AstraZeneca’s coronavirus vaccine was supposed to be the shot that dug the world out of the pandemic: a cheap, easy-to-administer dose that would protect not just citizens of wealthy nations but also those in the most vulnerable countries.

Instead, the inoculation, a collaboration between University of Oxford researchers and one of the world’s biggest drug companies, has been plagued with missteps as other vaccine rollouts gain speed. First, there was confusing basic science. Then missed delivery targets. Now, a confidence-sapping pause in Europe that followed reports of rare blood clots among a handful of the vaccinated.

If the stakes hadn’t been so high, the AstraZeneca saga might have felt like a soap opera, with soaring moments of scientific brilliance undercut by embarrassing mistakes. The Oxford team that developed the vaccine was bold — but also appeared arrogant to many scientists on both sides of the Atlantic.

Had the rollout of the AstraZeneca vaccine been handled differently, it might have been available far more widely by now, blunting a new wave of death and disease that is threatening lives around the world. Countries that have administered it widely, such as Britain, credit AstraZeneca with helping drive a dramatic drop in hospitalizations and deaths. But public confidence in the company’s vaccine has taken a major hit, slowing its acceptance and delaying the battle against the pandemic.

Nowhere have the consequences been clearer than in Europe, which bet heavily on AstraZeneca vaccine doses but has received just a third of what was promised. Now, many countries are shutting down yet again as the more contagious coronavirus variant first spotted in Britain races across the continent. Hungary broke records for deaths and cases Friday. France imposed a strict new shutdown in much of the country. Germany’s cases were up 50 percent last week. And opinion polls suggest public willingness to get an AstraZeneca vaccine is dropping.

“AstraZeneca has unfortunately underproduced and underdelivered,” European Commission President Ursula von der Leyen told reporters last week. “And this painfully, of course, reduced the speed of the vaccination campaign.”

AstraZeneca declined to comment on the record for this article, but pointed to a statement after European Union regulators reaffirmed the vaccine’s safety last week following review of the reports of blood clots.

The benefits “continue to far outweigh the risks,” the company said in the statement. “Analysis of AstraZeneca’s safety database on tens of millions of records for [the vaccine] did not show that these events occurred any more commonly than would be expected in millions of people.”

On Monday, the company released results of a large, long-awaited U.S. trial, saying that the vaccine was shown to be safe and 79 percent effective in preventing symptomatic disease. The company plans to request emergency use authorization in the United States within weeks.

The European Medicines Agency on March 18 said the benefits of the vaccine far outweighed the risks, while adding it can't rule out a link to rare blood clots. (Joshua Carroll/The Washington Post)

Bumpy science

The AstraZeneca vaccine surfed a wave of hype last spring. A front-page article in the New York Times declared that the Oxford vaccine was “sprinting fastest” and had leaped ahead of everyone else. Oxford scientist Sarah Gilbert said at the time she was 80 percent confident the vaccine would succeed — before a single person had received a shot in a clinical trial.

“From the very beginning, the Oxford group was having one press release after another, bragging how wonderful everything was,” said Hildegund C.J. Ertl, a scientist who works on the same vaccine technology at the Wistar Institute in Philadelphia and has collaborated with the Oxford scientists. “Talking about how wonderful something is before you’ve shown it is completely counterproductive. It was a big PR disaster.”

Adrian Hill, a key member of the Oxford team that developed the vaccine, argued that the early communication on the shot was accurate — and partly a response to Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, who predicted a coronavirus vaccine could be ready in 12 to 18 months.

“We disagreed. We said we’d shoot for September, and it’ll be this year. If that’s boastful, I’m sorry, but that was right,” Hill said in an interview. “We were frankly saying this could be done much faster.”

The scientists framed their work as a global solution — not just a shot for rich nations. AstraZeneca said it would not seek a profit on doses it made. It priced them at about $4 a shot — as little as a fifth of that of some of its competitors. The doses could be stored in ordinary refrigerators, unlike those from Pfizer-BioNTech and Moderna, making them easier to administer in developing countries with vulnerable health systems.

In May, months before rival vaccine makers Moderna or Pfizer-BioNTech launched large clinical trials, Oxford and AstraZeneca announced they would test their vaccine in 10,000 people in Britain.

Shortly after, the United States announced it would spend up to $1.2 billion for 300 million doses from the company that would begin to be available in October — the biggest initial U.S. order for a vaccine. But before shots could be administered in the United States, the AstraZeneca vaccine would need to be tested in a 30,000-person trial, a choice scientists made to ensure that multiple American vaccine trials would be roughly comparable — and large and diverse enough to adequately measure the safety and efficacy of the vaccines in many groups of people, including older adults and groups hit hardest by the pandemic. The trial wouldn’t begin until the end of August.

Even as Oxford’s trials raced forward, they hit snags. Rare neurological symptoms occurred in three people, two of whom received doses of the study vaccine, causing trials to be suspended worldwide to explore whether those might have been caused by the vaccine. There was no evidence of a connection, but the pause went on for weeks in the United States, setting the trial back.

