The hold AstraZeneca placed Tuesday on its COVID-19 vaccine trials is the first major setback in pursuit of a vaccine against a disease that has now killed 190,000 in the U.S. and nearly 900,000 worldwide.
One volunteer in a trial in the United Kingdom apparently developed a serious neurological problem after receiving the vaccine, though not much has been made publicly available about what happened.
AstraZeneca, which is running several large trials around the world, including one in the U.S., put a temporary hold on all of them pending an investigation.
It may seem surprising to stop a multimillion-dollar, 30,000-person trial because one person fell ill, but “it’s not at all unprecedented,” said Dr. Francis Collins, director of the National Institutes of Health, speaking Wednesday morning to a Senate committee.
Overall, only about 25% of vaccines that enter human testing end up receiving approval and being marketed to the public, according to a 2018 study.
That’s why the federal government has invested in six different candidate vaccines, Collins said, “because of the expectation that they won’t all work – though it would be lovely if they did.”
The government has pledged more than $10 billion to six companies now developing candidate vaccines, with the possibility of adding one or two more. The money is intended to cover development costs for most of the vaccines and production and distribution of 100 million doses of each by early next year.
If any vaccine fails to meet standards of safety and effectiveness, those pre-made doses will be thrown out. The government signed a $1.2 billion contract with AstraZeneca in May that calls for the company to make 300 million doses of its vaccine It’s not clear whether AstraZeneca has already begun making doses of its vaccine, currently called AZD1222.
Research trials are routinely stopped if the drug or vaccine being tested may have caused harm. During the stoppage, an independent Data Safety Monitoring Board, which oversees the trial, will review what happened and decide whether it is safe for the trial to resume.
Anytime there is a trial of 30,000 people – especially in this case, where many of the trial participants are older adults with other health conditions – someone will have an accident or a heart attack, said Barry Bloom, an immunologist at the Harvard T.H. Chan School of Public Health.
It will be challenging to determine whether the person’s problem was coincident to the trial or caused by it, Bloom and others said.
Collins said the hold should be reassuring to people who are concerned about the COVID-19 vaccine process because it shows safety is being taken seriously.
“This ought to be reassuring to anyone listening when we say we are going to first focus on safety and make no compromises – here is Exhibit A about how that is happening in practice,” Collins said. “I’m ready to roll up my sleeve as soon as they say it’s safe to take.”
USA TODAY posed and answered some common questions about what happened:
How common are vaccine trials halted?
All of the COVID-19 vaccine trials have proceeded without any problems for months. But it is not unexpected that some trial participants would have health problems.
“These are vaccines to prevent COVID-19 infection, not everything else that happens in life,” said Dr. Paul Offit, a vaccine development specialist at the Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania. The key question is: “Is it coincidental or causal?”
The trials intentionally include large numbers of older adults and those with other health problems to make sure any vaccine that reaches the general public will be safe and effective for groups most at risk from COVID-19.
The company did the right thing to stop its trial and investigate whether the vaccine may have caused the problem or simply happened around the same time, Offit said. “It’s prudent of the company to take a step back,” he said. “They’re doing testing now to try and figure out how to explain this disease.”
What does this halt mean for the AstraZeneca candidate vaccine?
The result will depend on whether the trial is stopped permanently, or just for a little while.
If the person’s illness is considered a result of the vaccine, the company or the Data Safety Monitoring Board could decide that AstraZeneca’s candidate vaccine, AZD1222, isn’t safe enough to give to large numbers of people.
Based on technology developed by Oxford University, the vaccine uses a chimpanzee virus to deliver a bit of protein normally found on the outside of the SARS-CoV-2 virus that causes COVID-19. Once a person has received the vaccine, their body will be primed to fight off the SARS-CoV-2 virus if exposed.
Harvard’s Bloom said he doesn’t think the chimpanzee virus could be the cause of the trial participant’s neurological problem. But he said the coronavirus itself can cause such problems.
In the 1970s, a flu vaccine was connected to cases of a rare neurological condition called Guillain-Barré syndrome, although it was never clear whether the vaccine or the flu virus caused the syndrome.
Viral infections, including COVID-19, have been known to cause rare neurological conditions.
What about the other vaccines being developed against COVID-19?
AstraZeneca’s trial stoppage does not affect any of the other candidate vaccines being tested, none of which rely on the chimpanzee virus.
That said, nearly every other vaccine is based on the same protein from the SARS-CoV-2 virus. If exposure to that so-called spike protein is the cause of the participant’s neurological problem, it could raise questions about the other experimental vaccines as well.
Two other candidate vaccines, one by Pfizer and a German biotech firm BioNTech, and another by Moderna, a Cambridge, Massachusetts-based biotech, also are in large, Phase 3 trials, of at least 30,000 people each. They both use a technology called messenger RNA for their vaccines, and their trials are expected to be completed as soon as next month. Novavax Inc., a Gaithersburg, Maryland, biotech that uses a third technology, is planning to start its Phase 3 trial this fall.
None of the other trials has reported neurological problems.
What happened to the patient?
AstraZeneca has not revealed any details about the trial participant other than he or she suffered an “unexplained illness.” The New York Times reported it was likely transverse myelitis, an inflammatory condition that affects the outer lining of the spinal cord. But the company said the diagnosis has not yet been confirmed.
“There is no final diagnosis,” the company said in a statement Wednesday, and “there will not be one until more tests are carried out.”
AstraZeneca also confirmed Wednesday the company stopped the clinical trial briefly in July because another participant developed neurological symptoms. That person was determined “to have an undiagnosed case of multiple sclerosis, which the independent panel concluded was unrelated to the vaccine.”
Transverse myelitis, if that is the latest participant’s final diagnosis, can cause limb weakness or paralysis, pain, bladder dysfunction and sensory problems, depending on the location of spinal inflammation.
Transverse myelitis strikes only about 1 in 250,000 to a million people, so to have it hit someone in a pool of less than 30,000 suggests there may be more than chance at play, said Dr. William Schaffner, an infectious disease and public health specialist at the Vanderbilt University School of Medicine, in Nashville, Tennessee. “It’s hard to measure a risk of about 1 in a million,” he said.
It’s highly unlikely the trials would have missed other cases of transverse myelitis, he said, because its symptoms are so debilitating.
But transverse myelitis is a very vague diagnosis that could have a lot of causes, said Dr. Anne-Louise Oaklander, an associate professor of neurology at Massachusetts General Hospital in Boston.
Transverse myelitis could be triggered by the disease multiple sclerosis, by a stroke, an infection, or by someone falling down the stairs and damaging their spinal cord, she said. The diagnosis tells you the problem is swelling in a part of the spinal cord, “it does not tell you what the cause is,” she said.
A vaccine could theoretically cause the body to cross-react with normal healthy cells, she said, triggering transverse myelitis. “It can wreak havoc. But an infection can do the same thing,” said Oaklander, who recently wrote a paper on the neurologic effects of infection with SARS-CoV-2. “We barely know what the virus does so far, much less what a vaccination does.”
How long could the trial be stopped?
It’s not clear how long the stoppage will last. If it turns out the person who had the bad reaction received a placebo instead of the active vaccine – as half the patients in the trials did – than AstraZeneca can safely resume its trials almost immediately, Schaffner said.
But if there’s a long, involved process to figure out whether the problem was created by the vaccine it could last a lot longer, he said.
Overall, Schaffner said, this event is a reminder that not everything goes perfectly in medical research.
Vaccine studies are not a straight line,” he said. “You have to be prepared for all kinds of things that can come up. This is an example par excellence of that.”
Contact Karen Weintraub at firstname.lastname@example.org
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