Yesterday AstraZeneca called a pause to the use of the novel Oxford developed vaccine. It will be investigating one of the UK participants in the clinical trial programme who had developed a rare condition. In this post I outline what the pause means, describe the process leading up to the announcement and consider what may be the implications for the future of the vaccine.
Oxford Vaccine Clinical Trials Programme
- Readers, I am sure, will be aware that at the end of July the Oxford team published results from a trial of 1077 young adult participants, 543 of whom had had the new vaccine.
- That study showed an excellent response in terms of immunity with only moderate, and easily controlled, side effects
- The next phase of the vaccine development programme involves a much wider series of studies in four separate age groups:
- 70 and over
- Those studies are testing both a single dose of vaccine and a double dose – 4-6 weeks apart
- Recruitment sites are in the UK, South Africa and Brazil
- I believe that maybe 15,000 people have been recruited to these studies
- A further site in India was about to start recruitment in the next weeks
- Only two weeks ago the National Institutes of Health announced a trial of the Oxford vaccine in 30,000 subjects in the USA
What does the pause’ mean?
- As it says ‘on the can’, worldwide there is a presumably temporary ban on any further use of the vaccine
- This applies to all the studies that are still actively recruiting
- All subjects who have already been enrolled in any of the studies above will remain in the trials, (and will continue to be followed up to identify their risks of getting Covid-19 infection or any serious side effect).
What initiated the pause?
- There is relatively little information in the public arena – this is not unreasonable and the pause only achieved widespread publicity because of the global interest in this and related vaccines
- At around 11:00 pm on 8 September, a tweet from AstraZeneca announced the case of a ‘potentially unexplained illness’ in one of the UK participants
- On Twitter this is reported as being a woman with an ‘inflammatory neurological disorder’ who is now said to be recovering. The exact nature of this condition can only be known to the investigators. There are two neurological conditions that rarely can follow vaccine
- The first is transverse myelitis which is an inflammation of the spinal cord. A case of this condition may have developed in a previous volunteer to the Oxford vaccine study, but which did not require medical attention.
- The other disorder is Guillain Barré syndrome which can follow flu vaccine (but also influenza)
- The pause would have been triggered (again I assume) by the UK trial’s Data Safety and Monitoring Board (DSMB)
- All trials internationally must have a DSMB, independent of the researchers and any companies involved.
- The DSMB will of necessity be notified by the researchers of any adverse events that occur in the trial participants. The DSMB can then ask for further information about the case or cases
- The trial researchers will not know which of the participants received the active vaccine and which received the inactive comparator vaccine
- The DSMB can ask for that participant’s status to be unblinded (ie active or non-active vaccine)
- I assume that this particular woman must have been in the active vaccine group
- Given the enormous public interest I then speculate that the DSMB, in discussion with the company and the researchers, felt that the vaccine should not be used further, pending investigation as to the likelihood of a relationship between the vaccine and the neurological disorder
How often does this happen?
- Clinical trials involving very large numbers of individuals are by design likely to result in some of the participants in either group developing various serious illnesses by chance alone.
- At the end of the trial, it would be necessary to compare between the two groups to see if those in the active vaccine group had an excess of any of these illnesses
- In this current announcement, it would appear that the participant had an unusual illness, and that there was a biologically plausible link to the new vaccine
- Again, given the large number of people studied, the occurrence of one or even a handful of cases of unusual conditions might be expected. I do not know how often one case has led to a pause, but say 3 cases would not be an unreasonable threshold.
How can or will the pause be ended?
- Proving a link between the vaccine and any very rare serious complication is not easy
- Extrapolating from one or even two cases at this stage is thus speculative at best
- The company has taken this report seriously and suffered a modest stock market reaction as a consequence
- There is a universal desire for vaccines such as the Oxford one to succeed
- The reasonable expectation is that the Oxford vaccine (and probably the other similar ones) is successful at stopping the infection without significant side effects for the overwhelming majority of people.
- How the pause will end is honestly difficult to answer, and this may also depend on the decision of government regulators
- Then, as always in this situation, there would need to be a debate about the balance of risks say between the risks of serious complications or death from the infection and (say) a 1/10,000 risk of a serious vaccine complication
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