Then some participants in the British trial unexpectedly received a first dose only half as strong as initially planned, and the explanations about why it happened were confusing, contradictory and slow to emerge. The problem appeared linked to an Italian subcontractor that used a different technique to measure the vaccine’s active ingredient.

Hill said researchers received regulators’ approval to give a new dose to trial recipients, and insisted that there was no mistake.

After the dosing error was revealed, the AstraZeneca team gave different explanations. Andrew Pollard, one of the lead Oxford research scientists, told The Washington Post last month: “It’s framed as an error, but actually it’s a scientific observation.”

That dosage issue later became a point of confusion when the company released trial results to the world in November. In the half-dose group, the efficacy of the vaccine shot up to 90 percent, compared with 62 percent in volunteers who received the full two-dose regimen.

The Oxford scientists were frank that they couldn’t explain why the unconventional dosing group had superior protection and said they were exploring explanations.

Ultimately, it became clear that instead of a four-week gap between shots, some participants in the half-dose group had received shots as much as three months apart, which could have explained the difference.

“We need to understand what’s behind it scientifically,” Moncef Slaoui, then the chief science adviser to Operation Warp Speed, said at a briefing.

U.S. scientists have expressed frustration about trying to understand how well the vaccine works and how to best use it given the existing data and confusing communication.

“The bottom line is the communication has not been good. And I don’t know whom to attribute that to, but clearly companies, especially vaccine development companies, have to have clear communication practices,” said Stanley Plotkin, inventor of the rubella vaccine. “And so there’s been misunderstanding, difficulty, even from the point of view of science, to understand what’s going on.”

Perhaps most important, some scientists say, the AstraZeneca team decided not to emphasize recruitment of older people for their initial clinical trials in the United Kingdom, and so no robust conclusion could be made about how well the vaccine protected people older than 65 — the group most at risk of serious illness.

“AstraZeneca has had some bad press, most of it undeserved, but some of it deserved,” said Paul Hunter, a professor of medicine at the University of East Anglia in Britain.

The company has defended its trials, saying its scientists were being cautious. But human studies by Pfizer-BioNTech and Moderna included plenty of older volunteers. The absence of data led some European countries to recommend against giving doses of the vaccine to older citizens.

Hill said if he could do things over, he wouldn’t change much — with the exception of potentially looking at the data even earlier, so that a vaccine could have been shown effective in August. He questioned why the AstraZeneca vaccine had to be subjected to further trials before being authorized in the United States.

“People are dying out there,” Hill said. “Why are they so hopelessly slow?”

European frustration

Europe bought into AstraZeneca’s promises that its vaccine would be a swift, effective solution, making it the centerpiece of a collective purchasing strategy negotiated on behalf of the E.U.’s 450 million residents. The European Commission bet heavily on AstraZeneca: 300 million doses in a mid-August contract, more than other vaccines.

European officials expected AstraZeneca’s vaccine to be ready first. But as fall edged into winter — and a deadly second wave washed away complacency — that started looking like a bad bet.

AstraZeneca was approved in the European Union at the end of January, six weeks later than rivals, at a time when a more contagious variant of the coronavirus was spreading across the continent and every day mattered. Compounding the already-delayed rollout, AstraZeneca chief executive Pascal Soriot had an unwelcome surprise for the Europeans: The bloc was supposed to receive 90 million doses by the end of March but would get only 30 million. Later, the company said its second-quarter delivery would fall short, too.

Europe erupted. There had been little warning — and in Britain, which approved the AstraZeneca vaccine a month earlier than the European Union, there had been no supply issues. E.U. leaders asked why.

“Everybody is getting kind of a bit, you know, aggravated or emotional about those things,” Soriot told Italy’s La Repubblica newspaper in an interview published Jan. 26. “It’s not a commitment we have to Europe. It’s a best effort.”

Von der Leyen, who as European Commission president had presided over the vaccine negotiations, imposed new rules that drug manufacturers needed to ask for permission before exporting E.U.-made vaccines outside of the bloc’s territory. Italy threatened to sue AstraZeneca for breach of contract. Latvian Foreign Minister Edgars Rinkevics vowed to “get nasty” in a late-January interview with The Post.

But European countries have had little recourse as Britain used its AstraZeneca doses to deliver a lightning-fast vaccine drive, bashing back a December surge and promising a far more normal summer. It has done so with a major dose of flag-waving after a broader pandemic response that was filled with missteps.

On a visit to a lab, “I could tell from the excitement of the scientists that this was promising and that the Oxford-AstraZeneca vaccine looked as though it would work,” British Prime Minister Boris Johnson wrote last week in an editorial in the Times of London. He was vaccinated Friday.

Even as Europe fought to get access to the AstraZeneca vaccine, leaders were undermining public confidence in the shot — a contradictory process that culminated with the pause in vaccinations last week.

