff. Yet here they’re trying to distance themselves from politically motivated, unsafe Emergency Use Authorizations from the FDA. (Of course, if the stuff they’re selling is unsafe or doesn’t work, that’s no good for market share, either.) Policy experts sometimes describe the process of industries controlling the agencies that oversee them through lobbying or other influence peddling as “regulatory capture.” Now the pharma companies seem to be worried about the direct inverse of that—political capture by leadership up the line that could threaten the market standing of the companies, not to mention the lives of their customers.
In response, the companies have to insist—to prove—that they’re holding themselves to the highest scientific standards. “There’s this alignment of interests. The public health community really wants these trials to be done carefully, and the president wants them to be done quickly. I think pharmaceutical companies are, with this pledge, aligning themselves with the public health community,” says Seema Shah, a bioethicist at Lurie Children’s Hospital of Chicago who has written on vaccine trial ethics. “The big question to me is, how much are these pharmaceutical companies willing to push back at the FDA? If the FDA signals it’s willing to grant an EUA when they don’t think there’s sufficient data, will they hold back?”
The newly available protocols signal that they might be willing—and more. “Pfizer traditionally has not shared the full in-depth study protocol for any of its programs until the publication of the pivotal trial data. We recognize, however, that the Covid-19 pandemic is a unique circumstance and the need for transparency is clear,” Amy Rose, a company spokesperson, wrote via email. “As a result, the company is making the full protocol for its self-funded Covid-19 vaccine pivotal study available to reinforce Pfizer’s long-standing commitment to scientific and regulatory rigor that benefits patients.”
Mostly, the protocols are just thick volumes of procedures—the instruction manuals for the trials. How big a dose of vaccine will participants in the experimental group get, and how many? How will they be monitored, and for what symptoms? For how long? What will count as an infection? How will the data be accounted for? Publishing the protocols in advance is all about accountability. These are the rules the companies plan to abide by, available for criticism but also to ensure that nobody does any shenanigans on the other end, cherry-picking data or changing what counts as success.
The details, though, also give some clues as to how the next few months will go. For one thing, both protocols take so much time to put into action that it’s next to impossible that a vaccine will be available before Election Day. Everyone has to get two doses, and the studies must allow enough time to monitor their outcomes.
(I emailed representatives of the other six signatories to the vaccine science pledge asking if they, too, planned to release their research protocols. Spokespeople at Johnson & Johnson, Merck, GlaxoSmithKline, BioNTech, Novavax, and Sanofi all declined to comment.)
Still, even public protocols might not be enough to get the scientific community on board. Hotez hopes the companies will release not only their protocols but also their full Phase III data. He also wonders what an EUA might mean for the other vaccine trials. Ordinarily, ethics would dictate that once a vaccine is available, trials of other candidates should stop. By definition, the risks of those trials now outweigh the potential future rewards. Except here, those other candidates might be better, safer, whatever. EUAs don’t have any guidelines for that, and neither the FDA nor the president have articulated any. They might be forthcoming, but Hotez says he thinks the president is more interested in reelection than vaccines. “He wants a vaccine released under EUA, sort of now, right? He’s never created a national road map or response to Covid-19, this is undermining his candidacy for reelection, and he feels he needs a victory in the area of Covid-19 to be successful,” Hotez says. “But I don’t see a way by which we’d know that vaccines were safe and effective if he tries to release a vaccine in October. So we’re in a bit of a standoff. The scientific community is holding a line.”
It has to; there’s a lot to be suspicious about. Moderna’s leadership has been criticized for questionable stock trades and hyping preliminary results. And in early September, AstraZeneca officials announced that they were pausing their vaccine trial due to an “adverse event”—some kind of medical issue that forced the researchers to stop and determine whether it was a consequence of taking the vaccine. And it wasn’t the first time. A participant got ill in the summer, but they turned out to have a neurological disorder unconnected to the vaccine. This time, an otherwise healthy 37-year-old woman developed a spinal inflammation that looked like a neurological disorder called transverse myelitis, which some scientists think could be an immune issue. That’s disconcerting when it comes to vaccines. But AstraZeneca didn’t release those details on purpose; Stat got them via leaks from a presentation the company made to investors, and CNN obtained an internal report. That’s not transparency. (The trial has since restarted in the UK, and a spokesperson told me they expect it to restart in the US soon.)
And all of these political and scientific pressures combine, like separate wildfires cresting the same hill. When they swirl together with general anti-science sentiment and vaccine hesitancy, you get a fire tornado of skepticism. That’s why the trustworthiness of the science will be so important, and so important to communicate—to three disparate groups of people beyond the science community. One is antivaxxers and the vaccine-hesitant. Another is the people who have little information, who may even be outside the health care system altogether. “But the third group is the one that’s the most interesting in this case. They’re worried about the rush. They’re worried about the fact that there’s political pressure. So they’re going to be a little skeptical until they see pretty good evidence that the vaccine being offered is good,” says Christine Grady, chief of the Division of Bioethics at the National Institutes of Health Clinical Center. “Yes, you can message it. It’s not easy to do, but you can. The way the trial was run, ethically and methodologically and rigorously, will matter a lot.” The key is making sure that the trials are run well, and then saying so loudly enough that people believe it.
Updated 9/19/20 1:44 PM PDT to include a link to the AstraZeneca clinical trial protocol.
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