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There have been reports that vaccination with the Oxford-AstraZeneca COVID-19 vaccine is suspended until further notice in Denmark after reports of cases of blood clots.
Prof Paul Hunter, Professor in Medicine, The Norwich School of Medicine, University of East Anglia, said:
“There have been a small number of reports of thromboembolism (blood clots forming in the blood vessels and then blocking blood flow) following administration of the AstaZeneca Vaccine possibly associated with a single batch of the vaccine.
“It is accepted practice especially with any new drug or vaccine to report any adverse event occurring after administration. In the UK this is known as the Yellow Card scheme. These reports are made whether or not the reporting doctor knows the event was caused by drug or vaccine. Indeed in an individual patient it is often impossible to know whether any adverse event was caused by the vaccine or would have just happened anyway. This is particularly difficult when the people being given the vaccine are likely to suffer from a range of such events anyway as for example, they are elderly or have pre-existing underling diseases. This is certainly the case for people in the first waves of administration. It is only by looking at trends from many such reports from many and comparing these what is known about the likelihood of such events anyway that conclusions about cause and effect can be drawn.
“Given the large number of different types of possible adverse events that could be reported it is highly likely that some apparent clusters of adverse events are identified in any campaign such as this even when the vaccine plays no role in the causation of the adverse event. So although most such identified clusters will not have been caused by the vaccine, that does not mean they can be ignored. Any such cluster still needs to be properly investigated.
“One of the issues that needs to be considered is how common thromboembolism is anyway. A recent paper from Oklahoma, in the US investigated the incidence of this condition during 2012 2013 and 2014 (Wendelboe AM, Campbell J, Ding K, Bratzler DW, Beckman MG, Reyes NL, Raskob GE. Incidence of Venous Thromboembolism in a Racially Diverse Population of Oklahoma County, Oklahoma. Thrombosis and haemostasis. 2021). The biggest factor affecting the incidence of thromboembolism in the community was age. The incidence of venous thromboembolism in the >80 years age group was 13.16, in the 70-79 age group 7.76 and in the 60-69 age group 5.10 per 1000 person years. So for every 1 million people immunised in these age groups we would expect to see about 1097, 645 and 425 episodes of thromboembolism in the month after immunization anyway. Now we do not know whether there was any particular aspect of the thromboembolic events in the recent reports from Europe that would make those cases more unusual and so more concerning.
“With the information currently available it seems likely that these reported adverse events are not caused by the vaccine, but we will see what conclusions the appropriate authorities come to after reviewing all the evidence.”
Prof Adam Finn, Professor of Paediatrics, University of Bristol, said:
“When something bad happens after you have had a vaccination, it’s natural enough to wonder whether the vaccine was the cause. However, when very large numbers of people are being vaccinated over a short period of time, a certain number of unexpected and unusual illnesses are going to happen in the period following vaccination by chance.
“If a pattern emerges then suspicion rises that there may be a causal link, especially if there’s a mechanism that could explain how the two events could lead one to the other.
“The position with the Oxford AZ vaccine at the moment is that there is no sign, anywhere, including the UK where very large numbers of doses have now been given, that blood clot-related illnesses are happening any more frequently than usual.
“That’s reassuring because it means either that the vaccine doesn’t cause blood clots at all or, at the very worst, that it’s an extremely rare event.
“It’s really important to monitor safety of any vaccine but especially one that is being so widely and that monitoring is going on continuously. The UK authorities will be communicating with those in other countries as well as continuing to do their own surveillance.
“In the meantime the risk benefit balance is very clear – better to get vaccinated as soon as the invitation arrives both to minimise your personal risk and to help get the epidemic under control so we can all progress towards a more normal future.”
Prof Jon Gibbins, Director of the Institute for Cardiovascular and Metabolic Research, University of Reading:
“I think that it is completely understandable that people may be worried about this but there are several factors that mean we need to be cautious about the link between the vaccine and clotting.
“Blood clotting, or thrombosis, occurs for a variety of reasons, the lead up to an even can often be undetected in the general population, and venous thrombosis is relatively common affecting 1 to 2 in 1000. Reports of what has triggered Denmark to pause the use of the Oxford AstraZeneca vaccine is not clear, but I note that the EMA has identified 22 cases of thrombosis among the 3 million who have received the vaccine so far, which is much lower than our 1 to 2 in 1000. Therefore, if there is any association between the vaccine and clotting, the risk is likely to be very low indeed.