In Denmark, Germany, Norway and elsewhere, regulators spotted reports of serious or fatal blood clots among young people who had been given doses of the AstraZeneca vaccine. They were just a handful — in Germany, seven people at the beginning of the week, out of 1.6 million people given doses of the vaccine in a month.

But regulators said it was statistically significant and halted vaccinations to investigate. Once Germany stopped, most other countries did the same, even though E.U. regulators and the World Health Organization begged them to keep going as they investigated.

In France, only residents younger than 65 were initially eligible for the vaccine, because the data for the elderly was so sparse. Then it expanded eligibility to include people up to 74. After Germany briefly suspended AstraZeneca’s use last week, France suddenly followed suit. On Friday, it gave a green light to use the vaccine again — but only for those 55 and older, because the blood clots were spotted mostly in younger people.

Through it all, the top E.U. regulator has been consistent: The shot is safe for everybody.

But the lurching back-and-forth has damaged public perceptions. Even before the uncertainty about the blood clots, teachers and medical workers unions in multiple countries had demanded Pfizer vaccine doses instead of AstraZeneca ones.

Vaccinations resumed Friday after Europe’s top regulator declared a day earlier that the advantages outweigh the risks.

Experts warned the public image of the vaccine would take a permanent hit. According to a survey poll by the Elabe Institute, a polling firm, published last week, almost 60 percent of the French said they do not trust the AstraZeneca vaccine, compared with 25 percent who said the same about the Pfizer shot. Polls in other countries show similar drops in confidence.

Global consequences

Amid the turmoil, some countries are abandoning their AstraZeneca purchases. New Zealand this month decided not to use its AstraZeneca order, opting to vaccinate exclusively with Pfizer’s vaccine and donate other manufacturers’ doses to countries that don’t have their own access. South Africa sold its AstraZeneca doses after researchers concluded it provides only “minimal protection” against mild to moderate covid-19 cases caused by the variant discovered in the country.

Other countries are still seeking out AstraZeneca doses: Australia and Canada are trying to buy more. And the United States sent some of its stockpile to Canada and Mexico last week, amid growing questions about the future of the doses in U.S. vaccination plans.

In the United States, an accelerating inoculation campaign is being fueled by three vaccines in increasingly plentiful supply: Pfizer-BioNTech, Moderna and Johnson & Johnson, raising questions about the need for another option. AstraZeneca’s fate depends on the 30,000-person, late-stage clinical trial being conducted at multiple sites in the United States, results for which were released Monday.

The trials found no increased risk of blood clots and, for people 65 and up, an efficacy of 80 percent, a development that may also help bolster European confidence in the vaccine.

Now the company plans to apply to the Food and Drug Administration for emergency use authorization. The agency will comb through the data and likely present its own analysis to its panel of outside experts. The vaccine could be cleared in late April or May.

Had the U.S. study data shown the two-shot AstraZeneca product to be less effective than the one-dose Johnson & Johnson vaccine, that would have raised an obvious question: Should the AstraZeneca vaccine be cleared, given the United States already has three effective vaccines?

Biden administration officials already were debating that question and the best course for public health in the United States and around the world.

The two-dose Pfizer and Moderna vaccines have efficacy of about 95 percent, according to clinical trial data. The Johnson & Johnson one-shot vaccine is 66 percent effective. U.S. regulators will examine the 79 percent efficacy rate for the new trial, which is better than the 62 percent found in Europe under the same protocol — two doses a month apart.

Within the FDA, there was some discomfort about Johnson & Johnson’s lower overall efficacy compared with Pfizer and Moderna, even though the shot cleared the 50 percent bar required for coronavirus vaccine authorizations. But those concerns were far outweighed by the appeal of a single-dose regimen, which offers tremendous savings of time and resources, and the vaccine’s high effectiveness against serious illness and death. The AstraZeneca vaccine shows similar protection against severe illness.

Some said the United States does not need the AstraZeneca vaccine, no matter what its efficacy. President Biden has said there will be enough vaccine doses from Pfizer-BioNTech, Moderna and Johnson & Johnson by the end of May to inoculate all U.S. adults.

“I don’t see any role for the AstraZeneca vaccine in the U.S.,” said Eric Topol, founder and director of Scripps Research Translational Institute. He hopes the U.S. study data will be good, that the FDA will authorize the vaccine and that the administration then will donate it to Covax, a global vaccine initiative linked to the WHO.

Elsewhere, the calculation involving AstraZeneca is far different. And in the European Union, where cases are up 30 percent in the past two weeks, policymakers say there is a desperate need for vaccinations.

“This is a safe and effective vaccine,” European Medicines Agency Director Emer Cooke told reporters as she cleared AstraZeneca for use. “If it were me, I would be vaccinated tomorrow.”

Birnbaum reported from Riga, Latvia; Johnson from Boulder, Colo.; and McGinley from Washington. William Booth in London, Quentin Ariès in Brussels, and Loveday Morris and Rick Noack in Berlin contributed to this report.