SII Seeks Emergency Nod But Adverse Event Raises Ethical Questions

How did the company decide that its COVID vaccine was entirely unrelated to the volunteer’s illness?

More than two weeks after a volunteer in the Serum Institute of India (SII)’s clinical trial for the Covishield vaccine claimed that the vaccine had made him seriously ill, SII has done little to clear the air. This, even as the company applied on Sunday to the Indian drug regulator for emergency permission to sell its vaccine in the country.

The company initially responded to the volunteer’s demand for compensation by calling his claims malicious, and threatening to sue him for Rs 100 crore. They argued that there was “absolutely no correlation” between the vaccine and the volunteer’s medical condition, and that this fact had been conveyed to him. But SII’s categorical assertions have raised further questions.

How did the company decide that the vaccine was entirely unrelated to the volunteer’s illness? Further, why didn’t SII pause the Covishield trial when it was investigating this link? After all, AstraZeneca, the UK-based company, whose vaccine was being trialled by SII, stopped its Phase 3 trial on two occasions to investigate similarly serious neurological adverse events.

Finally, was it fair of SII to threaten a volunteer who took on a personal risk to help bring the company’s vaccine to the market? Did SII fulfil its ethical responsibilities of protecting the dignity, rights, safety and well-being of the volunteer, as enshrined in India’s National Ethical Guidelines for Biomedical and Health Involving Human Participants?

The Quint spoke to clinical trial experts from across the country, and to the volunteer’s wife, to answer some of these questions.

What Happened to the Volunteer?

On 11 October, 10 days after he received the first dose of the trial vaccine, the volunteer, a 41-year-old Chennai resident and a marketing consultant, began experiencing severe headache, vomiting and mental confusion.

He went to the Sri Ramachandra Medical Centre, the trial site at which he had received the vaccine. Here, he remained hospitalised for fifteen days, in a disoriented state, with symptoms such as neck stiffness and light sensitivity.

Ultimately, as per his discharge summary from the hospital, the principal investigator at the trial site, SR Ramakrishnan, diagnosed him with acute encephalopathy, an illness that affects the brain and could be due to any of hundreds of causes.

Test results on 20 October also showed that the volunteer had two types of antibodies in his blood, called Anti Smith antibodies and Anti Ribonucleoprotein (RNP). Both are autoantibodies, which means they mistakenly attack the body’s own tissues, and are associated with autoimmune diseases like lupus.

A rheumatologist who examined the volunteer on the 23rd also suggested a diagnosis of lupus. Finally, tests revealed that the volunteer had Vitamin B12 and D deficiencies, and he was started on supplements.

The hospital then discharged him on the 26 October, asking to come back in a week so that the pending results for more tests could be reviewed. These included tests for other antibodies indicative of lupus (namely anti-phospholipid antibodies, antinuclear antibodies and anti-double stranded DNA antibodies).

What Was the Volunteer’s Experience?

In an interview with The Quint, the volunteer’s wife said the hospital never told her what caused her husband’s disturbing symptoms, if not the vaccine.

She recalled that her husband joined the trial because he wanted to do whatever he could to help the vaccine come to the market quickly. “If this was the solution to ending this pandemic, we were ready to volunteer. I was thinking of joining the trial too, but I was not as courageous as my husband in taking on this risk,” she said.

When her husband was initially hospitalised, doctors told her they didn’t know the cause, but that they couldn’t blame the vaccine without evidence. The illness was deeply disturbing to the family, because her husband had seemed healthy until then.

But at one point during his hospitalisation, he showed symptoms of psychosis, in which a patient loses touch with reality. She recalls that he had to be physically tied to the hospital bed as he grew agitated, and was started on psychiatric drugs.

A few days before being discharged, and after dozens of diagnostic tests, the doctors at Sri Ramachandra suggested that her husband had vitamin deficiencies, which could be behind his encephalopathy, she says.

“I was amazed at the idea: can such a deficiency cause such major problems in such a big man? He eats so well and always looked after his heath.”

The Volunteer’s Wife

The doctors also mentioned lupus as a possible cause for the encephalopathy, but “ruled it out” later, she told The Quint.

By the 26 October, her husband was feeling slightly better, and wanted to go home to see his children, she recalls. So, the family asked about being discharged from the hospital. They were told that further test results (for lupus antibodies) were awaited, and would be shared when ready.

