During a press conference in early September, President Donald Trump was asked when he thought a vaccine for COVID-19 might become available. His prediction was upbeat: “We’re going to have a vaccine very soon,” Trump said. “Maybe even before a very special day—you know what day I’m talking about.”
Trump was referring, of course, to the presidential election on November 3. But the odds of a vaccine materializing for public use before then appear slim. New drugs and vaccines ordinarily go through a lengthy review process prior to regulatory approval. Vaccines for COVID-19, however, are widely expected to be released under emergency use authorization (EUA) protocols, which allow for the sale of unapproved medical products during national health crises. On October 6 the White House agreed to new EUA guidelines that call on COVID-19 vaccine developers to monitor their phase III clinical trial subjects for at least two months for side effects and severe disease. The U.S. Food and Drug Administration, which administers EUAs, will host a widely anticipated meeting on October 22 to address standards for efficacy, safety and manufacturing of COVID-19 vaccines. But the FDA’s recommended two-month observation period puts a preelection vaccine approval out of reach.
EUAs could, however, make the first successful COVID-19 vaccines available to frontline workers by the start of 2021, although distribution in the general U.S. population will take longer, starting with elderly and other high-risk groups and then younger, healthier people who may not have access to them until late in the year, according to Paul Offit, a pediatrician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. The FDA has already granted hundreds of COVID-related EUAs for products such as diagnostic tests, medical devices and therapies—including for convalescent plasma and hydroxychloroquine (the latter was later revoked).
“All the COVID-19 vaccine developers are going for an EUA first,” says Eric Topol, a cardiologist and head of the Scripps Research Translational Institute in La Jolla, Calif., who has directed numerous multinational clinical trials (although none for vaccines). “It makes no sense to wait for formal licensure.”
Obtaining an EUA hinges on how independent reviewers judge a vaccine’s performance during periodic readouts of phase III clinical trial data. The trials are each enrolling tens of thousands of people and are also double-blinded—meaning that neither the subjects nor the experimenters know which participants got a vaccine versus a placebo. They were designed to continue until the number of symptomatic infections reaches 150 in the vaccinated and control groups combined. If a vaccine halves the risk of symptomatic infections among the vaccinated group, it will meet the FDA’s minimum bar for approval.
Reviewers examining the interim data readouts will be looking for better protection than that. Pfizer, which began a phase III trial for its vaccine on July 27, plans to conduct its first readout when the number of symptomatic cases reaches 32. The company expects that could happen this month, making it first in line for a potential EUA. Statistical thresholds are set such that if COVID case numbers in the vaccinated group are, at that point, at least five times lower than they are among unvaccinated subjects, then reviewers can declare overwhelming efficacy. In that event, the company will “consult with regulatory authorities about next steps,” which could include an EUA, says a Pfizer spokesperson. In an October 16 open letter, Pfizer chairman and CEO Albert Bourla wrote that if the efficacy data are positive, the company will apply for an EUA in the U.S. “soon after the safety milestone is achieved in the third week of November.” The company’s study protocol also includes data readouts at 62, 92 and 120 cases, respectively, although the amount of protection the vaccine has to achieve at each step declines progressively until it reaches the FDA’s minimum target of 50 percent.
Other companies racing to develop COVID-19 vaccines are taking a less aggressive approach: Cambridge, Mass.–based Moderna, for instance, plans for a first data readout when it reaches 53 cases among its study subjects and another at 106 cases. The company anticipates filing for an EUA in late November. Meanwhile Johnson & Johnson recently paused its clinical trials after a participant got sick. This delay follows a similar pause by AstraZeneca, which has since resumed its trials outside of the U.S.
What Happens Postapproval
A significant issue is how vaccine developers will continue to assess safety and efficacy after an EUA. The FDA has said they should include strategies for monitoring a vaccine’s long-term performance in their EUA applications and generate the data needed to support future licensing. The agency has also stressed that companies should continue collecting placebo-controlled trial data for as long as feasible. Yet Pfizer representatives said in an e-mail that if an interim readout shows overwhelming efficacy, they have the option to unblind the data, vaccinate placebo recipients and then follow all the subjects in an unblinded fashion—meaning experimenters and participants would know who got the vaccine. (A Pfizer spokesperson later said the company would only unblind the study with regulatory approval.)
The problem with unblinding the data is that a compromised control group “makes it harder to ascertain a vaccine’s risks and benefits and, in particular, how well it protects against severe disease—which isn’t as common as milder infections,” says Peter Gilbert, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, who helped design clinical trials for the leading U.S. candidates.
Topol argues that with a few more weeks, developers could amass the 150 cases that might allow them to more fully assess protection from severe disease, especially in elderly and other vulnerable populations. “There shouldn’t be any shortcuts,” he says. “We’re talking about giving these vaccines to billions of people. You can’t risk compromising public trust.”
Echoing those concerns, Patricia Whitley-Williams, an infectious disease specialist at Rutgers University’s Robert Wood Johnson Medical School, worries that doctors who mainly treat African-Americans and other people of color might be reluctant to recommend vaccines that they believe have not been adequately tested in these populations. Black Americans are hospitalized with COVID-19 at nearly three times the rate white Americans are, so with vaccination, “we need time to look at potential harms in all ethnic, age and gender groups,” she says.
Still, if a vaccine’s interim review shows very high efficacy—say, 90 percent or greater—there will be “appropriate pressure to offer it to control groups immediately,” Gilbert says. These sorts of scenarios are under discussion now, he says, and what is unknown is how many control subjects will opt to be vaccinated if given the opportunity. Gilbert adds that more safety and efficacy data will come from so-called phase IV studies, which monitor immunized people after a vaccine has reached the market. One way to conduct these studies is for researchers to scour health data for cases of severe COVID-19 and assess vaccination histories among them.
Vaccine developers are already gearing up for what is expected to be the largest immunization program in history. Larry St. Onge, president of life sciences and health care at the global shipping company DHL, says the “mRNA vaccines” developed by Pfizer and Moderna, which need to be stored at temperatures below –70 degrees Celsius, will face the greatest distribution challenges, especially in parts of the developing world where climates are harsh. Even as vaccine manufacturing ramps up to meet global demand, the logistics industry is building the capacity for vaccine delivery that “we don’t currently have in some countries,” St. Onge says. “This takes a lot of planning and forethought. But the world fully understands how important it is to get these vaccines out here so we can achieve some level of normalcy.”