“The highest NIH scores are very concerned,” said Dr. Avindra Nath, intramural clinical director and head of viral research at the National Institute for Neurological Disorders and Stroke, an NIH division. “Everyone’s hoping for a vaccine, and if you have a major complication it could get derailed.”
There remains a great deal of uncertainty about what happened to the nameless patient and the frustration of those who eagerly follow the progress of the vaccine tests. AstraZeneca, which is running the global study using the vaccine made by Oxford University, said the study volunteer had recovered from severe spinal cord inflammation and was no longer in the hospital.
AstraZeneca has not confirmed that the patient has transverse myelitis, but Nath and another neurologist said they understood it was. Transverse myelitis results in a range of symptoms that include inflammation along the spinal cord that can cause pain, muscle weakness, and paralysis. The UK regulator, the regulator for medicines and health products, has examined the case and allowed the UK retrial.
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Any decision to continue the study is complex because it is difficult to determine the cause of a rare injury that occurs during a vaccination study – and because scientists and authorities must weigh the risk of unusual side effects against a vaccine that could contain the pandemic.
“So many factors play a role in these decisions,” said Nath. “I’m sure it’s all on the table. The last thing you want to do is hurt healthy people.”
The NIH has not yet received any tissue or blood samples from the UK patient, and his investigation is “in the planning stages,” Nath said. US scientists could examine samples from other vaccinated patients to see if any of the antibodies they made in response to the coronavirus also attack tissues in the brain or spinal cord.
Such studies could take a month or two, he said. The FDA declined to comment on how long it would be before it decides whether to move forward.
Dr. Jesse Goodman, a professor and doctor at Georgetown University who was the FDA’s chief scientist and chief vaccine regulator during the Obama administration, said the agency will review the data and possibly consult UK regulators before allowing the US trial to resume not started until the breach was reported. Two other coronavirus vaccines are also in late-stage studies in the US
If the breach in the UK study is found to be caused by the vaccine, the FDA could suspend the study. If it can be resumed, regulators and scientists will certainly look out for similar symptoms in other study participants.
A volunteer in an earlier phase of the AstraZeneca trial had a similar side effect, but investigators found she had multiple sclerosis that was unrelated to the vaccination, according to Dr. Elliot Frohman, director of the Center for Multiple Sclerosis and Neuroimmunology at the University of Texas.
Neurologists who study diseases like transverse myelitis say they are rare – at the rate of maybe 1 in 250,000 people – and most often due to the body’s immune response to a virus. Less commonly, such episodes have also been associated with vaccines.
The exact cause of the disease is key to determining whether the study should be restarted. Sometimes an underlying disease is “exposed” by a person’s immune response to the vaccine, resulting in disease, as was the case in the MS patient. In this case, the trial could proceed without fear as the disease was not specific to the vaccine.
More worrisome is a phenomenon known as “molecular mimicry”. In such cases, a small piece of the vaccine may resemble tissue in the brain or spinal cord, causing an immune attack on that tissue in response to a vaccine component. If so, transverse myelitis would be likely to recur when the study resumed, said Dr. William Schaffner, an infectious disease specialist at Vanderbilt University School of Medicine. A second case would end the process, he said.
A massive swine flu vaccination program was halted in 1976 when doctors began diagnosing people who received the vaccine with a diagnosis of a similar disorder called Guillain-Barré syndrome. At the time, no one knew how common GBS was, so it was difficult to tell if the episodes were vaccine-related.
“It’s very, very hard to tell,” whether a rare event was caused by a vaccine, Schaffner said. “How do you attribute an increased risk for something that occurs in one in a million people?”
Before the US trials can restart, the FDA wants to know why the company and an Independent Data and Safety Monitoring Board (DSMB) in the UK believe the continuation is safe, Goodman said. The AstraZeneca study in the US has a separate safety agency.
FDA officials must review all details of the case and may request more information about the affected study volunteers before deciding whether to proceed with the U.S. study, Goodman said. AstraZeneca may also need to update the safety information it makes available to study participants.
It is possible that the volunteer’s health issue was a fluke that had nothing to do with the vaccine, said Dr. Amesh Adalja, a senior scientist at the Johns Hopkins Center for Health Security. Studies don’t usually stop because of a single health problem, even if it’s serious.
Still, many health care leaders have expressed frustration that AstraZeneca has not released further information on the health issue that led to the UK study being closed.
“There is so little information that it is impossible to understand what the diagnosis was or why the DSMB and sponsor were reassured,” Goodman said.
AstraZeneca has stated that it is unable to provide further information about the health issue. This would violate patient privacy, although it was not stated how.
However, according to leading scholars, there is an extraordinary need for transparency in a political climate where vaccines are hesitant and suspicious of the Trump administration’s handling of the COVID-19 response.
“While I respect the critical need for patient confidentiality, I think it would be really helpful to know how they view these issues,” Goodman said. “What was the diagnosis? If there was no clear diagnosis, what made you feel like the study could be restarted? There is so much interest and potential concern about a COVID-19 vaccine that the more information are available provided that would be more reassuring. “
The FDA must weigh the potential risks of an experimental vaccine against the risk of COVID-19, which killed nearly 200,000 Americans.
“There are also potential consequences of abandoning a study,” Goodman said.
If the AstraZeneca vaccine fails, the U.S. government will support six more COVID vaccines in the hopes that at least one will be successful. The potential problems with the AstraZeneca vaccine show this is a wise investment, Adalja said.
“This is part of the idea of not having just one vaccine candidate going forward,” he said. “It gives you a little more insurance.”
Schaffner says researchers need to remember that vaccine research is unpredictable.
“The investigators accidentally played up their own vaccine,” said Schaffner. “The Oxford investigators were out there this summer and said, ‘We’ll get there first.’ But that’s exactly why … Dr. [Anthony] Fauci and the rest of us said, “You never know what will happen when you get into large-scale experimentation with people.”