On the 29th, after being discharged, the volunteer and wife visited the hospital’s psychiatrist again, because the volunteer was feeling drowsy and wanted to discontinue the psychiatric drugs. His wife told The Quint that she asked the doctor again for an updated discharge summary and pending results, but was told they were yet to come.

Meanwhile, the psychiatrist agreed to discontinue the medicines, and opined that the volunteer had improved substantially. However, the volunteer’s wife mentioned that her husband was experiencing mood swings and depression.

“They didn’t show that much concern about his mental symptoms, because they were just happy that he had recovered from the coma-like situation.”

The Volunteer’s Wife

After the meeting with the psychiatrist, the volunteer’s wife said she called the principal investigator a couple of times for a copy of the remaining test results. She said the investigator promised to call back, “but he never did. So, I waited, because I didn’t want to interrupt him again and again. After that, nobody from their side contacted us. Till today, I don’t have the final results of the tests in my hand.”

The family then decided to visit another neurologist, who gave the volunteer an electroencephalogram (a test that evaluates the electrical activity of the brain), which threw up abnormal findings.

It was at this point that the family decided to send SII a legal notice, demanding a compensation of Rs 5 crore for vaccine-related adverse effects.

But the company never responded to their legal notice, the volunteer’s wife said, choosing to issue a press release. “Till now, they haven’t responded to our lawyer. All their statements have only been to the media.”

The family learnt of all further developments on the issue, such as the results of the investigation of the Drug Controller General of India into her husband’s illness, from newspaper and television reports.

Neither the Serum Institute of India nor SR Ramachandran responded to The Quint’s questions on the volunteer’s allegations.

Can the SII Vaccine Cause Acute Encephalopathy?

Experts whom The Quint spoke to said that there were few clear biological mechanisms through which this could happen. The AstraZeneca-Oxford vaccine, which SII is trialling, uses a virus that causes common cold in chimps to ferry a bit of genetic code from the SARS-COV-2 virus into the human body.

Theoretically, the vaccine could cause encephalopathy in the human body in two ways: either the chimp virus could cause the disease directly, or some component of the vaccine could trigger an autoimmune reaction (i.e., the vaccine could trigger the production of autoantibodies that mistakenly attack human tissues). But both events seem unlikely, say experts.

The chimpanzee virus used in the Astrazeneca vaccine, a type of adenovirus, doesn’t cause disease in humans. Moreover, even if it can infect human cells to deliver its genetic cargo, it has been engineered to not replicate in the human body. While human adenoviruses are known, on rare occasions, to cause encephalopathy in children, it is hard to imagine how a chimpanzee adenovirus can do so, says Gagandeep Kang, a microbiologist at CMC Vellore and a member of the board of The Coalition for Epidemic Preparedness Innovations (CEPI). CEPI is currently in an agreement with the SII, AstraZeneca and Gavi, the Vaccine Alliance to bring the AstraZeneca vaccine to low-income countries.

But other experts caution that the possibility of a link between the vaccine and encephalopathy mustn’t be ruled out without further research. T Jacob John, a virologist at CMC Vellore, says AstraZeneca must scour all recorded adverse effects from its trial to see if other cases of encephalopathy have occurred.

The second mechanism by which the vaccine could possibly cause such an illness is by inducing autoimmunity. Some vaccines are thought to induce a cluster of symptoms, including encephalopathy, in this way.

Scientists have documented this rare phenomenon in live virus vaccines, like the measles vaccine, and vaccines developed using animal brain material, like older rabies vaccines.

But neither SII’s Covishield, nor any other COVID vaccine in trials falls into these two categories of vaccines, points out Satyajit Rath, a Pune-based immunologist. This makes it hard to imagine how Covishield could trigger encephalopathy, he says. “The biological plausibility is extremely sketchy.”

Rheumatologist Debashish Danda at CMC Vellore suggests yet another variation to this mechanism, in which some component of the vaccine triggers an episode of acute illness only in those people who already have existing autoimmune illnesses like lupus.

This would be an extremely rare event, he says, because it wouldn’t affect all recipients, but only those who already have undiagnosed autoimmunity. He points out that two other participants in the United Kingdom arm of the trial for Astrazeneca’s vaccine developed neurological illnesses, with possible autoimmune causes.