“Importantly there is good emerging evidence that severe COVID-19 infection itself can cause harmful blood clots through the body’s own immune system, and so it may be the case that people are more at risk of clotting from not being immunised. We will need to see the detailed data in order to assess this properly, but at this point we also need to be careful not to cause unwarranted panic or resistance to vaccination.”
Dr Andrew Garrett, Executive VP, Scientific Operations, ICON Clinical Research, said:
“From what we have seen from the published data so far, the coronavirus vaccines are very safe. Of course, as vaccines are rolled out widely via within-country vaccination programs, adverse events will be observed in frequencies that reflect the scale of the roll-out. The very nature of vaccine prioritisation also means that many observed events will be confounded with the co-morbidities associated with the elderly and the clinically vulnerable. It is much harder to determine causality with observational data due to the absence of concurrent control and randomization, while disentangling the various potential effects can be a challenge – but this is why regulators such as the EMA have a Pharmacovigilance Plan for authorised vaccines.
“The vaccine clinical trials themselves were very large – much larger than for most clinical development programs for treatments – so they actually had a much higher chance than usual of detecting very rare adverse events whilst characterising common events (like injection site reactions) very well. For instance, the chances of observing at least one “1-in-10,000” very rare event is 78% with 15,000 participants in a clinical trial receiving an experimental vaccine. So there is a good chance of observing rare and very rare events prior to a vaccine being approved, and the clinical trials have the advantage of a control group to compare the frequency of events objectively. Furthermore the safety data from these reported clinical trials are still accumulating since participants in these studies are followed for two years.
“Once a vaccine (or any drug) is rolled out, the standard monitoring approach is to look at excess events of a particular type in a process known as signal detection. These events can be reported from various sources and in Europe are stored in the EudraVigilance system. Excess events, for instance, can be estimated by comparing the events recorded during the vaccine roll out with those from large databases of underlying event rates, including for similar products. These databases are maintained and updated by specific groups and include the FDA’s Sentinel database that uses electronic healthcare and administrative claims data. Particular types of event can also be reviewed in more detail through subgroup comparisons (like gender, age etc.). It is also possible to re-examine the clinical trials data for specific signs of an event that has been observed during roll-out. For instance by re-examining blood samples.
“It is inevitable that serious events will be observed during coronavirus vaccination, as they were prior to the vaccination program. It is the Sponsors’ and Regulatory Agencies’ responsibilities to monitor these events carefully and assess whether the frequency of events observed is disproportionate to what would normally have been expected, and if so to determine the potential cause. The Danish Medicines Agency has taken a cautious approach following the observation of blood clots and one death, and are investigating further whilst pausing vaccination for 14 days. In doing this they have had to balance the benefits and risks of potential vaccination delay in Denmark.”
Prof Anthony Harnden, Deputy Chair of the Joint Committee on Vaccination and Immunisation, said:
“Vaccine safety is critically important. Our UK regulator, the MHRA, review all reports of adverse events for both vaccines as they are reported. There have been more than 11 million doses of the Oxford-AZ vaccine administered in the UK and no excess reports of blood clots amongst those receiving the vaccine, compared with the expected rate in the population. The public should have confidence that both vaccines used in the UK vaccination programme are safe and highly effective at preventing severe disease, including the prevention of blood clots caused by Covid.”
Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice Magazine, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“It is by no means unusual for the introduction of a new vaccine to be interrupted by reports of adverse events such as this. This is a sign that adverse reaction monitoring systems are working – but not usually a sign that the adverse reactions are caused by vaccination.
“When vaccines are given to millions of people, it is only to be accepted that bad things will happen to some of them after they are vaccinated. What is important is to be able to assess whether such “adverse events” are causally associated with the vaccine.
“To this end, assessments of biological plausibility and, more importantly, calculations of whether the number of such events is more or less than would be expected by chance if people had not been vaccinated.
“With rare or uncommon outcomes, it can be particularly difficult to disentangle whether events are more common following vaccination. Organisations such as the Brighton Collaboration coordinate some of this work; and in England (as elsewhere) Public Health England has a rigorous vaccine surveillance strategy.
