Data – on reports of blood clotting cases in people who also had low levels of platelets in the UK, following the use of Oxford/AstraZeneca vaccine – were reported sparsely today by the Joint Committee on Vaccination and Immunization (JCVI) (https://www.gov.uk/government/news/jcvi-advises-on-covid-19-vaccine-for-people-aged-under-40).  Press-release by the Medicines and Healthcare products Regulatory Authority (MHRA) is little better.  This morning’s press conference did reveal that six cases had occurred in 6 million persons who had received their 2nd dose of Oxford/AstraZeneca vaccine, an estimated rate of 1 per million 2nd doses (95% CI: 0.4 to 2.2).

I wondered why event-rates by age-group were not presented at this morning’s press conference, as they had been previously.  Readers will recall that, at the 7 April press-conference chaired by Deputy CMO, JCVI and MHRA had focused on the age-relatedness of serious event-rate per 1 million administered 1st doses of Oxford/AstraZeneca which, at that time, decreased from 11 per 1 million doses for those aged 20-29 years through 8 per 1 million at age 30-39 years to 5 or fewer per 1 million doses for those aged 40+ years.

Indeed, today, the Winton Centre for Evidence and Risk Communication has updated its analysis by age-group, see https://wintoncentre.maths.cam.ac.uk/news/latest-data-mhra-blood-clots-associated-astra-zeneca-covid-19-vaccine/, as remarks at the press-conference hinted at.  But the Winton Centre has still not been allowed to publish, per age-group: either events/doses administered or the uncertainty which qualifies the smoothed central estimates.  As Winton Centre is pained to explain: “For the potential harms: numbers of cases of the blood clot reactions provided by MHRA up until April 28th in five-year age-bands (the data has not yet been publicly released in 5-year age bands). These observed rates were smoothed using a Poisson regression on age, with log-link.”

The updated central estimates, which I assume relate primarily to 1st doses, were as follows:

19 per 1 million doses at 20-29 years (95% CI: a to b)

15 per 1 million doses at 30-39 years (95% CI: C to d)

12 per 1 million doses at 40-49 years (95% CI: e to F)

10 per 1 million doses at 50-59 years (95% CI: g to h)

8 per 1 million doses at 60-69 years (95% CI: j to k)

The extent to which a and d overlap is of interest.  Likewise, the extent of overlap between C and F but sharply increased COVID-risks at 40+ years is by now the dominant consideration.

The Winton Centre also explains (without detail): “We have also looked at the data broken down by sex. Currently the MHRA data shows no statistically significant difference between the likelihood of men or women developing the specific blood clots – although there are slightly more cases in women than men, this could be due to chance variation, or possibly under-reporting amongst men.”

Missing are the following:

1. Why the increased event-rate per 1 million 1st or unknown doses?
2. Why did JCVI/MHRA not differentiate event-rates by whether 1st dose of Oxford/AstraZeneca vaccine was administered in January to March 2021 (i.e. before the early April alert) versus subsequently?
3. Why no update on mortality following reports of blood clotting in vaccinated persons in the UK who also had low levels of platelets?

Answers are likely to be inter-related; and understandable.  First, there is generally an increase in Yellowcards submissions after an alert such as by MHRA in early April 2021.  Age or gender patterns could easily be different for delayed reports of blood clotting cases in vaccinated people who also had low levels of platelets – that is, based on submissions received after March 2021 but which pertained to doses administered in January to March 2021.

Secondly, following the 7 April 2021 alert, persons under 30 years of age would not have received Oxford/AstraZeneca vaccine as their 1st dose.  Hence, in theory, the event-rate in the youngest age-group increases only on account of retrospective reporting.

For other age-groups, the number of doses administered increases, as either first or second doses.  But Yellowcard submissions about relevant adverse events increase also because the public and professionals are on the qui vive.

Events with fatal outcome will be especially likely to be reported.  However, the public also now knows to seek help early; and doctors know how to diagnose and to treat with immunoglobulins so that mortality-rate will have reduced.

In summary, I urge MHRA and JCVI to have greater respect for the statistical reporting standards: for example, please cite 95% uncertainty intervals for event-rates per 1 million doses and ensure that key counts (not just rates) are reported.

Also, explain something of the challenges and complexity that underlie pharmacovigilance which are likely to have contributed to the observed doubling in Yellowcard submission-rate.

