Vaccine thrombosis mechanism proposed but VITT remains an enigma

Australian haematologists have reacted cautiously to a proposed molecular mechanism that scientists say may explain the rare vaccine-induced immune thrombotic thrombocytopenia (VITT) seen in some people who receive the Astra Zeneca (AZ) COVID-19 vaccine.

Researchers from Cardiff University in the UK and Arizona State University say their work has demonstrated the ability of platelet factor 4 (PF4) to interact strongly with the adenovirus vector used to deliver the AZ vaccine.

In Science Advances they propose that in a small number of pre-disposed individuals the binding of viral vector as a complex with FP4 results in a misplaced immunity that result in  antibodies against PF4, which bind to and activate platelets, causing them to aggregate and cause thrombosis.

Interest focused on the adenovirus vector because both AstraZeneca and Johnson & Johnson vaccines use one and both have shown the ultra-rare side effect of VITT

The UK team used a technology called CryoEM to flash-freeze preparations of ChAdOx1, the adenovirus used in the AstraZeneca vaccine and bombard them with electrons to produce microscopic images of the vaccine components. They were then able to look in atomic level at the structure of the outer protein cage of the virus – the viral capsid – and other critical proteins that allow entry of the virus into the cell.

In particular, the team detail the structure and receptor of ChAdOx1, which is adapted from chimpanzee adenovirus Y25 – and how it interacts with PF4. They believe it is this specific interaction – and how it is then presented to the immune system – that could prompt the body’s own defences to view it as foreign and release of antibodies against this self-protein.

The research team used computational models to show that one of the ways the two molecules tightly bind is via electrostatic interactions.

First author on the study Dr Alexander Baker, an Honorary Research Fellow at Cardiff University, said: “We found that ChAdOx1 has a strong negative charge. This means the viral vector can act like a magnet and attract proteins with the opposite, positive charge, like PF4.

“We then found that PF4 is just the right size and shape that when it gets close to ChAdOx1 it could bind in between the negatively charged parts of ChAdOx1’s surface, called hexons.”

The research team are hopeful that armed with a better understanding of what may be causing rare VITT they can provide further insights into how vaccines and other therapies, which rely on the same technology, might be altered in the development of the next generation vaccines and therapies.

“With a better understanding of the mechanism by which PF4 and adenoviruses interact there is an opportunity to engineer the capsid, or outer shell of the vaccine, to prevent this interaction occurring. Modifying ChAdOx1 to reduce electronegativity may reduce the chance of causing thrombosis with thrombocytopenia syndrome,” said Dr Baker.

Missing link

However Professor Beng Chong, Senior Specialist in Haematology at NSW Health Pathology, said the findings were another piece of the jigsaw but did not ‘solve the mystery’ of VITT causation.

He said that anti-PF4 antibody has been identified previously in patients with the clotting disorder TTS and is known to promote clot formation, but is not proven as the missing link.

“The main weakness of this research is that they have not yet produce evidence in human nor in animal studies that the vaccine/PF4 complex could actually induce production of the disease-causing anti-PF4 antibody. Until they or other scientists produce this crucial evidence, their  hypothesis remains unconfirmed,” he said

Dr Roger Lord, senior lecturer (Medical Sciences) at the Australian Catholic University, Brisbane, said that the PF4 interaction has only been shown in vitro and remains to be demonstrated if it occurs clinically.

He noted that studies done to model this mechanism in animal models have failed to induce any thrombotic events or extended clotting times.

“The proposed mechanism suggested for the formation of TTS following vaccination with AZ is not consistent with available data and will still require further clarification to determine if the adenovirus interaction with PF4 can cause this rare clotting event and under what specific conditions,” said Dr Lord.

“Presently AZ adenovirus vector + PF4 + PF4 antibodies does not appear to equal formation of TTS,” he concluded.

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