Results from AstraZeneca’s key US trial of its COVID-19 vaccine, issued by press release on Monday morning, exceeded experts’ expectations. But less than a day later, US health officials questioned the results, which still have not been released in full.
In a trial involving more than 32,000 volunteers, about two-thirds of whom received the vaccine, the shots had a 79% efficacy in preventing symptomatic COVID-19, the company said. This was based on 141 cases of the disease that occurred across the vaccine and placebo arms of the trial. There were no cases of severe disease requiring hospitalization among people given the vaccine, compared to five in the placebo arm, National Institute of Allergy and Infectious Diseases (NIAID) chief Anthony Fauci said during a White House press conference on Monday.
“The good news is also that there was comparable efficacy across ethnicity and age,” Fauci said.
But early Tuesday morning, NIAID released a highly unusual statement casting some doubt on the company’s report of its results. The company “may have included outdated information from that trial,” the statement said, “which may have provided an incomplete view of the efficacy data.”
The statement said that late on Monday, the Data Safety Monitoring Board, the independent panel of medical experts tasked with overseeing AstraZeneca’s US trial, notified NIAID and other health officials that it was “concerned” about the way the results had been presented.
On Tuesday morning, AstraZeneca responded to the concerns raised by the independent panel of experts. “The numbers published yesterday were based on a pre-specified interim analysis with a data cut-off of 17 February,” the company wrote. “We have reviewed the preliminary assessment of the primary analysis and the results were consistent with the interim analysis. We are now completing the validation of the statistical analysis.”
The company promised to “immediately engage” with the independent panel to “share our primary analysis with the most up to date efficacy data,” saying it would issue results within the next two days.
“As an FDA advisory committee member I want to see all the data — all the data that has been collected. Any experience with this. Anything that’s relevant to the decision,” said Paul Offit, a vaccine expert at the Children’s Hospital of Philadelphia, who sits on the FDA’s vaccine advisory committee. “Because the most important thing we consider with these vaccines is safety. Safety, safety, safety.”
Appearing on Good Morning America on Tuesday, Fauci said that the DSMB wrote a “rather harsh note” to AstraZeneca, copying Fauci, saying that they felt the data in the press release “might in fact be misleading a bit.”
“It really is unfortunate that this happened,” Fauci said. “This is really what you call an unforced error, because the fact is this is very likely a very good vaccine.”
Other experts expressed similar concerns about how the company had presented its data.
“It is a good vaccine, but this sort of public relations stuff makes it all a bit messier and more complicated. It’s more difficult for the public to parse out what’s going on. We just want a clean straightforward process that is easy to interpret,” Natalie Dean, a biostatistician at the University of Florida, told BuzzFeed News. “We don’t really have any details. But just the appearance of it all isn’t doing anyone any favors.”
The statement from NIAID caught many scientists off-guard.
“We’re in uncharted territory. DSMBs don’t normally do things like this,
and the bar for a federal agency to issue a statement raising concerns
about a high profile corporate trial is surely very, very high,” John Moore, a virologist at Weill Cornell Medical College in New York, told BuzzFeed News by email.
The statement from US health officials is just the latest in a series of problems that the AstraZeneca COVID-19 vaccine trials have faced.
Earlier results from trials in the UK and Brazil — run by the University of Oxford, which developed the vaccine — had indicated around 70% efficacy overall. But scientists were critical of those trials, which had included an array of experimental subgroups with patients of different age ranges, doses, and intervals between the two shots of the vaccine, making it very hard to interpret the numbers.
This also meant that the Oxford team had been unable to gather enough data to answer a key question: Does the vaccine protect older people who are most vulnerable to COVID-19 from getting sick? That caused some nations, initially including Germany, to delay authorizing the vaccine for use in older age groups.
The new trial finally has enough data to answer this question, according to the company’s release. Analysis of the results among people ages 65 and older indicated 80% efficacy in preventing symptomatic COVID-19.
“These findings reconfirm previous results observed in AZD1222 trials across all adult populations but it’s exciting to see similar efficacy results in people over 65 for the first time,” Ann Halsey of the University of Rochester School of Medicine, who co-led the trial for AstraZeneca, said in the company’s release.
Crucially, the new trial, run in the US and several other countries, is a much simpler design than those run by the Oxford team, with just two experimental groups. Volunteers were either given two doses of the vaccine four weeks apart or two saline injections as a placebo control.
Moore, who has been a prominent critic of the Oxford-run trials, last week described the US trial to BuzzFeed News as a “rigid protocol” that should produce findings that are easier to assess.
The company has not yet released any data beyond the results summarized in its press release but said a paper “will be submitted for publication in a peer-reviewed journal.” The results will also be submitted as the centerpiece of AstraZeneca’s application to the FDA to have the vaccine authorized for emergency use in the US.
“We are preparing to submit these findings to the US Food and Drug Administration and for the rollout of millions of doses across America should the vaccine be granted US Emergency Use Authorization,” Mene Pangalos, AstraZeneca’s executive vice president for biopharmaceuticals, said in Monday’s release.
These results suggest that AstraZeneca’s two-dose vaccine is a little more effective at preventing COVID-19 than the single-shot vaccine made by Johnson & Johnson, which was 66% effective in preventing disease in its major trial. Both seem less effective than the two-shot vaccines made by Pfizer/BioNTech and Moderna, which exceeded 90% efficacy. All four vaccines seem to provide very strong protection against severe COVID-19.
The new trial results come after a safety scare for the AstraZeneca vaccine last week, when many European nations temporarily withdrew the vaccine from use after reports of rare but serious blood clots.
The European Medicines Agency then analyzed data for almost 20 million people who were given the vaccine, finding 18 cases of cerebral venous sinus thrombosis (CVST), which can prevent blood draining from the brain and cause hemorrhages, and seven cases of disseminated intravascular coagulation (DIC), which causes clots in tiny blood vessels throughout the body. While the agency was unable to rule out a link with the vaccine, it said that benefits of the vaccine in preventing COVID-19 far outweighed the risk of these serious but very rare conditions, and recommended that vaccination resume.
AstraZeneca said it found no cases of CVST in its trial. This was expected, since the condition is very rare and only around 21,000 people were given the vaccine in the trial.
Even before Tuesday’s statement from US health officials, some experts were concerned that the vaccine’s troubled history might make it less attractive to the US public than the alternatives that are already available.
“The FDA now has to make a decision, but even if this vaccine is approved it could be difficult to persuade the public to take it,” Moore told BuzzFeed News on Monday. “Perception can become reality in situations like this, and the public trust simply may not be there now.”
Last week, the Biden administration announced that it would loan millions of pre-manufactured doses of the AstraZeneca vaccine to Canada and Mexico, where it has already been approved.
Dan Vergano contributed reporting for this story.