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An international team of scientists believe they may have found a molecular mechanism behind the extremely rare blood clots linked to adenovirus COVID-19 vaccines.

Scientists from Cardiff University and Arizona State University worked with AstraZeneca to investigate vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome (TTS), a life-threatening condition seen in a very small number of people after receiving the Oxford-AstraZeneca or Johnson & Johnson vaccines.

The global team used state-of-the-art technology to analyse the AstraZeneca vaccine in minute detail to understand whether the ultra-rare side effect could be linked to the viral vector.

Their findings suggest it is the viral vector – in this case an adenovirus used to shuttle the coronavirus’ genetic material into cells – and the way it binds to platelet factor 4 (PF4) once injected that could be the potential mechanism.

In very rare cases, the scientists suggest, the viral vector may enter the bloodstream and bind to PF4, where the immune system then views this complex as foreign. They believe this misplaced immunity could result in the release of antibodies against PF4, which bind to and activate platelets, causing them to cluster together and triggering blood clots in a very small number of people after the vaccine is administered.

Their findings are published today in the international journal Science Advances. 

Professor Alan Parker, an expert in the use of adenoviruses for medical applications from Cardiff University’s School of Medicine, said: “VITT only happens in extremely rare cases because a chain of complex events needs to take place to trigger this ultra-rare side effect. Our data confirms PF4 can bind to adenoviruses, an important step in unravelling the mechanism underlying VITT.

“Although very rare, it is critical we fully investigate vector-host interactions of the vaccine at a mechanistic level to help us understand both how the vaccine generates immunity – and how it may lead to any rare adverse events, such as VITT. Establishing a mechanism could help to prevent and treat this disorder.

“We hope our findings can be used to better understand the rare side effects of these new vaccines – and potentially to design new and improved vaccines to turn the tide on this global pandemic.”

Both the AstraZeneca and Johnson & Johnson vaccines use an adenovirus to carry spike proteins from the coronavirus into people to trigger a protective immune response.

When both vaccines showed the ultra-rare side effect of VITT, scientists wondered whether the viral vector had some part to play. Another important clue was that neither the Moderna nor Pfizer vaccines, made from an entirely different technology called mRNA vaccines, showed this effect.

The 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, which the Singharoy group at ASU specialise in, 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.

The Medicines and Healthcare products Regulatory Agency (MHRA) continues to advise that vaccination is the best way to protect people from COVID-19 and the benefits far outweigh the risk of any known side effects.

The MHRA advises that anyone experiencing symptoms, including a severe headache that is not relieved by painkillers, shortness of breath, chest/abdominal pain or blurred vision after vaccination should seek medical advice urgently.

Researchers from Cardiff University will join the UK’s first interdisciplinary research centre in international trade when it launches in early 2022.

The Centre for Inclusive Trade Policy (CITP) is one of six new national centres designed to tackle urgent social and economic issues by providing robust research evidence to support government decision-making.

Funded by an £8m grant from the Economic and Social Research Council (ESRC) and additional support from its contributing universities, the Centre brings together experts from all four UK nations to conduct innovative trade policy research.

Dr Ludivine Petetin from Cardiff University’s School of Law and Politics and the Wales Governance Centre said: “The CITP aims to be a ‘go-to’ location, both for expert, innovative research and for policy formulation.

“There will be a key focus on inclusivity regionally and institutionally across the four nations of the UK, and across disciplines and voices in society, including citizens’ juries, governments, firms, individuals and across generations to contribute to internationally path-breaking and impactful research.”

Having left the EU, the UK is in the process of devising its own trade policy, which will shape economic and welfare outcomes for generations to come. International trade is changing rapidly and becoming more complex after facing major challenges from COVID-19, trade wars, disruptive digital technology and climate change.

Led by the University of Sussex Business School and the University of Nottingham, the research project involves scholars in economics, law, business management, politics and international relations from Cardiff University, Queen’s University Belfast, the University of Cambridge, the University of Strathclyde and universities overseas.

In addition to the universities, the Centre will also work with nine partners including Ernst & Young LLP (EY), Fieldfisher LLP, the International Trade Group of the Professional and Business Services Council, the British Chambers of Commerce, the Trade Justice Movement and trade officials in all four UK administrations.

To help build long-term capacity for trade policy development and analysis, the Centre will also run a competition for funds for early and mid-career researchers.

Professor Dan Wincott, Blackwell Professor of Law and Society at the School of Law and Politics and the Wales Governance Centre in Cardiff University, said: “The Centre will strengthen academic expertise on Trade Policy and build links with policy and professional communities.

“The CITP has been designed with devolution in mind. It provides an exciting opportunity to work with colleagues across the UK and the wider world and link this work with public debate and policy development in Wales.”

A reliable early warning system to detect tsunamis could be a step closer thanks to research from Cardiff University.

Researchers say their analysis of ocean soundwaves triggered by underwater earthquakes has enabled them to develop artificial intelligence (AI) that allow prediction of when a tsunami might occur. The results are published today in the journal Scientific Reports.

It is hoped this technology could assist experts in gaining accurate real-time assessments of these geological events.

Dr Usama Kadri, from Cardiff University’s School of Mathematics, said: “Tsunamis have a devastating impact on communities. Developing accurate methods to detect them quickly is key to saving lives.

“Our findings show we are able to classify the type of earthquake and retrieve its main properties from acoustic signals, in near real time. These methods will complement existing technology for real-time tsunami analysis and provide another tool for experts working to detect them.

“This work is an integral part of a larger project for creating a more reliable early tsunami warning system.”

For their research, the team analysed deep ocean sound recordings following 201 earthquakes that happened in the Pacific and the Indian Ocean.

Tsunamis often occur after vertical earthquakes, where tectonic plates on the earth’s surface move mainly up and down rather than horizontally. This motion causes the displacement of a large amount of water, creating very long waves that can cause widespread damage onshore.

The vertical motion results in compressing the water layer which sends specific sound signals that carry information on the dynamics and geometry of the fault. Mr Bernabe Gomez, a PhD student in the research team, used this information to train artificial intelligence (AI) algorithms to recognise when a vertical earthquake has occurred, which, they say, could be used to pinpoint future tsunamis in real-time.

Dr Kadri added: “Tectonic movements are very complicated, with horizontal and vertical elements. Some earthquakes have higher capability to generate tsunamis than others. Employing digital signal processing techniques, we can analyse sound recordings of underwater earthquakes, that train artificial intelligence (AI) algorithms to classify the type of earthquake and its moment magnitude. This is a significant step for a reliable early tsunami warning system since the type of earthquake can dictate if a tsunami will be generated at all.”

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