• VITT (vaccine-induced thrombosis and thrombocytopenia) is a very rare adverse event characterised by presence of blood clots with low levels of platelets following vaccination with the University of Oxford/AstraZeneca COVID-19 vaccine.
  • Between 9 December 2020 and 5 May 2021, there have been over 260 cases of VITT out of a total of 30.8 million doses of the University of Oxford/AstraZeneca vaccine administered in the UK.
  • The overall risk of VITT following a dose of the University of Oxford/AstraZeneca vaccine is 10.9 per million doses. This varies according to age groups and it is estimated to be around 1 in 100,000 for people over 50 and 1 in 50,000 for people aged between 18 and 49 years.
  • Following an age-based risk-benefit analysis, the Joint Committee on Vaccination and Immunisation (JCVI) concluded that people aged under 40 should be offered an alternative to the University of Oxford/AstraZeneca COVID-19 vaccine.
  • The biological mechanisms responsible for VITT are still under investigation. Initial evidence suggests that VITT is triggered by an over-reaction of the immune system.
  • VITT has not been associated with the other COVID-19 vaccines currently deployed in the UK (Moderna and Pfizer/BioNtech).
  • VITT cases have also been reported following vaccinations with the Johnson & Johnson/Janssen vaccine, a vaccine deploying the same technology as the University of Oxford/AstraZeneca one. This vaccine has not yet been approved for use in the UK. However, there is currently no evidence to show that it is the technology that is triggering VITT.
  • There is currently no evidence that VITT concerns have specifically had an impact on vaccine uptake in the UK population. However, the latest ONS data does show that vaccine hesitancy was almost twice as high among adults aged 16 to 29 years than the general population between 31 March and 25 April 2021 and that side effects were among the biggest concerns.
  • This is part of our rapid response content on COVID-19. You can view all briefings on COVID-19 vaccines produced by POST and the House of Commons Library in Vaccination and COVID-19.

The University of Oxford/AstraZeneca COVID-19 vaccine and blood clotting

Since the beginning of the national immunisation programme, the safety of COVID-19 vaccines deployed in the UK has been closely monitored using a national system called the Yellow Card Scheme (see POST’s previous Rapid Response on Monitoring COVID-19 vaccine safety in national immunisation programmes).

This has shown that severe adverse effects following COVID-19 vaccines are very rare overall and that the University of Oxford/AstraZeneca vaccine is associated with very rare blood clots. Following an initial review on 7 April 2021 the Medicines and Healthcare products Regulatory Agency (MHRA) concluded initially that there were 4 cases of blood clots (thrombosis) with low level of platelets (thrombocytopenia) per million doses administered of the University of Oxford/ AstraZeneca vaccine. More evidence on this link emerged and, based on data up to the 28 April 2021, the MHRA estimated that there were 10.5 thrombosis with thrombocytopenia cases per million doses of the University of Oxford/ AstraZeneca vaccine.

According to the latest data, out of the 30.8 million doses of the University of Oxford/ AstraZeneca vaccine administered in the UK between 9 December 2020 and 5 May 2021, there have been over 260 cases of thrombosis with thrombocytopenia cases, equivalent to 10.9 cases per million doses (although it varies by age groups, see below).  The vast majority of events have been reported following the first dose and only 8 after the second dose. Deaths occurred in 20% of the cases (about 50 people in total).

Vaccine induced thrombosis and thrombocytopenia (VITT) and thrombosis and thrombocytopenia syndrome (TTS) are terms used to describe this condition. The Expert Haematology Panel (EHP) has produced guidance on VITT identification and treatment.

How has the guidance changed for the University of Oxford/AstraZeneca COVID-19 vaccine?

The risk of developing VITT following the University of Oxford/AstraZeneca vaccine is very small. The Winton Centre for Risk and Evidence Communication analysed this risk according to age groups and compared it with the benefits of the vaccine for each group, quantified as prevented ICU admissions due to COVID-19 every 16 weeks. Prevented ICU admissions were evaluated in relation to different level of virus exposure: the higher the number of COVID-19 cases in the population, the higher the risk of infection is and therefore ICU admission. Based on this analysis of infection and adverse events data, collected up to 1 April 2021, on 7 April the Joint Committee on Vaccination and Immunisation (JCVI) initially advised that adults aged under 30 without underlying health conditions should be offered an alternative COVID-19 vaccine to the University of Oxford/AstraZeneca one, if available.

Further evidence from the MHRA collected up to 28 April 2021, combined with increasingly lower infection rates in the population (therefore a lower probability to develop complications from COVID-19 for younger groups), led the JCVI to conclude on 7 May 2021 that adults aged under 40 should be offered an alternative to the University of Oxford/AstraZeneca vaccine ‘where available and only if this does not cause substantial delays in being vaccinated’.

The latest MHRA guidance on COVID-19 vaccines and blood clots states that the risk is currently estimated to be around 1 in 100,000 for people over 50 and 1 in 50,000 for people aged between 18 and 49 years. For people aged between 18 and 49 the guidance states that ‘if are offered the [University of Oxford/AstraZeneca] vaccination you may wish to go ahead after you have considered all the risks and benefits for you.’

