Caution over blood-clotting is sensible. Panic is not

We need to learn as much as possible about side effects from the AstraZeneca and Johnson & Johnson vaccines—while persisting with their mass use

April 15, 2021
HD57medical / Alamy Stock Photo
HD57medical / Alamy Stock Photo

The scare over blood-clotting as a potentially lethal side-effect of some of the Covid-19 vaccines has worsened with the announcement that it’s not just the AstraZeneca (AZ) vaccine that is implicated. Now the vaccine made by the pharmaceuticals giant Johnson & Johnson (J&J), which has become a central plank of the US vaccination programme, has been found to have the same complication—leading the US Centers for Disease Control and Prevention (CDC) and the Food and Drugs Administration (FDA) to recommend a temporary suspension of its use.

Because both vaccines are relatively cheap compared with others, such as those made by Pfizer and Moderna using the new mRNA technology, and also because the J&J vaccine needs only a single shot rather than the two required of the other vaccines for full effect, they have been seen as crucial to global efforts to combat the virus. The problems now cast a shadow of uncertainty over those efforts, and could be a serious setback for low- to middle-income countries.

It’s unfortunate, but not particularly surprising: any new pharmaceutical intervention on such a massive scale might be expected to bring to light extremely rare side effects. In such unprecedented circumstances, there is no standard protocol for what to do about them. Is there a good case for disrupting the global vaccination programme at such a delicate stage?

Many think not. The news has prompted reporters and health-care experts to seek inventive ways of conveying the minuscule risks. Never before has it seemed so apparent that our brains are not adapted to a rational assessment of the statistics of risk. In particular, taking a positive action that incurs an extremely small risk feels instinctively more dangerous than doing nothing, even when (as in this case) “doing nothing” carries an inherently greater hazard: a continued vulnerability to a potentially deadly virus. One analogy put it rather nicely: so much greater are the risks of death from a driving accident—to which we give barely any thought in our daily lives—that you’d be at the same overall risk driving 45 miles to get a Pfizer shot as you would driving five miles to get an AZ jab. (The exact numbers can be debated; the point remains.)

In other words, the risks of serious consequences of a blood-clotting side effect are smaller than ones we routinely take without thinking. For the AZ vaccine (now often called Vaxzevria), the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) currently says that “the overall risk of these blood clots is approximately four people in a million who receive the vaccine.” By comparison, drug side effects are generally classified as “very rare” if they occur in one in 10,000 cases (100 in a million). The figures for the J&J vaccine might be even smaller: so far just six cases of clotting complications have been reported for 6.8m doses administered in the US, and only one of those was fatal.

Those numbers are likely to change as more data becomes available: clotting-related health problems are common, so won’t immediately be linked to vaccination. For the AZ vaccine, at least, the connection is revealed by an unusual clinical presentation involving activation of antibodies that can induce the aggregation of platelets, the cells in the blood that produce clotting. It’s actually quite likely that vaccine-induced clotting has been somewhat under-reported so far, and indeed the pause in the J&J rollout is partly to give healthcare systems a chance to get up to speed on spotting it. But it’s doubtful that the problem will be vastly greater than it already appears. These numbers are so small that it’s no wonder they didn’t show up in clinical trials on tens of thousands of people.

The real point is that the risks from Covid-19 are much greater: if you catch it in the UK, there has been on average a 3 per cent chance of dying (albeit with the risks mostly focused on older people). What’s more, blood clotting is one of the known complications caused by the virus too, possibly affecting as many as one in five infected individuals.

The issues are complicated by the role of other risk factors, however. The chance of clotting seems to be higher for women: the US cases from the J&J vaccine were all in women, while incidences from the AZ vaccine seem to be about twice as high for women. And the risk might be greater for younger people, for whom the danger of serious illness from Covid is lower. All the J&J cases occurred among women aged 18-48, and most of those for the AZ vaccine were for people younger than 60, although the numbers are still too small to be sure about any age dependence.

“As one analogy put it, you’d be at the same overall risk driving 45 miles to get a Pfizer shot as you would driving five miles to get an AZ jab”

That’s the reasoning behind the decision in the UK to offer an alternative to the AZ vaccine for under-30s: the risk-benefit trade-off is deemed then to tip in favour of greater caution. The risk of serious harm from blood-clotting due to the AZ vaccine for a 25-year-old (most such incidences lead to a full recovery) is currently estimated as only about twice the risk of dying from the coronavirus. “The closer you get to someone who’s right down at 20, and otherwise blameless [!] in their health,” says the UK’s Chief Medical Officer Chris Whitty, “the more you have to think through these really very rare side effects—the risk/benefits might get closer to parity.”