In the first case, after a vaccine recipient developed transverse myelitis in July, Astrazeneca said the volunteer had an undiagnosed case of multiple sclerosis. Multiple sclerosis, in which the sheath covering the spinal cord breaks down, often has autoimmune causes. In the second case, in September, news reports again suggested that a patient developed transverse myelitis, although the company refused to confirm the diagnosis.

If more such cases occur in vaccine recipients, this could be an early signal that the vaccine affects people with autoimmunity differently, says Able Lawrence, a clinical immunologist at Lucknow’s Sanjay Gandhi Post Graduate Institute of Medical Sciences. But both Danda and Lawrence caution that it is impossible to draw such a link based on three cases of autoimmune illness out of the thousands of vaccine recipients in the AstraZeneca and SII trials put together.

Previous studies looking for such links between neurological disease in vaccinated people with autoimmunity have failed to show strong evidence for the idea.

Did the Patient Have Lupus?

Lawrence said that the anti-Smith antibodies, which the volunteer had, are highly specific to lupus; this means that there’s a good chance that an individual with these antibodies either has lupus today or will go on to develop it within a year.

Still, a diagnosis of lupus cannot be made based on Smith antibodies alone. The volunteer’s doctor would also have had to find out whether the volunteer ever had symptoms of the disease, such as joint pains and rash. Plus, they would need to know whether anyone in his family had a history of autoimmune illnesses, such as rheumatoid arthritis. “In upto a third of patients with lupus, there is a strong family history for such illnesses,” says Danda.

The volunteer’s wife said that he never suffered any such symptoms in the past.

Can Lupus or Vitamin Deficiencies Cause Acute Encephalopathy?

It is possible for lupus to present suddenly as encephalopathy, says Lawrence, but whether that happened in the volunteer’s case is impossible to say without further details. Vitamin B12 and Vitamin D deficiencies are usually linked with chronic disease, rather than a sudden encephalopathy, adds Danda, but these can also be a consequence of autoimmunity.

How Did SII Decide That the Vaccine was Unrelated to the Volunteer’s Illness?

To determine whether a vaccine is causing the SAE, investigators typically ask atleast five questions: first, is there a biological mechanism by which the vaccine can cause the illness? Second, does the illness occur consistently among vaccine recipients? Third, did it occur soon enough after the vaccination? Fourth, can alternative causes explain the illness, and fifth, is the frequency of the illness greater in the vaccinated population compared to unvaccinated?

In the Chennai volunteer’s case, the adverse event occurred within ten days of the first vaccine dose. This satisfies the criteria of occurring soon enough after vaccination for investigators to consider a causal link, Danda says.

But as Kang and Rath point out, the biological mechanism by which the vaccine can cause the illness is not immediately clear. And strength and consistency of association are hard to establish when only a single case of encephalopathy occurs among thousands of vaccinated people.

Still, the link between a drug or a vaccine and an adverse event is often not black or white, says CS Pramesh, the director of Mumbai’s Tata Memorial Hospital.

“There are many shades of gray.”

So, depending on how many of the five criteria of causality they can check, investigators describe this relationship along a spectrum, ranging from “certainly related” and “probably related” to “possibly related” and “unlikely to be related”.

The statements from AstraZeneca on the two adverse events that occurred in its trial reflect this ambiguity. According to a document that the company shared with trial participants in September, independent reviewers thought the neurological adverse events were either “unlikely to be associated with the vaccine” or that “there was insufficient evidence to say for certain that the illnesses were or were not related to the vaccine.”

In contrast, SII’s latest press statement is categorical about the vaccine being completely unrelated to the adverse event. But this certainty is neither seen in the discharge summary given to the volunteer, nor was it conveyed to his family.

“We are still waiting for them to tell us why the vaccine wasn’t the cause.”

The Volunteer’s Wife

Did SII Follow All Indian Regulations and Best Practices in Dealing With the SAE?

SII claims it followed all rules while reporting and investigating the volunteer’s illness. But the company seems to have dropped the ball on the best practices when it came to following up on the participant after discharge.

In any trial, when a patient experiences a serious adverse event, investigators typically follow them until their symptoms resolve, says Gagandeep Kang. A protocol published by AstraZeneca for its Phase 3 trial also says that if a volunteer’s symptoms haven’t resolved at the last assessment, they must be followed up as long as “medically indicated”.

