NIH and FDA Examine Serious Side Effect That Surfaced in COVID Vaccine Trial

By Arthur Allen and Liz Szabo, Kaiser Health News

Monday, September 14, 2020 (Kaiser News) – The Food and Drug Administration is considering whether to follow UK regulators in resuming a coronavirus vaccine trial that was halted when a participant sustained brain injuries. spinal cord, even as the National Institutes of Health launched an investigation into the case.

“The higher NIH levels are of great concern,” said Dr. Avindra Nath, intramural clinical director and leader of viral research at the National Institute of Neurological Disorders and Stroke, a division of NIH. “Everyone hopes to have a vaccine, and if you have a major complication, everything could go off the rails.”

Much uncertainty remains about what happened to the anonymous patient, to the frustration of those who avidly follow the progress of vaccine testing. AstraZeneca, who is leading the global vaccine trial it produced with the University of Oxford, said the trial volunteer had recovered from severe inflammation in the spinal cord and was no longer hospitalized.

AstraZeneca has not confirmed the patient has transverse myelitis, but Nath and another neurologist said they understood it to be. Transverse myelitis produces a set of symptoms involving inflammation along the spinal cord that can cause pain, muscle weakness, and paralysis. The UK regulatory body, the Medicines and Health Products Regulatory Agency, has reviewed the case and has cleared the UK trial for resumption.

AstraZeneca “need[s] be more open with a potential complication of a vaccine that will eventually be given to millions of people, ”said Nath. “We would like to see how we can help, but the lack of information makes this task difficult.”

Any decision on whether to continue the trial is complex because it is difficult to assess the cause of a rare injury occurring during a vaccine trial – and because scientists and authorities must weigh the risk of effects. rare secondary compared to a vaccine that could curb the pandemic. .

“So many factors go into these decisions,” Nath said. “I’m sure everything is on the table. The last thing you want to do is hurt healthy people. “

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The NIH has yet to obtain any tissue or blood samples from the British patient, and its investigation is “in planning,” Nath said. US scientists could examine samples from other vaccinated patients to see if any of the antibodies they’ve generated in response to the coronavirus are also attacking the brain or spinal cord tissue.

Such studies could take a month or two, he says. The FDA declined to comment on how long it would take before deciding to go ahead.

Dr Jesse Goodman, a professor at Georgetown University and a physician who was chief scientist and chief vaccine regulator at the FDA during the Obama administration, said the agency will review the data and possibly consult with UK regulators before ‘authorize the resumption of the US study, which had just started when the injury was reported. Two more coronavirus vaccines are also in late testing in the United States

If it determines that the injury in the UK trial was caused by the vaccine, the FDA could suspend the trial. If this allows it to resume, regulators and scientists will surely be on the lookout for similar symptoms in other trial participants.

According to Dr. Elliot Frohman, director of the Center for Multiple Sclerosis and Neuroimmunology at the University of Texas, a volunteer in an earlier phase of the AstraZeneca trial had a similar side effect, but investigators found she was in pain. multiple sclerosis unrelated to vaccination. .

Neurologists who study diseases like transverse myelitis say they are rare – occurring at a rate of about 1 in 250,000 people – and strike most often due to the body’s immune response to a virus. Less commonly, these episodes have also been linked to vaccines.

The precise cause of the disease is central to the decision of the authorities to resume the trial. Sometimes an underlying medical condition is “caught on” by a person’s immune response to the vaccine, leading to illness, as has happened with the patient with MS. In this case, the trial could proceed without fear, as the disease was not specific to the vaccine.

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More worrying is a phenomenon called “molecular mimicry”. In such cases, a small piece of the vaccine may be similar to tissue in the brain or spinal cord, causing an immune attack against that tissue in response to a component of the vaccine. If this were the case, another occurrence of transverse myelitis would be likely if the trial were to resume, said Dr William Schaffner, an infectious disease specialist at Vanderbilt University School of Medicine. A second case would end the trial, he said.

In 1976, a large swine flu vaccination program was halted when doctors began to diagnose a similar disorder, Guillain-Barré syndrome, in people who had received the vaccine. At the time, no one knew how common GBS was, so it was difficult to tell if the episodes were vaccine-related.

Eventually, scientists found that the vaccine increased the risk of the disease by one more case in 100,000 vaccinated patients. The typical seasonal influenza vaccination increases the risk of GBS in about one additional case in 1 million people.

“It’s very, very difficult” to determine whether a rare event was caused by a vaccine, Schaffner said. “How do you attribute an increased risk for something that happens in one in a million people?”

Before allowing the restart of trials in the United States, the FDA will want to see why the company and an independent Data and Safety Oversight Board (DSMB) in the United Kingdom felt it was prudent to continue, has Goodman said. The AstraZeneca trial in the United States has a separate safety committee.

FDA officials will need to review all details of the case and may request more information about the affected study volunteer before deciding whether or not to allow the US trial to continue, Goodman said. They can also ask AstraZeneca to update the security information it provides to study participants.

It’s possible that the volunteer’s health issue was an unrelated coincidence with the vaccine, said Dr. Amesh Adalja, senior researcher at the Johns Hopkins Center for Health Security. Studies do not usually focus on a single health problem, even if it is serious.

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Still, many health executives have expressed frustration that AstraZeneca failed to release more information on the health issue that led it to end its trial in the UK.

“There is so little information on this that it is impossible to understand what the diagnosis was or why the DSMB and the sponsor were reassured” that it was safe to continue, Goodman said.

AstraZeneca said it was unable to provide more information about the health issue, claiming it would violate patient privacy, although he did not say how.

But there is an exceptional need for transparency in a political climate marked by vaccine reluctance and mistrust of the Trump administration’s handling of the COVID-19 response, say scientists from foreground.

“While I respect the critical need for patient privacy, I think it would be really helpful to know what their assessment of these issues has been,” Goodman said. “What was the diagnosis? If there was no clear diagnosis, what made them think the trial could be restarted? There is so much interest and potential concern about a COVID-19 vaccine that the more information can be provided, the more reassuring it will be. “

The FDA will need to balance any possible risks of an experimental vaccine with the danger posed by COVID-19, which has killed nearly 200,000 Americans.

“There are also potential consequences if you stop a study,” Goodman said.

If the AstraZeneca vaccine fails, the U.S. government is supporting six more COVID vaccines in the hope that at least one will be successful. The potential problems with the AstraZeneca vaccine show it’s a wise investment, Adalja said.

“It’s part of the idea of ​​having just one vaccine candidate,” he said. “It gives you a little more confidence.”

Schaffner said researchers should remember that vaccine research is unpredictable.

“Investigators inadvertently promoted their own vaccine,” Schaffner said. “The Oxford investigators were there this summer saying, ‘We’re going to get there first.’ But that’s exactly the kind of reason… Dr. [Anthony] Fauci and the rest of us said, “You never know what’s going to happen once you get into large-scale human trials.” “

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