To be clear, we’re talking here about minuscule numbers in both respects—and even for a 20-something it still means that you’d increase your chances of staying alive by having an AZ jab rather than none at all. That’s why the MHRA is not actually imposing an age restriction but merely a choice: younger people will still be given the option of the AZ jab if no other is available. “Vaccines are the best way to protect people from Covid-19 and the benefits continue to outweigh any risks,” the agency affirms.

An urgent question now is to understand how the clotting complication arises—which might do more to identify specific groups most at risk and suggest measures that can be taken to avoid it. Both the AZ and the J&J vaccines use the same technology: they contain a harmless adenovirus (related to a common-cold virus) that injects into our cells a piece of DNA encoding the “spike protein” coronavirus uses to attach to and infect cells. The spike protein poses no threat by itself, but its presence stimulates the body to produce antibodies that can latch onto it and trigger an immune response. If coronavirus then invades the body, these antibodies will detect it from its spike proteins and trigger the immune system to kill infected cells, stopping the virus from spreading through the body.

Researchers are now trying to understand what component of the vaccine causes the side effect: it could be the adenovirus, or some additive, or some factor related to the manufacturing process. One clue is that the kind of clotting seen from the vaccines resembles the condition called heparin-induced thrombocytopenia, a rare side effect for people taking the blood-thinning agent heparin. (This suggests that heparin shouldn’t be given to people who are receiving these vaccines.) But as yet, the reasons for this similarity—or even whether it is genuine—remain unclear: the specific form that the vaccine-related blood disorder takes might actually be rather varied. It’s a hard problem to study with so few cases to go on. All the same, the question couldn’t be more urgent—not least because further vaccines to tackle more virulent and evasive new variants of the virus are surely going to be needed.

Another urgent question is whether the blanket suspensions of the AZ and J&J vaccines are warranted at all. Here, expert opinions differ. The CDC/FDA decision was made, the authorities attest, from “an abundance of caution.” Paul Offit of the Children’s Hospital of Philadelphia, a specialist on vaccines, told Science that under the circumstances “this was the only thing they could do.” But the European Medicines Agency has not recommended pausing the AZ vaccine, although it is currently reviewing both it and the J&J vaccine. Several European countries decided unilaterally on a temporary suspension anyway, and some of those which have restarted are now using it only for older people: over 55 in France, over 65 in Sweden. But some specialists insist that, for a risk this tiny, a warning to recipients—like those accompanying most medicines—should suffice.

The lack of any consensus, coupled to some debate about whether the clinical-trials data for the AZ vaccine was reported accurately—after much torrid discussion, the efficacy needed only a very small revision from 79 per cent to 76 per cent—will surely have stoked public fears that the vaccines haven’t been properly checked out. There are many reports of vaccination centres having unclaimed shots because people are preferring to “wait for one of the others” rather than take an AZ jab. One recent poll showed that a majority of people in France distrusted the AZ vaccine even before the clotting issue was verified. And inevitably the news is being seized on by anti-vaccination groups to spread disinformation and alarm. I’m sure I’m not alone in having had to try to persuade a family member whose vaccine hesitancy has been deepened by the blood-clotting problems and attendant (but misplaced) fears that the vaccines have been rushed through with inordinate haste.

Such setbacks could be particularly severe in low-wealth countries that are already challenged by limited vaccine availability. To see rich nations offering their populations alternative vaccines that poorer nations simply can’t access themselves fosters fears that substandard or dangerous shots—even though there is still no reason to regard the AZ and J&J vaccines as either—will be fobbed off on the poor. One doctor in Malawi told the New York Times that “we fought so hard with vaccine messaging, but what has happened this past week has brought us back to square zero.”

That problem reinforces the importance of trust in authorities. While Boris Johnson has insisted that he has “full confidence” in the AZ vaccine, and Matt Hancock has said it is “safe for all ages,” one has to hope that anyone liable to be influenced by their comments has not read Failures of State, an exposé of the UK response to the pandemic by the Sunday Times reporters John Calvert and George Arbuthnott—which essentially disqualifies both figures as trustworthy sources. We must hope that more credence is still given to the likes of Whitty, the MHRA, and the NHS. Once again, we see that technologies are not panaceas, and that openness, honesty and effective messaging are vital if we are to find a way out of this ongoing crisis.