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Blunders Eroded U.S. Confidence in Early Vaccine Front-Runner

On the afternoon of Sept. 8, AstraZeneca officials had a conference call with the Food and Drug Administration. The discussion covered important ground: What would AstraZeneca need to do to win the F.D.A.’s blessing for the coronavirus vaccine it was developing with the University of Oxford?

But the AstraZeneca representatives neglected to mention a crucial development: Two days earlier, the company had quietly halted trials of its vaccine around the world, including a late-stage study in the United States. It acted after a participant in Britain fell ill.

A few hours after the conference call, the story broke about the halted trials. That was how key F.D.A. officials heard the news, according to people with knowledge of the discussions.

The F.D.A.’s commissioner, Dr. Stephen Hahn, was stunned by AstraZeneca’s failure to disclose the halt to regulators, one of the people said. The U.S. government had pledged more than $1 billion to AstraZeneca to finance the development and manufacturing of its vaccine and to supply the United States with 300 million doses if it proved effective. F.D.A. regulators expected to be kept in the loop.

The episode might have been chalked up to a simple miscue. But it was part of a pattern of communication blunders by AstraZeneca that have damaged the company’s relationship with regulators, raised doubts about whether its vaccine will stand up to intense public and scientific scrutiny and, in at least one instance, slowed the vaccine’s development.

The result is that a vaccine that was expected to account for a substantial portion — by one metric, as much as 60 percent — of the total vaccine supply in the United States faces an uncertain future. Two other highly effective vaccines are nearing federal authorization. But with more than 2,000 Americans dying daily, a delay of even a few weeks in deploying another effective vaccine could have deadly repercussions.

Federal officials and public health experts viewed AstraZeneca’s vaccine, which is less expensive and easier to store for long periods than some rival vaccines, as a leading candidate to help bring a swift end to the pandemic.

AstraZeneca officials repeatedly said they hoped to roll out their vaccine in the United States as early as October. Today, though, AstraZeneca hasn’t even finished enrolling people in its U.S. clinical trial. A key reason: The trial was grounded for nearly seven weeks because the company was slow to provide the F.D.A. with evidence that the vaccine was not associated with neurological symptoms that had appeared in two clinical-trial participants, according to the people with knowledge of the discussions.

On Tuesday, Oxford researchers published detailed data from their clinical trials in the scientific journal The Lancet. The study built on findings that the developers had announced last month showing that their vaccine worked, but that its effectiveness varied widely depending on the strength of doses.

Regulators in Britain, India and several other countries, armed with data from clinical trials outside the United States, are expected to authorize the vaccine’s use in the coming weeks. But in the United States, where regulators have been frustrated with AstraZeneca and want to examine data from a greater number of participants, that approval appears further off.

Developing vaccines is hard, and it is common for the work to fall behind schedule. Moderna and Pfizer, whose coronavirus vaccines appear to be 95 percent effective and are awaiting federal authorization, also faced delays. And even with the problems, AstraZeneca and Oxford’s vaccine is likely to be among the fastest ever developed.

Yet independent scientists and industry analysts have criticized AstraZeneca and Oxford for not being sufficiently transparent about their early results, the design of their studies and safety issues. Most critically, it is not clear how well the vaccine works.

“The world bet on this vaccine,” said Dr. Eric Topol, a clinical trial expert at Scripps Research in San Diego. “What a disappointment.”

He added, “If they just were upfront on safety, on efficacy, on dosing, on everything, from the get-go, they’d be in such a better position. But what they’ve done now is diminish credibility, and I don’t know how they’re going to regain that.”

In an interview on Tuesday, Prof. Andrew Pollard, the lead investigator of the Oxford vaccine trial, said the Oxford team had been “as transparent as we can all along.” He noted the team’s publication of peer-reviewed articles and trial blueprints.

“We continue to share all data with the F.D.A. and other regulators around the world in a timely manner,” said an AstraZeneca spokeswoman, Michele Meixell.

An F.D.A. spokeswoman declined to comment.

Years in the Making

Scientists at Oxford had been laying the groundwork for a vaccine for years.

The vaccine uses an approach that scientists have been testing for decades. It involves genetically modifying a harmless virus, known as an adenovirus, that causes the common cold in chimpanzees so that it can train the immune system to respond to a threatening virus — in this case, the one that causes Covid-19.

In 2018, Oxford researchers had run a safety study using a vaccine deploying that approach to protect against the coronavirus that causes Middle East respiratory syndrome, or MERS. Last December, as the virus now known to cause Covid-19 was spreading undetected in China, a second trial to test that MERS vaccine got underway in Saudi Arabia.

