Accordingly, it is important to place the reported thrombotic events into context, and to think about how many thrombotic events we might normally expect in a population of a comparable size to the population that has received the Astra Zeneca vaccine.
In addition to the fact that there is not a clear mechanistic explanation as to why the Astra Zeneca vaccine would cause thrombotic events, the above considerations give us some reason to doubt that the vaccine is directly causing these incidents. It is imperative that any vaccine approved for use meets standards of safety and efficacy. In approving it for use, regulators have already been satisfied that the Astra Zeneca vaccine meets these standards. However, since this is a new vaccine without a long-term safety record, it is very important that its performance is closely monitored. When we observe serious adverse events in the vaccinated population, it is important to establish that these events were not directly caused by the vaccine. This is why the EMA and WHO are currently reviewing these adverse events.
- Preliminary Reviews suggest that the number of thrombotic events in individuals who have received the Astra Zeneca vaccine is not greater than the number we would normally expect in this population.
- It is crucial that we closely monitor these adverse events. The regulation of new medical interventions always requires us to manage uncertainty.
- A precautionary approach to managing this uncertainty may be important for ensuring continued confidence in vaccination.
- Regulators must weigh the potential risk suggested by these reports of adverse events following vaccination against the harm that suspension of the vaccine could have.
- The harm of suspending the use of the Astra Zeneca vaccine depends on how many preventable deaths we can expect by suspending its use.
- Amongst other things, this will depend on (i) how many people will be delayed in receiving a vaccine as a result (ii) the mortality risk of the people who would be prevented from receiving a vaccine, (iii) the prevalence of the virus at the time of the suspension, and (iv) the number of people who have received one dose of the Astra Zeneca vaccine, but not a second.
Notably, in countries that have not yet vaccinated older age groups, the risks of a suspension in this regard will be higher. The study cited above suggests that (unvaccinated) 70-74 year olds infected with the coronavirus have an average risk of death of 1.674% – for those over 80, the risk is 8.292%.
It is perhaps also tempting to think that the precautionary approach is the right one just because it ‘puts safety first’ – perhaps ‘you cannot be too careful’. In the current circumstances though, this is not obviously true. In a pandemic, time is lives; a week spent unvaccinated is a week spent living with a higher mortality risk of COVID-19. You can be too careful in minimising one kind of risk when doing so involves leaving people exposed to a much greater risk.
However, that does not answer the question of whether we should continue to use the vaccine. How we should manage these adverse events, and the uncertainty they engender, is a complex ethical question. A number of European countries have suspended the use of the Astra Zeneca vaccine following reports of individuals experiencing thrombotic events after receiving the vaccine. The European Medical Association’s (EMA’s) preliminary review on the 10th March suggests that these events have included cases of pulmonary emboli (including one reported fatality), and deep vein thrombosis.
The regulation of a new medical intervention always requires us to manage uncertainty. We have written elsewhere about the management of the uncertainty regarding the efficacy of the Astra Zeneca vaccine earlier in the pandemic. In the current context, we now have to think about how to manage uncertainty regarding a potential safety concern with the vaccine. But in both cases, the following is true: the more evidence available, the greater the certainty that regulators can have that a vaccine is safe and that it works. But gathering evidence takes time. This means, that the higher the standard of evidence we require, the greater the delay before people can access the intervention.
Accordingly, it is crucial that regulators weigh the potential risk suggested by reports of adverse events following vaccination against the harm that suspending the use of the vaccine could have.
An important reason that regulators might adopt a precautionary approach is to ensure that these reported events do not unduly undermine confidence in the vaccine. Making ‘safety’ an absolute priority in the response to these adverse events will help the public to have confidence in the vaccines that are being used in the pandemic response.
More recently, the BBC reports that, as of the 16th March, there have been 37 reported thrombotic events amongst 17 million people that have received the vaccine in Europe.
The risks in the above passage concern an infected individuals’ mortality risk. A third factor that is relevant to calculating the number of preventable deaths is the prevalence of the virus at the time of the suspension. In times of higher prevalence, we can expect a larger number of infections and therefore deaths. According to the latest data release, the ONS estimates that there is currently a low prevalence of the virus in England, around 1 in 270 (0.37%). However, in countries with a higher prevalence, suspension of the vaccine would lead to more deaths. Crucially, there is a currently a wide prevalence range in countries across Europe according to data from the European Centre for Disease Prevention and Control, with prevalence rates ranging from 4 to 1’572 per 100’000 people (0.004% – 1.572%).