What is the cause of vaccine-induced thrombosis and thrombocytopenia (VITT) following the University of Oxford/ AstraZeneca vaccine?

The biological mechanisms triggering VITT following the University of Oxford/AstraZeneca vaccine administration are still under investigation. There have been only a few studies, based in Germany, the UK, Denmark and Norway. Initial evidence suggests that episodes of VITT are caused by an over-reaction of the immune system. Individuals with thrombosis with thrombocytopenia show high levels of antibodies against a molecule called ‘platelet factor 4’ (PF4), whose role is to promote coagulation. Antibodies recognising a person’s own molecules (rather than molecules present in viruses, bacteria, etc.) are called ‘autoantibodies’. PF4 autoantibodies have the unwanted effect of activating platelets, thereby leading to formation of blood clots. In the meantime, they also work as ‘tags’ against platelets, directing the immune system to destroy them. This reaction leads to both low platelet levels and blood clots.

Scientists have reported a similar very rare phenomenon following the administration of heparin (an anticoagulant drug commonly used to treat or prevent blood clots), which is called heparin-induced thrombocytopenia (HIT). None of the thrombosis with thrombocytopenia cases following the University of Oxford/AstraZeneca vaccine have been exposed to this drug.

Although VITT is thought to be an immune phenomenon (and therefore the immune response triggered by the second dose should be higher), it is still not well understood why the majority of VITT cases (254 cases) has been reported after the first dose of the University of Oxford/AstraZeneca vaccine and only 8 after the second one. Some experts suggest that this could be potentially due to the fact that the amount of second doses of the University of Oxford/AstraZeneca vaccine administered is still very low when compared to the first doses (these are estimated to be 7.5 million and 23.3 million respectively according to the latest MHRA data).

Are individuals at risk of thrombosis more at risk of developing vaccine-induced thrombosis and thrombocytopenia (VITT) following the University of Oxford/AstraZeneca vaccine?

According to the PHE guidance for healthcare professionals on blood clotting following COVID-19 vaccination, the Expert Haematology Panel advised that there is no evidence that individuals with a prior history of thrombosis or known risk factors for thrombosis are more at risk of developing VITT. The University of Oxford/AstraZeneca vaccine is not recommended for those who previously experienced heparin-induced thrombocytopaenia and thrombosis (HIT), but previous episodes of thrombocytopaenia by itself do not represent a risk.

Although hormonal contraception increases the risk of thrombosis, the Faculty of Sexual and Reproductive Healthcare stated that it is currently unknown how hormonal contraception affects the risk of thrombosis with thrombocytopenia that has been observed after AstraZeneca COVID-19 vaccination. The FSRH recommends users of hormonal contraception to be vaccinated according to JCVI guidance.

What is known about other COVID-19 vaccines approved in the UK and blood clots?

According to the Public Health England Guidance for health professionals on blood clotting following COVID-19 vaccination, there have been only 2 cases of thrombosis with thrombocytopenia reported for the Pfizer/BioNTech vaccine until 31 March 2021 in the UK. There is currently no evidence suggesting that these rare events were caused by the Pfizer/BioNTech vaccine.

VITT is not currently associated with either the Pfizer/BioNTech or the Moderna vaccines (both mRNA-based). A pre-print (study not yet peer reviewed) retrospectively analysed health records in a US-based population and compared the risk of cerebral venous thrombosis and portal vein thrombosis (two types of venous thrombosis that are thought to occur in VITT) following COVID-19 with the risk of developing them following vaccination with these two mRNA vaccines. The preprint showed that their risk is higher in COVID-19 patients than in people receiving either of these mRNA-based COVID-19 vaccines. The authors could not make a direct comparison with the risks of thrombosis following the University of Oxford/AstraZeneca vaccine because it is not currently used in the US. Moreover, they could not assess whether these kinds of thrombosis following COVID-19 were similar to what has been described in VITT, given that data on the levels of PF4 autoantibodies (the ‘signature’ associated with VITT) were not available.

Thrombosis with thrombocytopenia has also been reported with the Johnson & Johnson/Janssen COVID-19 vaccine, one of the vaccines already secured in the UK (see below). The MHRA is currently performing a rolling review of this vaccine, but has not yet approved it. As per agreements following the withdrawal of the United Kingdom from the European Union, the MHRA can approve the vaccine through a reliance procedure, relying on EMA’s previous assessment while considering the newest safety data emerging.

The Johnson & Johnson/Janssen vaccine

The Johnson & Johnson/Janssen vaccine is a single-dose vaccine based on an adenovirus technology (similar to the University of Oxford/AstraZeneca vaccine). The UK already secured 30 million doses of this vaccine. On 21 April 2021 the results of the Phase 3 clinical trials were published. The study involved 39,321 participants (half receiving the vaccine and half receiving a control injection) and it assessed safety and efficacy against COVID-19 disease. The study was paused on 11 October 2020 following a suspected serious adverse event. It resumed on 27 October 2020 following a data and safety monitoring board review that found no evidence that this event was related to the vaccine.