So when Covid-19 emerged, Oxford researchers had at the ready a vaccine platform that had been shown to be safe in use against a similar coronavirus.

When Chinese researchers released the genetic sequence of the virus that causes Covid-19 on Jan. 9, an Oxford vaccine researcher, Dr. Sarah Gilbert, was able to start work the very next day.

Dr. Gilbert’s team raced to insert genetic material from Covid-19 into its adenovirus platform. By March, the vaccine was being tested in monkeys in Montana.

A next step for Oxford was to find a pharmaceutical company to shepherd the vaccine through development — and, eventually, to mass-produce and distribute it.

At the time, the Trump administration was fighting for first-in-line access for certain vaccines. British health officials, who provided early funding to the Oxford team, believed that any homegrown vaccine should be quickly and easily accessible to Britons. “They made it pretty clear to me and others that they wanted to know about the deal and they were anxious about vaccine nationalism,” Dr. John Bell, an Oxford professor and a member of the British government’s vaccine task force, said in an interview in September.

AstraZeneca was not Oxford’s first choice. Dr. Gilbert’s team had been in discussions with “a previous company or two,” Adrian Hill, one of the Oxford scientists, said last month. One was the American pharmaceutical giant Merck, The Wall Street Journal reported.

But those talks fell apart, and AstraZeneca, a British company, emerged as a safe alternative. The company agreed to distribute the vaccine worldwide at cost — only a few dollars per dose — until at least July 2021 and in poorer countries forever.

The downside was that AstraZeneca, which is known for drugs to treat cancer, asthma and other chronic conditions, had scant experience with vaccines.

Hundreds of Millions of Doses

From the start, Oxford scientists expressed great confidence. In April, Dr. Gilbert told a British newspaper that she was 80 percent sure the vaccine would work, even though it had not been tested in humans. By then, Moderna had already started testing its vaccine candidate on people.

The Oxford team’s claims encountered skepticism from some scientists who expressed doubts about the approach and the ambitious timeline. “Some were a little cynical of the hubristic claims that were being made,” said Stuart Neil, a virologist at King’s College London.

The British and American governments nonetheless poured money into the vaccine.

Britain ordered 100 million doses, with the goal that 30 million would be delivered by September.

In the United States, Operation Warp Speed, the federal initiative to fast-track vaccine development, in May made what was then its biggest investment. The government awarded AstraZeneca up to $1.2 billion for development and manufacturing of the vaccine in exchange for 300 million doses. Alex M. Azar II, the health secretary, played up the deal as “a major milestone” in the program’s work. AstraZeneca’s stock hit a record high.

Those 300 million doses represent 60 percent of what the United States has ordered from the three manufacturers that have announced late-stage results so far. If other vaccines reach fruition or if the U.S. government exercises options to buy more doses, the reliance on the AstraZeneca candidate would decline substantially.

More countries soon placed orders. Even if other vaccines become available, the AstraZeneca offering is on track to account for 43 percent of all doses available in low- and middle-income countries, according to Airfinity, an analytics firm that tracks deals between vaccine manufacturers and governments.

AstraZeneca, however, would not begin testing its vaccine in the United States until August, three months after the Warp Speed deal. That was long after Oxford had started running trials elsewhere in the world — a delay that would prove fateful for the United States.

A Strange Discrepancy

In Britain, Oxford researchers wrapped up their first safety trial in May. No serious problems surfaced. Their next step was a larger so-called Phase 2/3 study, involving thousands of British participants, to assess how well the vaccine worked.

Oxford hired an outside manufacturer to produce large quantities of the vaccine for the trial. But when researchers received a sample of the vaccine and measured its strength, they noticed something strange. Using a different measurement technique than the manufacturer, Oxford found the concentration of viral particles in the vaccine to be double the level that the manufacturer had found.

Oxford researchers didn’t know which measurement to trust. They decided to use a lower-strength dose. That way, even if their measurement was wrong, the dosage was sure to be safe, albeit smaller than originally intended.

Participants would get two injections, which were supposed to be about a month apart. Oxford began administering the vaccine. Within a few days, participants reported fewer side effects like sore arms or slight fevers than participants had during the first trial. The Oxford researchers later identified an ingredient in the outside manufacturer’s vaccine batch that had skewed their measurement upward. That confirmed they were using a half-strength dose.

