Why adenovirus vaccines can cause rare blood clots

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Although rare, some people have developed blood clots after receiving an adenovirus-based COVID-19 vaccine. Photo editing by Steve Kelly; Insight Imaging/Getty Images
  • So far, healthcare professionals have administered more than 11 billion doses of COVID-19 vaccine worldwide.
  • However, there have been reports of a low risk of blood clotting complications from adenovirus-based COVID-19 vaccines.
  • A recent study offers a possible explanation for why this happens in some people.
  • Research has revealed that the electrical charge of adenovirus promotes adhesion of blood proteins associated with blood clotting.

Vaccines provide excellent immunity against severe infection with SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Studies have shown that vaccines can reduce risk of hospitalization and death of more than 99% and up to 71.6% against infection with the Omicron variant.

There are three main types of COVID-19 vaccines that are currently widely used:

  • mRNA vaccines: These use lab-made messenger RNA to teach the body’s immune cells to make a protein that triggers the body’s immune response.
  • Viral vector vaccines: These vaccines use a harmless virus called a “carrier virus,” which is modified to instruct immune cells to produce antibodies to fight infection.
  • Inactivated viral vaccines: These contain a dead version of a virus that cannot replicate but can trigger the body’s immune system to create antibodies to protect against the live virus should it invade.

The two main viral vector vaccines used are ChAdOx1, developed by the University of Oxford-AstraZeneca, and Ad26.COV2.S, developed by Johnson & Johnson (J&J). Both vaccines use adenovirus as vector viruses to mount an immune response against SARS-CoV-2.

Despite their success, adenovirus vaccines have been associated with Small number people who have had thrombosis with thrombocytopenia (TTTS), a life-threatening blood clotting disorder.

A recent study by scientists from Arizona State University and the Mayo Clinic, published in the journal Scientists progress, shed light on possible mechanisms. The authors also detailed the interaction between the AstraZeneca vaccine and proteins stored in blood platelets called platelet factor (PF4). PF4 is released when platelets are activated.

The blood clotting disorder TTS is a very rare condition.

A recent review by the Global Advisory Committee on Vaccine Safety (GACVS) for the World Health Organization (WHO) reported that 1 in 250,000 adults in the UK and around 1 in 100,000 vaccinated adults in the European Union (EU) have developed TTTS.

According to one dataset, approximately 63.8% of the world’s population has received 1 dose of a COVID-19 vaccine, which amounts to more than 11.04 billion doses worldwide. Studies and real-world data have shown that the risk of death with or from COVID-19 is 93.4% lower in those vaccinated (3 doses).

Despite the low incidence of TTTS, mass vaccination has resulted in some people developing the disease. Scientists don’t understand the exact mechanism behind TTS.

However, they believe that vaccination with an adenovirus causes platelet factor 4 (PF4), a protein in the blood, to bind to the adenovirus, forming a complex. Platelets are the tiny blood cells that help the body form clots to stop bleeding. Some people form antibody against this antigen-PF4 complex, which causes platelets to clump together, leading to an increased risk of blood clots.

To study blood clots associated with the Oxford-AstraZeneca COVID-19 vaccine, researchers used state-of-the-art computer modeling to understand how the adenovirus-based vaccine interacted with proteins in the human body.

The team began by defining the structure of the AstraZeneca viral vector before using ARBD (Atomic Resolution Brownian Dynamics) computer modeling to demonstrate the electrostatic interaction between the vaccine particle and PF4.

The team found that PF4 formed stable complexes with adenoviruses. They discovered that the negative charge of the vaccine particle attracted the positive charge of the PF4 protein.

As a possible solution to combat this, the scientists added heparin, a drug used to stop blood clotting, to the simulations. They saw that this prevented the PF4 from sticking to the vaccine particle.

The researchers then performed cellular experiments to confirm the ARBD modeling results.

When asked if the same clotting mechanism could be responsible for the complications associated with the J&J adenovirus vaccine, the manuscript’s first author, Dr. Alexander Baker responded:

“I think it’s a little early to say that’s the main/only driver. That being said, yes, we’ve shown that the capsid of adenovirus type 26 (J&J) can also bind to PF4 with a similar affinity.

Study co-lead Dr Abhishek Singharoy, an assistant professor in the School of Molecular Sciences at Arizona State University, said: “It is really essential to fully study the vector-host interactions of the vaccine at a mechanistic level…[T]This will help understand both how the vaccine generates immunity and how it can lead to rare adverse events, such as [vaccine-induced immune thrombotic thrombocytopenia] LIVES. »

However, some important questions remain:

  • Why does TTTS occur in such a small number of vaccinated people?
  • Do these findings mean scientists can redesign the vaccine to prevent TTTS?
  • Can scientists reduce the negative charge of the vaccine particle?
  • Clinically, can we predict which people are at higher risk of getting TTTS and can we develop alternative modified vaccines to prevent clots from forming in these high-risk people?

Despite these questions, Dr Raghav Palankar, a researcher at the Institute for Immunology and Transfusion Medicine in Germany, called the research “completely game-changing fundamental discovery with important translational implications.

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