On 27 February 2021, the US Food and Drug Administration (FDA) granted an emergency use authorisation for the Johnson & Johnson/Janssen vaccine. In the emergency use authorization review memorandum the FDA reported that the serious adverse event leading to the study pause was a particular episode of thrombosis in a 25-years old participant. Shortly after, on 11 April 2021, the European Medicines Agency (EMA) recommended it for EU authorisation. Vaccinations temporarily stopped in the US and the EU at the beginning of April 2021 following reports of very rare blood clotting (6 cases out of 6.8m doses administered).

On 14 April 2021, one case of thrombotic thrombocytopenia after the Johnson & Johnson/Janssen vaccination programme in the US was described in detail in the New England Journal of Medicine (NEJM). The authors suggested that this rare serious adverse event could be related to the adenoviral technology used for both the University of Oxford/AstraZeneca and the Johnson & Johnson/Janssen vaccines. On 16 April 2021, Janssen (the manufacturer) responded to this hypothesis on NEJM, arguing that the two vaccines use different adenoviral vectors containing slightly different parts of the spike protein, therefore the biological effects may be quite different.

A link between VITT and the Johnson & Johnson/Janssen vaccine was identified by safety reviews performed by the FDA (in conjunction with the Centre for Disease Control, CDC) and the EMA, but they both concluded that these events are very rare and that the benefits of the vaccine outweigh the risks for adults aged 18 and older.

Vaccinations resumed at the end of April 2021. According to the latest data, 15 cases of VITT have been identified in about 7 million doses administered.

Vaccine-induced thrombosis and thrombocytopenia (VITT) and adenovirus-based vaccines: what is the link?

Rare VITT events following adenovirus-based vaccines generated a series of questions for scientists, ranging from the biological mechanisms involved to the impact of the fear of potential adverse effect on global vaccination efforts. There is currently no evidence that the adenovirus vaccine technology itself is the cause of VITT episodes and data from other vaccines using the same technology (including the Russian vaccine Sputnik V and the vaccine produced by the Chinese company CanSino Biologics) is not available at the moment.

One pre-print (not-peer reviewed) analysed the components in different batches of the University of Oxford/AstraZeneca vaccine and hypothesised that VITT might not in fact be caused by the vaccine technology. Instead, it questioned whether the preservatives used in the vaccine or remnant proteins from the production process might be involved in the very rare VITT episodes. As of the time of writing, similar studies on other adenovirus-based vaccines are not available and there is still no clear understanding of this process.

Is the fear of rare blood clots increasing vaccine hesitancy in the UK?

There is overwhelming evidence that the vaccines currently deployed in the UK are safe and effective in protecting from COVID-19 disease and transmission (see POST Rapid Response COVID-19 vaccines and virus transmission). Vaccine benefits (including the impact of vaccines on reducing the risk of long-COVID) largely overweight their risk. However, there are some concerns that reports of rare blood clots could have an impact in vaccine uptake. There is no evidence available linking the latest VITT reports to a decrease vaccination rates in the UK.

Recent surveys have captured public attitudes towards COVID-19 vaccines in relation to the latest developments:

  • University of Bristol, King’s College London and the NIHR survey – 4,896 UK adults aged 18 to 75 were surveyed between 1 and 16 April 2021. It found that, although the majority of respondents stated that they are confident about vaccine safety and effectiveness, only 17% of the interviewees (a reduction from 24% reported at the end of March) said that they would prefer the University of Oxford/AstraZeneca vaccine if given the choice. 23% of respondents said that they believe that the University of Oxford/AstraZeneca vaccine causes blood clots (an increase from 13% reported at the end of the month). Moreover, vaccine hesitant people were more than twice as likely than the general population (57% vs 23%) to believe this statement.
  • Office for National Statistics – 16,360 people 16 years and older in Great Britain were surveyed between 31 March to 25 April 2021. This found that vaccine hesitancy was reported by 7% of respondents (a decrease from the 9% reported at the beginning of 2021). The highest rates of vaccine hesitancy (13%) were among adults aged 16 to 29 years. Side effects were among the top three reasons for reporting negative sentiment towards the vaccine.
  • Office for National Statistics – 50 in-depth interviews about vaccine refusal were conducted in the UK from February to March 2021. This found that safety concerns were reported by many participants. The study identified the potential role of social media and unverified information sources in generating concerns about the contents or side effects of COVID-19 vaccines. It also found that there was an appetite for more information, including on safety. For more on this topic, read the POST rapid response on COVID-19 vaccine misinformation.

Acknowledgements

POST would like to thank Professor Calman A. MacLennan (University of Oxford; University of Birmingham; Oxford University Hospitals NHS Foundation Trust) and Professor Michael Makris (The University of Sheffield) who acted as external peer reviewers in preparation of this article.


Photo by Steven Cornfield on Unsplash

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