‍

The UK vaccination programme continues at pace – 35 million people have received their first dose of Astra Zeneca, Pfizer or Moderna vaccines.  Data demonstrates all three vaccines are highly efficacious in preventing Covid and its complications.  More than 10,000 lives have been saved to date.  The UK is in the fortunate position of having good supply of all three vaccines.  Because a rare adverse event of thrombosis with thrombocytopenia has been noted in about 10-20 per million people following the Astra Zeneca vaccine, with a slight gradient of higher risk of this adverse event in younger people, JCVI has taken a further precautionary approach and advised a preference for an alternative vaccine to Astra Zeneca in adults under the age of 40 wherever possible.  JCVI have been able to advise this whilst infection rates remain low and vaccine supply is good.  JCVI still advises that it is better to receive Astra Zeneca vaccine in all adult age groups than no vaccine at all, but whenever possible an alternative vaccine is offered to those well adults under the age of 40.  JCVI will continue to monitor the safety profile of all vaccines, the vaccine coverage and infection rates in the UK population and any emergent variants of concern.

The vaccination programme against Covid-19 has been enormously successful in the UK, with a marked reduction in infection and transmission, saving many lives.  There has, however, been the worry caused by reports of thrombosis affecting the cerebral venous sinus (CVST) associated with reduced platelet levels in some in the post-vaccination period.  These were particularly noticed in the younger population and in women, although in the latter this may reflect the populations initially targeted as the gap has become less marked as increasing numbers are vaccinated.

The numbers remain small and it is clear that the risks of CVST are much greater following infection with Covid-19 and remain similar to those reported in the normal population.  However, the proximity to the vaccination with the AZ vaccine remains a worry and as the overall number of infections fall the potential risks and benefits of using the vaccine in the younger population is less clear.  It is therefore pragmatic advice from the JCVI to suggest looking at an alternate in the less than 40 population.  While CVST has been reported following the other vaccines, the numbers are much less and it is unclear whether the mechanisms are the same, or just reflect what would be expected in the normal population.  The mortality rate from CVST has been reported at approximately 20% and this is likely to fall with the increasing awareness of its possibility, and the availability of effective treatment.

The AZ vaccine remains the ‘workhorse’ of the vaccination campaign, because of its less stringent storage requirements, and in the older population, where the risks from infection are so much greater it can be used freely.  Alternate products can be offered to those under 40 and supplies are such that the targets for vaccination campaign will not be missed.

The risks from the AZ vaccine appear to follow only the first dose and so those that have received this can have the second without worry.

If an alternate is not available then serious consideration does need to be given to receiving the AZ vaccine as, although the risks remain very low from the vaccine, there is an increasing awareness of the development of the condition known as long-Covid, that may impact on 30% of those infected, and is not only very debilitating but, as the name suggests, can cause prolonged suffering.  It may also occur in a third of those in whom the infection was symptomless. It is important, therefore, to continue with the universal vaccination programme without delay.

‍

This action/recommendation by the JCVI is quite reasonable, given the current evidence supporting a link between the AZ vaccine and severe clotting complications, as well as the decreasing prevalence of COVID-19 cases in the population, and the safety of alternative, available COVID-19 vaccines.

Younger people will suffer less risk of severe disease and death from COVID-19, so it makes sense to reduce their risk from adverse vaccine effects also.

When smallpox was finally eradicated in the UK, the smallpox vaccine (which also had severe adverse effects) was phased out in 1971: https://www.ncbi.nlm.nih.gov/books/NBK545998/  Similarly, when wildtype polio was eradicated from various countries, including the UK, the vaccine was switched from the live attenuated oral form – to the inactivated form (in 2004 in the UK: https://vk.ovg.ox.ac.uk/vk/polio), to reduce the risk of vaccine reversion to wildtype virus – with all the disease-related complications (including paralysis) that this could produce.

‍

The JCVI advice issued this morning reflects the current UK situation and is contingent on things going as hoped and expected over the next 2-3 months.  Actually the risk benefit balance for people in their 30s – based on an expected third wave of COVID at some point later this year once lock down restrictions are lifted – is clearly in favour of receiving the AZ vaccine if offered.  However – since no thrombosis signal at all has been observed for the two mRNA vaccines – then it’s even more favourable for those two vaccines.  Given adequate supplies of the Pfizer vaccine are now predicted to permit the UK programme to progress at full speed, the logic of preferring to offer people that option whenever possible is self-evident.  However, it’s worth noting that the MHRA and all other regulators and the WHO still recommend the AZ vaccine for anyone from age 18 years and this vaccine will play a key in the control of the pandemic globally just as it has protected millions of people and saved thousands of lives in the UK already.

