AstraZeneca vaccine: clot or not?

In mid-March, several European countries paused the distribution of the AstraZeneca COVID-19 vaccine following reports of blood clotting disorders in people who had received the jab.

The Australian government has now mirrored this restriction, with ATAGI recommending the Pfizer vaccine over the Astrazeneca vaccine in adults under 50 years of age.

A review of the cases by the European Medicines Agency (EMA) concluded that these severe and rare blood disorders weren’t more common among vaccinated people than among the general population, and that the benefits of the vaccine outweighed any risk. However, the EMA could not rule out a link between the vaccine and the clots.

Last week, a 44-year-old man in Melbourne was hospitalised with severe thrombosis and a low platelet count – a similar case to those observed in Europe. The man had received the AstraZeneca vaccine a few days earlier.

The AstraZeneca vaccine has now being jabbed into millions of arms in a relatively standardised way. Adverse events have been meticulously monitored. Why is it so hard to investigate whether AstraZeneca causes this rare blood clotting?

“This needs urgent epidemiologic investigation to show whether this is a background event or it’s vaccine-related,” says Professor Tony Cunningham, a leading vaccine expert and director of the Centre for Virus Research at the University of Sydney. 

“If it is vaccine related, what part of the vaccine is causing it? Who is susceptible? Can we very quickly diagnose it and treat it?”

There are many questions scientists are still trying to answer, which is “why it is so difficult to pin down the connection between the two”, says Cunningham.

Correlation is not causation

When an adverse event occurs hours, days, or weeks after a vaccination, it is crucial to understand whether a causal link exists. A temporal link is necessary but not sufficient to determine if the vaccine causes such an event. To confirm causality, scientists also need to find a biological mechanism linking the vaccine directly to the medical condition.

A good example is an early form of the oral polio vaccine that caused vaccine-associated paralytic polio in some people. The vaccine used an attenuated form of the virus to generate immunity. About 1 person in every 2.4 million vaccinated people developed the disease. The virus strain from the vaccine could be found in the spinal fluids of affected patients. The link was clear. 

But these sorts of tests aren’t always possible, either because there aren’t specific biomarkers to look for or because they are impractical. “Determining causality is really difficult,” says Professor Hassan Vally, an epidemiologist at La Trobe University.

It’s still an emerging picture, adds Professor Raina MacIntyre, head of the Biosecurity Program at the Kirby Institute for Infection and Immunity in Society. But there is an indication that causation is possible, she says.

A possible biological mechanism was recently published by a German-led research team. According to the group, the rare blood disorders could be vaccine-induced pro-thrombotic thrombocytopenia (VIPIT), similar to the already known heparin-induced thrombocytopenia (HIT).

HIT happens when heparin binds to platelet factor 4 (PF4) – a protein on platelets’ surface. This elicits the immune system to create antibodies against PF4, which cause a drop in platelet count (thrombocytopenia). At the same time, that binding sets off inappropriate platelet activation, which causes dangerous blood clots.

The research team demonstrated that patients who developed clotting disorders after vaccination showed the anti-heparin/PF4 antibodies, as in HIT, although they had not been exposed to heparin.

The adenovirus vector used in the AstraZeneca vaccine may bind to platelets, resulting in a similar effect to the heparin-platelet complex. Thrombocytopenia has been previously reported after administration of adenoviral gene transfer vectors, says MacIntyre.  

Rare adverse events aren’t a surprise

The occurrence of rare adverse events is not a surprise considering the global scale of the COVID-19 vaccination campaign. Such events aren’t unusual for vaccine development. In fact, they aren’t uncommon with any approved pharmaceutical. Aspirin, an over-the-counter painkiller, has rare side effects.

AstraZeneca’s clinical trials,  which included a total of about 40,000 participants, did not report blood clot events associated with low platelet count. “The fact that we didn’t see this association in the clinical trial indicate that, whatever is going on, it’s a very weak signal,” says Vally.

But clinical trials will never be large enough in scale to pick up these extremely rare events. “Clinical trials don’t have the statistical power to detect very rare side effects,” says MacIntyre.

That is why surveillance systems are in place to detect any possible adverse effect caused by the vaccine once it is rolled out to a much larger population.

Cunningham, who has been running clinical trials for over 20 years, says no vaccine has been scrutinised this carefully before. “Very rare side effects can only be picked up through post-marketing surveillance,” he says.

“This is incredibly rare,” Vally adds. “Whichever way you do the arithmetic of risks of severe outcomes from COVID-19 and risks of side effects from the vaccine, it comes up clearly in favour of getting the vaccine – given that we’re in the middle of a pandemic, and millions of people have died.”