For the 20-something-year-old Hispanic man, volunteering for AstraZeneca’s Phase 3 Covid-19 vaccine study was an easy decision. His father, after all, had been briefly hospitalized with Covid-19, and, even beyond that personal motivation, signing up was “the right thing to do,” he told STAT.
The clinical trial participant, who lives in the western U.S., got his first shot in early September — he doesn’t know if he got the actual vaccine or a saline placebo, in line with the study’s double-blinded design — and he had been expecting to get a booster shot about four weeks later. But on Sept. 6, AstraZeneca, which is developing the vaccine with the University of Oxford, placed a halt on its studies of the vaccine around the globe due to safety concerns about a concerning illness in a participant in the U.K.
That hold has now been lifted everywhere except for the U.S. — meaning that study sites in the U.S. have not been administering second doses for the past month, and won’t do so until the trial resumes. It isn’t clear yet when that will happen, which has left the study participant who spoke with STAT and others in his situation in a sort of limbo. His scheduled appointment last week to get his booster shot was canceled, and he doesn’t know if he’ll ever be able to get the second dose.
Independent vaccine experts say there’s no need to worry about this group or their data, because such trials are carefully designed to account for situations in which participants can’t get a second dose. Asked about the participants who can’t currently get their second dose as scheduled, a spokesperson for AstraZeneca said: “We currently expect minimal impact based on the trial plans for 2nd dose timing.”
Still, such participants occupy an unusual position in a trial shutdown that is being closely watched as a potential indicator of the prospects of a frontrunner in the race to develop a vaccine to curb the devastation of the Covid-19 pandemic.
For the participant who spoke with STAT — and others in his same position who can’t currently get their booster shot — the trial halt has become a waiting game. “Now, we’re waiting as the lab rats in the corner,” said the participant, who requested anonymity because he was worried he could face consequences if study investigators found out he had spoken to the press.
It’s not clear how many participants fall into this bucket — AstraZeneca wouldn’t say — though it’s likely a small number, because the trial only officially started three weeks before the halt was placed, and dosing likely started later still. Some trial sites in the U.S. hadn’t yet begun enrolling participants at all by the time of the pause.
It’s also not clear whether participants whose second dose has been delayed will be able to get it at all. But according to the study protocol that AstraZeneca released last month, participants are due to get their second dose 28 days after the first, with leeway within a three-day window in both directions. It’s common for such trials to simply not give the second dose to participants who can’t get it within the established time frame, said Mark Slifka, a vaccine expert at Oregon Health and Science University whose research focuses on how long people are protected from a prior vaccination or infection.
There are many reasons why a vaccine trial participant may not be able to get their second dose as planned — they may become pregnant or move out of state, for example — and such trials are designed with the expectation that some fraction of them will be in that position, Slifka said. “There’s just unexpected circumstances that are not vaccine-related where a person just is unable to continue on with the study,” Slifka said. “It’s known that that happens.”
These circumstances, however, are vaccine-related. AstraZeneca has not said whether it will give participants a second dose if it would fall outside the prescribed window. But in this situation, it is possible that the trial investigators may feel they have an ethical responsibility to give these participants their second dose — or two doses of vaccine later, after unblinding, for participants who were randomized to the control arm.
In the event that does happen for some participants, there’s not reason to worry. “In general, spacing vaccines out with longer intervals between them is usually not associated with a decline in the immune response,” said Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn.
While data from previous studies of the vaccine suggest that a second dose may be able to increase the effectiveness of the vaccine, preliminary results suggest a booster might not be strictly necessary for an immune response. In an earlier-stage study of the same vaccine in the U.K., some participants were given just one dose of the vaccine, while others got a second dose, too, between four and eight weeks later. The study found that a single dose could elicit immune responses, but that antibody responses were boosted following a second dose.
AstraZeneca wouldn’t say how the trial will handle data from participants who can’t get their second dose as scheduled when it restarts. Its study protocol states that all randomized participants who receive at least one dose, regardless of whether they adhere to the protocol or continue to participate in the trial, will have their data scrutinized in what’s known as the “full analysis set.”
In general it’s typical for such trials to analyze data from such participants in what’s known as an “intent-to-treat” analysis, which accounts for deviations from the protocol. That’s separate from the “per-protocol” analysis, which includes data from only those participants who followed the protocol precisely. AstraZeneca’s study protocol states that its per-protocol analysis will include those participants in the full analysis set who “receive the correct dose of randomized treatment and who do not have a serious protocol deviation.”
When it comes to the AstraZeneca trial participants who can’t currently get their second dose, “the good news is they’re not going to be ignored. The good news is they’re going to be followed for safety, and they’ll also be followed for protection,” Slifka said.
Slifka also pointed to the size of AstraZeneca’s trial — the U.S. study aims to eventually enroll 30,000 participants — as cause for reassurance. “By having such a large trial, it also helps buffer against small changes like this that might have been unexpected,” Slifka said.
Matthew Herper contributed reporting.