When the confusion over the dosing emerged months later, it would complicate efforts by scientists and public health officials to understand how well the vaccine worked.

In the meantime, public health authorities were increasingly embracing the inexpensive, easy-to-produce vaccine. In June, Soumya Swaminathan, the World Health Organization’s chief scientist, called it “probably the leading candidate.” In July, the head of the British government’s vaccine task force, Kate Bingham, told lawmakers that it was “the most advanced vaccine anywhere in the world.”

Trump administration officials, too, were enthusiastic. The White House chief of staff, Mark Meadows, told congressional leaders on July 30 that the Oxford-AstraZeneca vaccine could win emergency authorization from the F.D.A. as early as September, two people briefed on the discussion previously told The New York Times. (A spokesman for Mr. Meadows disputed that he had discussed AstraZeneca’s prospects.)

Such optimism was premature.

Federal health officials had said in June that in order to authorize a vaccine, the F.D.A. would likely need to see late-stage data from at least 30,000 trial participants. By then, Oxford’s trials in Britain and Brazil were underway, and even if their results were pooled they would fall short of that F.D.A. threshold. (The agency has never closed the door on relying entirely on data from overseas trials to authorize a vaccine.)

AstraZeneca planned for its U.S. trial to include 30,000 people. But that trial was weeks away from even starting.

Neurological Symptoms

Then came a safety scare.

A British participant in the Phase 2/3 trial developed neurological symptoms consistent with transverse myelitis, an inflammatory syndrome that affects the spinal cord and is often caused by viral infections, according to a notice given to participants dated July 12. That trial was briefly paused.

The Road to a Coronavirus Vaccine

Words to Know About Vaccines

Confused by the all technical terms used to describe how vaccines work and are investigated? Let us help:

    • Adverse event: A health problem that crops up in volunteers in a clinical trial of a vaccine or a drug. An adverse event isn’t always caused by the treatment tested in the trial.
    • Antibody: A protein produced by the immune system that can attach to a pathogen such as the coronavirus and stop it from infecting cells.
    • Approval, licensure and emergency use authorization: Drugs, vaccines and medical devices cannot be sold in the United States without gaining approval from the Food and Drug Administration, also known as licensure. After a company submits the results of  clinical trials to the F.D.A. for consideration, the agency decides whether the product is safe and effective, a process that generally takes many months. If the country is facing an emergency — like a pandemic — a company may apply instead for an emergency use authorization, which can be granted considerably faster.
    • Background rate: How often a health problem, known as an adverse event, arises in the general population. To determine if a vaccine or a drug is safe, researchers compare the rate of adverse events in a trial to the background rate.
    • Efficacy: The benefit that a vaccine provides compared to a placebo, as measured in a clinical trial. To test a coronavirus vaccine, for instance, researchers compare how many people in the vaccinated and placebo groups get Covid-19. Effectiveness, by contrast, is the benefit that a vaccine or a drug provides out in the real world. A vaccine’s effectiveness may turn out to be lower or higher than its efficacy.
    • Phase 1, 2, and 3 trials: Clinical trials typically take place in three stages. Phase 1 trials usually involve a few dozen people and are designed to observe whether a vaccine or drug is safe. Phase 2 trials, involving hundreds of people, allow researchers to try out different doses and gather more measurements about the vaccine’s effects on the immune system. Phase 3 trials, involving thousands or tens of thousands of volunteers, determine the safety and efficacy of the vaccine or drug by waiting to see how many people are protected from the disease it’s designed to fight.
    • Placebo: A substance that has no therapeutic effect, often used in a clinical trial. To see if a vaccine can prevent Covid-19, for example, researchers may inject the vaccine into half of their volunteers, while the other half get a placebo of salt water. They can then compare how many people in each group get infected.
    • Post-market surveillance: The monitoring that takes place after a vaccine or drug has been approved and is regularly prescribed by doctors. This surveillance typically confirms that the treatment is safe. On rare occasions, it detects side effects in certain groups of people that were missed during clinical trials.
    • Preclinical research: Studies that take place before the start of a clinical trial, typically involving experiments where a treatment is tested on cells or in animals.
    • Viral vector vaccines: A type of vaccine that uses a harmless virus to chauffeur immune-system-stimulating ingredients into the human body. Viral vectors are used in several experimental Covid-19 vaccines, including those developed by AstraZeneca and Johnson & Johnson. Both of these companies are using a common cold virus called an adenovirus as their vector. The adenovirus carries coronavirus genes.
    • Trial protocol: A series of procedures to be carried out during a clinical trial.

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