The University of Oxford-AstraZeneca coronavirus vaccine has hit headlines over fears it may cause blood clots in 'extremely rare' cases.
The jab – one of three approved vaccines in the UK's immunisation arsenal – has been linked to 79 blood clot cases, of whom 19 patients had died by 31 March.
While definitive proof the vaccine is responsible has not yet been found, the UK's jab regulator says the link is getting stronger.
It is therefore recommending healthy people under 30 in the UK be offered an alternative coronavirus vaccine, like Pfizer-BioNTech or the not-yet-widely-available Moderna.
Anyone who has received their first Oxford-AstraZeneca dose, regardless of their age, should have the second jab, unless they developed a clot. There is not enough evidence to support giving an Oxford-AstraZeneca first dose followed by a different type of coronavirus vaccine.
The EU's medicines regulator wants unusual blood clots to be listed as a "very rare" side effect of the jab, but stressed the benefits of getting immunised outweigh the risk for most.
How common is the potential side effect?
The UK's clot cases and deaths occurred after 20.2 million doses of the vaccine were administered, according to the Medicines and Healthcare products Regulatory Agency (MHRA).
Around four in 1 million people who have the jab may therefore be at risk of developing a clot. The death risk with the complication could be one in 1 million.
According to the BBC, "that's roughly the same risk as being murdered in the next month or – if you get in a car and drive for 250 miles – the risk of you dying in a road accident on that journey".
All the clot cases have occurred after the first vaccine dose, however, relatively few second jabs have been administered.
The World Health Organization has said a link between the vaccine and clots is "plausible" but "very rare", based on the nearly 200 million people who have received the jab globally.
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Health secretary Matt Hancock has said the vaccine is "safe, effective and the benefits outweigh the risks for the vast majority of adults", comparing the post-jab risk of a clot to that of "taking a long-haul flight".
Boris Johnson said the jab has "already saved thousands of lives", adding everyone should "continue to have full confidence in vaccines".
England's deputy chief medical officer Professor Jonathan Van-Tam has also stressed changing prescription practices is relatively common in medicine.
Dr Michael Head, from the University of Southampton, agreed, adding: "It’s important to emphasise adverse events happen with all medicines and vaccines are no exceptions.
"There were some cases of severe anaphylaxis with the Pfizer vaccine early in the UK rollout. These were openly investigated, guidance subsequently updated and the rollout continued with high public confidence."
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Why are clots occurring?
In short, we do not know.
The same side effect does not appear to be arising with the Pfizer-BioNTech coronavirus vaccine, which is also being widely administered across the UK.
The two jabs have different technologies.
Pfizer-BioNTech is an RNA vaccine. It is made up of tiny fragments of the virus' genetic code. When in the body, the jab makes the coronavirus' spike protein, which the infection uses to enter cells. The immune system recognises the spike protein and launches a response. Immune cells are then ready if the individual is exposed to the coronavirus.
The Oxford-AstraZeneca vaccine, however, is based on a modified version of a virus that typically causes common cold-like symptoms in chimps.
In this case, genes for the coronavirus' spike protein were put into the jab. When injected into an individual, the spike protein is produced, promoting an immune response.
Speaking of the clots, Professor Anthony Harnden, from the Joint Committee on Vaccination and Immunisation (JCVI) – the organisation behind the under-30 recommendation, said: "It could be related to the vaccine platform. We're not seeing this with the RNA vaccines."
If that is the case, the same side effect could arise with the Janssen coronavirus jab, which is not yet approved in the UK.
Prof Harnden stressed, however, "we can't speculate" if similarly-acting vaccines may cause the same side effect.
The vaccine's clot cases are somewhat unusual in that they are low in platelets; cells that help form clots to stop bleeding.
"They all [the clot cases] have a very odd antibody [immune protein]," says Professor Beverley Hunt, from King's College London. "It's to a molecule called platelet factor 4."
Prof Hunt likened the cases to heparin-induced thrombocytopenia. In some patients, the blood thinner heparin causes specific antibodies to bind to so-called heparin-platelet factor 4 complexes, activating cells that can cause clots.
"A few people who get heparin make an antibody to heparin and anti-platelet factor 4," said Professor Hunt.
"[We] could speculate if [you are] making antibodies to some constituent of the Oxford-AstraZeneca vaccine, something makes them [the vaccines] make a unique antibody that cross-reacts with platelet factor 4.
"We don't know what part of the vaccine may do that."
As to why platelet numbers are low, Prof Hunt said: "You're activating the platelet and consuming them all in forming clots, therefore the circulating platelet count will fall."
Levels of D-dimers, protein fragments produced when a clot is broken down, are "very high" in these patients.
Prof Hunt added, however, she could "sit here all day and think of a number of mechanisms".
Not everyone is convinced the blood clot issue is Oxford-AstraZeneca specific.
"I'm agnostic as to whether it's a vector [the modified chimp cold virus] problem or an S[pike]-protein problem," said Professor Adam Finn, from the University of Bristol.
"[It could be] the RNA vaccines are [only] not doing it due to [their] dose or where the S-protein goes in terms of release."
