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The Sciences

COVID-19 Vaccine: A Clinical Trial Participant Falls Sick. What Happens Next?

We have a low tolerance for severe adverse events because vaccines are administered to healthy people. The bar for safety is high.

The author first published the contents of the following article as a Twitter thread. They have been compiled and published here with permission, with light edits for clarity. The images are from WHO’s course on vaccine-safety training.

Editor’s note: A 40-year-old Chennai-based clinical trial participant for a COVID-19 vaccine has sent a legal notice to the Serum Institute of India seeking Rs 5 crore as compensation for a “severe adverse effect”. On the evening of November 29, Serum Institute dismissed the allegations and has threatened to counter-sue this person for defamation. More here.

No vaccine – or drug, from aspirin to zinc – is absolutely risk free. But no vaccine is licensed wherein the benefits don’t hugely outweigh any risks. To know risk is rare is no consolation when adverse events following immunisation (AEFIs) occur, but it’s important as a society to understand that the risks exist and are measured.

The most common adverse events following vaccination are minor – such as pain, redness and swelling – but occasionally rare and serious adverse events can happen, like seizures, anaphylaxis or severe allergic reactions.

We have a low tolerance for severe adverse events because vaccines are administered to healthy people. The bar for safety is high. Vaccine trials include more people at each stage so that safety is tracked in increasing numbers.

Therefore, phase I trials for safety have around 10-100 people. Phase II trials have around 100-1,000 people for safety/immunogenicity. Phase III trials are conducted with 1,000-10,000 or more for safety/efficacy. After vaccines are licensed, safety surveillance continues in phase IV – or programmatic use.

But today, the focus is on pre-licensure assessment. What happens if a study participant becomes seriously ill?

First, the participant must be looked after and provided all the necessary care. Then the principal investigator at the site must report all that they know about the participant and her illness to the institutional ethics committee (IEC), the sponsor – usually the company making the vaccine – and the regulator, which in India’s case is the Drugs Controller General of India.

The investigator offers her opinion regarding whether the illness is related to vaccination, and that opinion and all the data is sent to the sponsor. The sponsor will inform the independent data safety monitoring board (DSMB).

The DSMB usually has independent experts – such as clinical trialists, disease specialists and trial statisticians – who will review the data in detail and prepare a report that the sponsor has to share with trial-site IEC and the regulator.

AEFIs are of five types:

1. Vaccine product related reaction – for example intussusception (telescoping of the intestine) seen in the first week after rotavirus vaccination. It happens in some places (but not all) in 1 in 16,000 or 1 in 60,000 vaccinated children.

2. Vaccine quality-defect-related reaction – for example if an inactivated polio vaccine was not completely inactivated and caused polio (read about the Cutter incident).

3. Immunisation error-related reaction – for example if the wrong diluting fluid is used and children become paralysed.

4. Immunisation anxiety-related reaction – for example a student getting scared at a school-based immunisation and fainting.

5. Coincidental event – this is an AEFI that is not due to any of the above. For example, a child develops a fever after being vaccinated – but it is dengue, not vaccine-related.

Vaccine adverse events occur with a certain frequency. Knowing the background rates of occurrence is important so we can figure out what events are due to the vaccine and what would have happened if there was no vaccine.

Image: WHO

Adverse events are classified as ‘very common’ (more than 10%), ‘common’ (1-10%), ‘uncommon’ (0.1-1%), ‘rare’ (1 in 10,000 cases) and ‘very rare’ (1 in 100,000 cases or less).

The measles vaccine has very rare serious adverse effects but the risk-benefit analysis is heavily weighted towards vaccination because of the serious consequences of the infection itself.

Image: WHO

But when thousands of people get vaccines in trials, some rare events are likely to only be picked up in the phase III stage or later. And also some illnesses are bound to occur to vaccinated people even if the vaccine is safe.

So how do we decide what is what?

In other words, when there is a serious adverse event, it is important to determine its relationship to the vaccination. Was the event definitely, probably or possibly caused by the vaccine? Or was it definitely not caused by the vaccine?

Vaccine safety experts use an approach called causality assessment, which is based on five principles. This needs expertise.

Image: WHO

And even then, an absolute determination may not be possible. But if an association cannot be ruled out, then the researchers, the sponsor and the DSMB will take extra care to follow up on the AEFI, which might be an early safety signal.

Every new treatment or prevention requires experimentation and carries risk. We must respect those who participate in clinical trials as volunteers for a greater good. And as clinical researchers, our responsibility is to make sure to do all that we can to minimise risk.

But if a participant becomes ill – especially in a vaccine trial – all medical and psychological support possible has to be provided, as we do our best to assess relatedness. That is an individual as well as collective responsibility.

Gagandeep Kang is a professor of microbiology at the Wellcome Trust Research Laboratory, division of gastrointestinal sciences at the Christian Medical College, Vellore. She has worked on the development and use of vaccines for rotaviruses, cholera and typhoid, conducting large studies to define burden, test vaccines and measure their impact. (Courtesy CMC)