The authors are working on the UK Pandemic Ethics Accelerator project – @PandemicEthics_. This project was funded by the Arts and Humanities Research Council (AHRC) as part of UKRI’s Covid-19 funding. All authors are affiliated to the University of Oxford.
The EMA’s preliminary review goes on to claim that there is no indication that the vaccine caused these conditions, and that the “number of thromboembolic events in vaccinated people is no higher than that seen in the general population”, citing 22 cases of thromboembolic events among the 3 million people vaccinated with the AstraZeneca vaccine in the European Economic Area as of the 9th March.
Managing Uncertainty
The second factor contributing to the number of preventable deaths a suspension would cause is the mortality risk of the people who would be prevented from receiving a vaccine for the suspension period. For example, in England, those aged 56 and over are currently being invited to book appointments for vaccination. A recent study suggests that the average risk of death for (unvaccinated) 55-59 year-olds infected with coronavirus is 0.323%. So, suspending the use of the vaccine would be delaying protection for a relatively low risk group. But even preventing these individuals from receiving a vaccine would still translate to some preventable deaths. In the week ending 5th March 2021 alone, ONS data suggests that there were 53 deaths that included COVID-19 on the death certificate in this age-band alone in England and Wales.
The first Astra Zeneca vaccine was given to a patient on the 4th Jan 2021, and there have been 37 reported cases of thrombotic events, as of 15th March (70 days later).
By Jonathan Pugh, Dominic Wilkinson, and Julian Savulescu
A final factor to consider is the number of people who have received one dose of the Astra Zeneca vaccine, but not a second. The reason for this is that, depending on its length, a suspension of the vaccine may extend the dosing period for these individuals, potentially diminishing the effect of the vaccine for some of them. The UK government figures do not provide a fine-grained breakdown of the data in this regard, but the figures suggest that 22’842’941 people have had one dose of an approved COVID-19 vaccine, but not a second.
Using these figures, if we extrapolate the 37 reported cases of a thrombotic events in a 17m population over the course of 70 days, that gives us an expected yearly rate of around 193 cases in a population of this size. This expected yearly incidence would fall a considerable way below the number of thrombotic events that you would normally expect in a population of this size, according to rates indicated by the study cited above. This is so even if you assume that the population were wholly constituted by individuals in the lowest risk age band.
In the UK, by the 16th March, 1,610,280 people have received two doses of an approved COVID-19 vaccine, and 24,453,221 have received one dose. This still leaves a large number of people who have not yet received a vaccine in the UK. In other European countries, fewer people have been vaccinated.
The risks of suspending the use of the Astra Zeneca vaccine depends in part on how many preventable deaths we can expect by suspending its use. A number of factors in addition to the efficacy of the vaccine will influence this, and many of these factors will differ across countries. The first factor is how many people will be delayed in receiving a vaccine as a result of the suspension. Fortunately, the Astra Zeneca vaccine is not the only vaccine available in Europe, so its suspension will not wholly prevent vaccination; however, it is possible that at least some people’s vaccinations will be delayed by a suspension of the Astra Zeneca vaccine.
Although the incidence of venous thrombosis is very rare in young individuals (<1 per 10 000 per year), it has an incidence of around 1% per year in the elderly. This suggests that in a population of 17 million people young people (i.e. those with the lowest risk of thrombosis), you would normally expect around 1700 cases of thrombotic events.
Since aging is one of the strongest risk factors for venous thrombosis, the number of cases you would expect in a population of this size will increase sharply as the age of the population increases. According to the figures in this study, you would expect around 170’000 cases in a population of 17m elderly people.
Summary Points
One natural response to the uncertainty prompted by reports of adverse events is to adopt a precautionary approach – it is better to be safe than sorry. The precautionary approach calls for suspending the use of the vaccine until we gain a rigorous understanding of these 37 reported thrombotic events, so that we can be absolutely satisfied that they have not been caused by the vaccine.
The fact that thrombotic events have occurred in individuals who have received the vaccine does not mean that the vaccine caused these events. Correlation is not the same as causation.