Kang points out that such follow-ups are important for two reasons. First, trial investigators have a duty of care towards all participants. And second, it helps them understand how the adverse event panned out, and whether it had long-term effects. Given this, “the allegation that the volunteer hasn’t been followed up is worrying,” she says.

And when particularly serious adverse events occur, like the one in this trial, the investigator has a responsibility to try contacting a participant multiple times, says Tata Memorial’s Pramesh. SII did not respond to questions about the volunteer’s allegations that the investigators did not share their final report with them.

Should SII Have Paused the Trial as AstraZeneca Did?

There is disagreement among experts on this issue: some believe SII should have followed in the footsteps of AstraZeneca, which halted its trial in both July and September to investigate the two serious adverse events that occurred, while others argue that there could be valid reasons for SII investigators to have chosen not to do so.

Kang explains that investigators typically call for a halt if investigators or ethics committees strongly suspect that a serious adverse event is linked to the vaccine being tested. But if the principal investigator and ethics committee in the SII trial felt the chances of a link between the encephalopathy and the vaccine was low, they may not have thought it necessary.

It is impossible to stop a trial for every serious adverse event, Kang says, because in any Phase 3 trial, dozens will occur that will have little to do with the vaccine.

For instance, in a Phase 3 Indian trial for the Rotavac rotavirus vaccine, out of 6796 participants, 1,424 experienced serious adverse events. Eventually, only three of these events were deemed to have some link with the vaccine, Kang, an investigator in the Rotavac trial, says. Similarly, in a 2009 trial for a malaria vaccine, out of 8,923 participants, 1,784 experienced serious adverse events. While the SII trial was smaller, with only 1,600 participants, it would still have seen several such events, says Kang.

Pramesh adds that the two adverse events in the AstraZeneca trial happened much before the one in the Indian SII trial, and investigators tend to be more cautious in a trial’s early stages.

“In early stages, when you are faced with a serious complication, independent committees may temporarily decide to stop the trial, because you want to err on the right side of safety. As your knowledge of the vaccine increases, and you have seen a few thousands of people treated, you can make a judgement that what happened is less likely to be linked to the vaccine, or that the benefits of the vaccine overweigh possible harm. And you may choose not to stop. So, to conjecture about why the investigators didn’t stop the trial without having full details isn’t right,” he says.

But others such as Rath say that the extraordinarily rapid pace of COVID vaccine development calls for extra caution from everyone involved, even if it means halting trials more often than investigators would normally do.

If clinical trials do not stop for every single serious adverse event in normal times, he argues, even vaccines do not get licensed as quickly as they are being in the current pandemic.

“Everybody is applying for an Emergency Use Authorisation. When vaccine development is proceeding at such an unprecedented rate, it’s reasonable for society at large to be concerned about whether everything is being done right. So, there is a burden of bending over backwards on part of not just commercial vaccine developers, but also regulatory authorities, to provide this reassurance,” he says.

Was SII’s Behaviour Towards the Volunteer Ethical?

Whether or not the vaccine is linked to the adverse event suffered by the Chennai volunteer, many experts agree that SII’s threat to sue the participant, in response to the legal notice, was a poor decision.

Anant Bhan, Adjunct Professor & Researcher in Bioethics at Mangaluru’s Yenepoya University, says that because trial volunteers have no say in causality assessments, they have a right to opt for legal recourse if they are unhappy with such assessments.

“But if that leads to this kind of response from the sponsor (SII), there could be a breakdown of trust between participants and them. Other participants may wonder: what if something like this happens to us? Will we also be targeted in this way?”

Rath is particularly concerned about the way SII’s first response to the legal notice was to blame the volunteer, instead of reassuring observers that the company had followed due processes in investigating the SAE.

“This is why I am concerned – because of the paternalistic way in which both state and non-state authorities are functioning. It’s as if to say that we know best, and nobody else needs to know anything.”

(Update: A quote from the volunteer's wife and the date of the volunteer's hospital discharge were changed for accuracy.)

(Priyanka Pulla is freelance science journalist based in Bangalore.)

(The reporting for this story was funded by The Thakur Family Foundation. The Foundation exercised no editorial control on the contents.)