Rogue antibody and mystery pathogen behind AstraZeneca blood clots: study - Sydney Morning Herald
A rare gene combined with exposure to a mystery pathogen may have caused the blood clotting issues that plagued AstraZeneca's COVID-19 vaccine.
Australia pinned much of its COVID-19 response strategy on AstraZeneca's vaccine, with 50 million doses produced by CSL's Broadmeadows plant.
Vials of AstraZeneca's COVID-19 vaccine.Credit:AP
But at the height of the pandemic last year, as millions of Australians were preparing to roll up their sleeves, the vaccine was linked to an extremely rare but deadly blood clot disease.
It left many with a tough choice: get jabbed and take the three-in-100,000 risk of clots, or decline the vaccine and take your chances with the virus. In total, 173 Australians suffered clots, and eight people died.
Exactly what caused the clots has remained a mystery. But this month a team of Australian scientists led by Flinders University's head of immunology Professor Tom Gordon reported in the journal Blood that they had traced the culprit down a single gene – and a mystery pathogen.
"This was very unusual," Gordon said. "In 35 years of looking at blood autoantibodies I have never seen anything like this."
"Exceptionally dangerous"
AstraZeneca's vaccine is built around an adenovirus vector – a harmless virus modified to carry the genetic code of COVID-19's spike protein.
After vaccination, the virus infects our cells, which then use the genetic code to produce copies of the spike protein. In turn, our immune system learns to recognise the spike and builds an arsenal of antibodies designed to fight it.
But scientists suspect the adenovirus itself can accidentally bind to a crucial natural protein in the body known as PF4. A small signalling molecule, it's used to get blood to thicken – important in repairing cuts, for example.
In rare cases, people develop antibodies that can recognise and bind to this combination of adenovirus and PF4. By binding, the antibodies activate PF4, causing it to signal platelets in the blood to clump together.
"Once you clump platelets you get widespread clotting. So they are exceptionally dangerous," Gordon said.
But that explanation leaves a gaping hole. We all have PF4. Why did only a few people get clots?
A rogue antibody
Working with rogue antibody samples from five people in Adelaide who suffered clots after the vaccine – including one person who died – Gordon's team made several key discoveries.
First, they discovered the rogue antibodies slotted perfectly into a groove on PF4 that was only exposed when PF4 was exposed to AstraZeneca's adenovirus.
Then they found the antibodies from the five people were almost identical.
Antibodies vary a lot from person to person; the immune system can make perhaps a million trillion unique types. Pulling identical antibodies from five unrelated people is extremely rare and suggests genes are playing a role.
Genetic sequencing revealed each patient was expressing a gene known as IGLV3-21*02, which was likely responsible for the unique antibody.
Case closed? Not quite.
About four people in every 100 have IGLV3-21*02, but the risk of clotting from AstraZeneca's vaccine was a fraction of that. Something more must have been going on.
The final clue was hidden in the disease's speed. It can take weeks for antibodies to be generated to a new virus, but some people suffered clotting just days after getting vaccinated. That suggested, Gordon said, their immune systems had already experienced this strange combination of adenovirus and PF4 – or something that looked a lot like it.
"How can it be? We don't know. That's one of the great mysteries," he said.
Professor James McCluskey, an expert on the genetics of immunity and a deputy vice-chancellor of the University of Melbourne, called the study "rather remarkable".
Then-prime minister Scott Morrison at an AstraZeneca laboratory in 2020.Credit:Nick Moir
"Antibody genes … can vary genetically from one individual to another. For all these patients to have the same [gene] is just intuitively improbable by chance. So it looks real," he said.
AstraZeneca's vaccine remains in use in Australia, but official health advice is to opt for Pfizer or Moderna if you're under 60. But AstraZeneca continues to be distributed, particularly in low-income countries.
Gordon hopes his study will open up new ways to either test people for genetic susceptibility to the condition or design medicines to treat it.
Liam Mannix's Examine newsletter explains and analyses science with a rigorous focus on the evidence. Sign up to get it each week.
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