“It can be particularly difficult when the condition associated (and possibly but not necessarily caused by) vaccination is an established sequela of the disease the vaccine is used to prevent. With Guillain-Barré syndrome and influenza vaccination, for example, the number of cases following vaccination is so small that it is hard be certain whether or not there is an increase above background rates; by contrast, influenza definitely does cause Guillain-Barré syndrome. So, to avoid Guillain-Barré syndrome, given that it’s hard to avoid exposure to influenza, the safest option is to be vaccinated (since vaccination reduces your likelihood of getting influenza and thus of getting Guillain-Barré syndrome caused by influenza; and this effect hugely outweighs any minute risk from vaccination).
“The jury is still out on whether the events reported in Denmark – and, indeed, the death reported in Vienna – are causally linked to the vaccine. My guess would be that they are more likely to be chance associations, rather than causally linked.”
Dr Phil Bryan, MHRA Vaccines Safety Lead, said:
“Vaccine safety is of paramount importance and we continually monitor the safety of vaccines to ensure that the benefits outweigh any potential risks.
“It has not been confirmed that the report of a blood clot, in Denmark, was caused by the COVID-19 Vaccine AstraZeneca.
“The Danish authorities’ action to temporarily suspend use of the vaccine is precautionary whilst they investigate.
“Blood clots can occur naturally and are not uncommon. More than 11 million doses of the COVID-19 Vaccine AstraZeneca vaccine have now been administered across the UK.
“Reports of blood clots received so far are not greater than the number that would have occurred naturally in the vaccinated population.
“The safety of the public will always come first. We are keeping this issue under close review but available evidence does not confirm that the vaccine is the cause.
“People should still go and get their COVID-19 vaccine when asked to do so.”
Background
The MHRA encourages anyone to report any suspicion or concern they have beyond the known, mild side effects on the Coronavirus Yellow Card site. Reporters do not need to be sure of a link between a vaccine and a suspected side effect but are still encouraged to report.
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“This is a super-cautious approach based on some isolated reports in Europe. The problem with spontaneous reports of suspected adverse reactions to a vaccine are the enormous difficulty of distinguishing a causal effect from a coincidence.
“This is especially true when we know that Covid-19 disease is very strongly associated with blood clotting and there have been hundreds if not many thousands of deaths caused by blood clotting as a result of Covid-19 disease. The first thing to do is to be absolutely certain that the clots did not have some other cause, including Covid-19.
“A sensible approach is to investigate and be sure that the benefit and risk balance is in favour of the vaccine. Since we know with great certainty that the vaccine prevents Covid-19 with its attendant disease, and we are almost totally uncertain that the vaccine can have caused this problem, the risk and benefit balance is still very much in favour of the vaccine in my view.
“If however, there is no shortage whatsoever of alternative vaccines, then an extreme precautionary approach as taken in Denmark may be justified; if however this action stops some people getting the vaccine who are then vulnerable to Covid-19, then it is a mistaken use of precaution.
“As far as one can tell there has not been a “signal” of such problems in the UK and even if there were a “signal”, based on spontaneous reports, there needs to be a proper, rapid, epidemiological study to see if it is coincidence or not.”
All our previous output on this subject can be seen at this weblink:
www.sciencemediacentre.org/tag/covid-19
Declared interests
Prof Paul Hunter: “Only conflict of interest is that I had my immunization on Tuesday and it was the AZ vaccine.”
Prof Adam Finn: “AF is an investigator in clinical trials of the Oxford AZ vaccine and other COVID-19 vaccines. He is a member of JCVI, member of WHO SAGE working group on COVID-19 vaccines and chair of the WHO Euro technical advisory group of experts on immunization.”
Prof Jon Gibbins: “Jon is funded by the British Heart Foundation for his research on thrombosis, including work on Covid-19-caused blood clotting in the lungs.”
Dr Andrew Garrett: “I am employed by ICON which is a Contract Research Organization. ICON provides pharmaceutical services to the pharmaceutical and biotechnology industries. ICON conducts clinical trials on behalf of Sponsors, including vaccine trials. I am a member of the UK Statistical Authority’s (UKSA) Research Accreditation Panel.”
Dr Peter English: “No COI.”
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs. I am a participant in the Oxford/Astra Zeneca trial, and on 13th January 2021 learnt I had received the active vaccine.”
None others received.