Professor Ian Douglas, from the London School of Hygiene & Tropical Medicine, agreed, adding: "The reality of the incredible COVID [the disease caused by the coronavirus] vaccine roll-out speed and volume means we will continue to find out more about these rare clots, and we may well see new safety signals with any of the vaccines.
"This is the nature of all effective medications – their rarer side effects only emerge when we use them at large scale."
Why is the vaccine not recommended for under-30s?
It all comes down to the perceived risk-benefit analysis.
The coronavirus' overall death rate is somewhat muddled and will unlikely become clear until after the pandemic. The fatality risk is known to vary significantly according to a patient's age, weight, ethnicity and underlying health.
Children rarely become seriously ill with the coronavirus, however, it is said to kill one in eight people over 75 who become infected.
Among symptomatic people in their 40s, one in 1,000 are said to die when infected.
"The risk-benefit balance [of the vaccine] is very obvious the older you get," said Prof Finn.
With young, healthy people rarely become seriously ill with the coronavirus, the regulator has recommended they be offered a different vaccine if possible, as the risk-benefit balance of the Oxford-AstraZeneca jab becomes more blurred.
It is not a case of young people being more at risk of the clots themselves.
"We felt the benefits [of the vaccine] outweighed the [clot] risks in anybody over 30, but under 30 it was not clear," said Prof Harden.
"The EMA [European Medicines Agency] and MHRA have authorised this vaccine for all age groups. They still feel it is safe and effective for all age groups, and have left it up to JCVI equivalents around the world to make their own decisions."
France recommends the Oxford-AstraZeneca vaccine be given only to people aged 55 or over. In Germany, the advice is to immunise those over 60 or in a high-priority group. Norway, not part of the EU, and Denmark have suspended the jab entirely.
Speaking of the UK's decision, Prof Harnden said: "We thought there was enough doubt in our mind [that] the benefit did not outweigh the risk in the very young age group."
Professor Lim Wei Shen, from the JCVI, has said the move was made "out of the utmost caution rather than because we have any serious safety concerns".
Of the 19 deaths in the UK, three were under 30. Nearly two-thirds of the overall cases were in women.
Nevertheless, the EMA's executive director Emer Cooke has said there is no available evidence of "specific risk factors such as age, gender or previous medical history of clotting disorders".
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How does the clot risk compare to that of the pill?
The contraceptive pill is said to be the most common form of birth control among sexually-active women, with around 3.75 million taking it in 2000 in the UK.
The combined pill, made up of artificial oestrogen and progesterone, is recognised as having a "very low risk" of blood clots.
The US Food and Drug Administration estimates three to nine women in every 10,000 on the combined pill will develop a serious blood clot every year.
This is compared to one to five in every 10,000 who are not pregnant or taking birth control.
Some have pointed out it is unclear whether the post-vaccine clots would have occurred without having the jab, with no one being immune to the complication.
Nevertheless, the EMA has said that by mid-March, it may have expected one to two cases of clots in people under 50 given the vaccine, but instead saw 12.
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When it comes to the pill, Professor Finn noted it does not treat an illness, yet millions of women still accept the birth control's blood-clot risk given its benefits.
"The pill is probably the commonest cause of cerebral venous sinus thrombosis," added Professor Hunt. This occurs when a clot forms in the brain's venous sinuses, which prevents blood draining from the vital organ.
Obesity can also cause blood clots, with a quarter of adults in the UK being very overweight.
Prof Finn added that you can also make risk-benefit comparisons which are "rather more mundane": "The risk of dying in a car [for example]."
Road fatalities killed on average five people a day in the UK in 2013.
Does the coronavirus cause clots?
The coronavirus itself is thought to make blood stickier in severe cases, leading to clots that can cause strokes and even gangrenous limbs.
Professor Sir Munir Pirmohamed – chairman of the Commission on Human Medicines – told the BBC 7.8% of coronavirus patients develop blood clots on their lungs, while 11.2% endure deep vein thrombosis in their legs; a blood clot in a vein that can become dislodged.
Meanwhile Professor Lawrence Young, from Warwick Medical School, added: "As increased blood clotting is a common feature of COVID-19, it could be this effect is due to people getting infected with the virus soon after vaccination or it could be a direct effect of this particular type of vaccine."
Are the clots treatable?
Official guidance recommends patients be given an intravenous immunoglobulin (antibody) that blocks the antibodies causing the problem.
"Then [we] back up once the patient is relatively safe, with anticoagulation with agents that aren't heparins," said Prof Hunt.
While some take aspirin to reduce their risk of clots, this is not recommended after a Oxford-AstraZeneca vaccine.
"[The clotting is] very unusual in how it's responding," said Prof Hunt. "It's an immune response, [based on] the current data.
"Taking aspirin is not going to be helpful. Taking an anticoagulant probably isn't going to be helpful. It'll increase your risk of bleeding."
Anyone who develops a persistent headache, blurred vision or confusion for four or more days post-vaccination should seek medical attention.
The same applies to those who experience unusual bruising, breathlessness or chest pain.