Do we know why these events happen; what do we know about a possible causal mechanism?

A definitive link between vaccination and these very rare side effects of blood clots with low platelet counts hasn’t been established, but the data so far suggest this is possible.  Analysis of the blood from some of the patients that developed these rare side effects has been shown to contain antibodies against a protein expressed in platelets known as PF4.  This is similar to patients with heparin-induced thrombocytopenia.  In this condition, these antibodies can bind to PF4 and heparin on the surfaces of platelets and cause their depletion.  It is possible that certain features of the adenovirus vectors that are used in the Astrazeneca and Johnson & Johnson/Janssen vaccines may be acting in a similar way to heparin, and lead to the depletion of platelets.

What does it mean that the MHRA say “Our position remains that the benefits of the COVID-19 Vaccine AstraZeneca against COVID-19, with its associated risk of hospitalisation and death, continues to outweigh the risks for the vast majority of people”?

The incidence of these very rare cases remains extremely low at about 10 per million people.  For many people, the risk of developing serious disease, hospitalisation or death due to COVID-19 is much higher.  However, in the UK we are very fortunate in that we have a range of different coronavirus vaccines available for use.  This allows the UK to offer the mRNA based Pfizer or Moderna vaccines to younger adults, where the benefits to risk are more finely balanced.

Any other comments about this development?

It has been mentioned many times that nobody is safe until everybody is safe.  Since the Astrazeneca and Johnson & Johnson/Janssen vaccines are relative cheap to produce, and are able to be stored at standard refrigerator temperatures, they will play incredibly important roles in vaccinating harder to reach communities and those in less developed nations across the globe.  This is especially the case for the Johnson & Johnson/Janssen vaccine, as full protective immunity can be achieved after just one injection.

Although those in the younger age groups may consider themselves much less likely to be seriously affected by COVID-19 and that they do not need to be vaccinated, they may still be able to transmit infection to others, especially to their elderly relatives.  Therefore it is essential that as many people as possible in all age groups are fully vaccinated to protect the wider population.

‍

As virus transmission levels fall then so does the risk of suffering serious COVID19, a risk that is already low in younger age groups.  Therefore, the potential benefits of having the AZ vaccine in these younger age groups no longer outweigh the risks, even though those risks of serious adverse effects – particularly blood clotting events – are incredibly low.

When other safer alternatives are available then it makes perfect sense to use these instead.

It’s also worth remembering that serious adverse effects have mainly been reported after receiving the first dose of the AZ vaccine, so if you have already had your first dose then it’s important that you still have your second dose to get good levels of immunity.

‍

We now have over 200 cases of confirmed vaccine-induced thrombocytopenia and thrombosis (VITT) which have been discussed at the daily meetings of the Expert Haematology Panel (EHP).  The condition is an immune reaction to the vaccine which triggers the production of platelet factor 4 antibodies that can cause intense activation of the blood clotting system, causing formation of blood clots in veins and arteries, and most commonly the venous channels draining blood from the brain.  The presentations can be dramatic and the mortality rate of those developing this condition is currently 19%.  The EHP is working daily to support clinicians treating these cases and to review the most effective management strategies.  We have only known about this condition for 6 weeks so have been intensely focussed on it during this time.  Early recognition and diagnosis has helped to bring down the fatality rate but we have further to go before we fully understand the mechanisms and best treatment.

The condition can affect anyone at any age, and males and females are equally at risk, however some of the most dramatic presentations have been in young women and hence the JCVI’s previous recommendation to offer alternative vaccines to men and women under 30 years old.  Since then the pandemic in the UK has dropped further, due to such a speedy and successful vaccine rollout.  Therefore the risks of covid-19 infection have fallen and the balance of risks for each age group, in the current climate, has changed.  This is under continuous review by the UK regulatory bodies and the advice given today by the JCVI is that for those under the age of 40, who have no underlying condition to increase their risk of covid-19 infection, should be offered an alternative vaccine where possible.

‍