Hard choices emerge as the link between AstraZeneca vaccine and rare coagulation disorder becomes clearer Science

ScienceThe COVID-19 reporting is supported by the Heising-Simons Foundation.

What was a worrying suspicion four weeks ago is now widely accepted: the AstraZeneca COVID-19 vaccine can, in very rare cases, cause a disease characterized by dangerous blood clots and low platelets. In Europe, at least 222 suspected cases were reported among 34 million who received their first dose of the vaccine. More than thirty were killed.

As the link became clearer, a possible mechanism driven by an erroneous immune response focused. Health officials are now facing tough questions about who should and should not have Vaxzevria, which some countries already restrict to older age groups, which is pushing up the vaccination schedules.

Researchers emphasize that the problems do not spell Vaxzevria’s end at all. In the vast majority of cases, its benefits outweigh the risks, and the vaccine, cheap and easy to store, is still the best hope for vaccinating a large number of people in low- and middle-income countries. And some scientists suggest that a simple strategy can reduce the risk while stretching stocks: halve the dose of the vaccine.

Negative charge

Some of the first researchers to describe the condition made their observations in the New England Journal of Medicine (NEJM). One team describes 11 patients in Germany and Austria; the other has observations on 5 patients in Norway. Both teams found that the patients had unusual antibodies that cause clotting reactions, which deplete the platelets and block the blood vessels, which can lead to fatal stroke or embolisms.

The symptoms look like a rare reaction to the drug heparin, called heparin-induced thrombocytopenia (HIT), in which the immune system makes antibodies against a complex of heparin and a protein called platelet factor 4 (PF4), which causes the platelets to to form dangerous blood clots. the body. Recipients of galvanized vaccines also have antibodies to PF4, the researchers found.

The researchers who studied the German and Austrian patients, led by coagulation expert Andreas Greinacher of the University of Greifswald, initially called the syndrome vaccine-induced prothrombotic immune thrombocytopenia, or VIPIT; both teams now propose a slightly simpler name, vaccine-induced immune thrombotic thrombocytopenia (VITT).

In their paper, Greinacher and his colleagues also speculate on a possible mechanism. Vaxzevria consists of an adenovirus designed to infect cells and stimulate them to produce the ear protein of the virus. Among the approximately 50 billion virus particles in each dose, some can break apart and release their DNA, Greinacher says. Like heparin, DNA is negatively charged, which can help it bind to PF4, which has a positive charge. The complex can then cause the production of antibodies, especially if the immune system is already strongly ready due to the vaccination. An immune response to extracellular DNA is part of an ancient immune defense caused by serious infection or injury, Greinacher says, and free DNA itself can indicate the body to increase blood clotting.

Alternatively, the antibodies may already be present in the patients, and the vaccine may only amplify them. Many healthy people contain such antibodies to PF4, but it is controlled by an immune mechanism called peripheral tolerance, says Gowthami Arepally, a hematologist at Duke University School of Medicine who works as an external consultant at AstraZeneca. “When you are vaccinated, the mechanisms of peripheral tolerance are disrupted,” she says. “When that happens, does it trigger autoimmune syndromes that you are prone to, like HIT?”

Early suggestions that the rare reactions may be due to a COVID-19 infection before vaccination were not substantiated. For example, none of the five patients in Norway were infected. Others have suggested that antibodies against the vein protein of the virus – which seeks to produce many vaccines – somehow cross-react with PF4. This can cause problems for almost all COVID-19 vaccines. But so far there is no evidence that the messenger RNA vaccines produced by Pfizer / BioNtech and Moderna, which received tens of millions of people, cause similar clotting disorders.

Initial studies by Greinacher’s team, posted as a pre-print, also do not support the theory. Among more than 200 patients recovering from COVID-19, they found only a few with antibodies that responded to PF4, and those who responded relatively poorly. More importantly, Greinacher says, the platelet-activating antibodies isolated from VITT patients did not respond to the coronavirus vein protein. At a news conference Friday, Greinacher called the finding “fantastic news for the vaccination program.”

To determine the mechanism, it is crucial to understand whether other vaccines made from a modified adenovirus, which include Johnson & Johnson and CanSino, as well as the Russian Sputnik V, do something similar. On April 9, EMA said it was investigating four cases of similar clotting seen in U.S. patients who received the Johnson & Johnson vaccine, which has been used in the United States since early March but has yet to make its debut in Europe. not. The cases may be coincidental, Greinacher says, but “it’s at least very suspicious.”

Weigh the risks

EMA emphasizes that the benefits of Vaxzevria outweigh the risks. Nevertheless, many countries have restricted its use to younger people. Germany uses the vaccine only in people older than 60, in France older than 55. They argue that younger people are at lower risk of becoming seriously ill and dying from COVID-19, making it more difficult to reduce the risk of side effects. to justify effects. In the UK, a vaccine advisory panel has recommended that people under the age of 30 be offered another vaccine. (The country has used Vaxzevria more than any other European country, and on April 7, the UK Regulatory Agency for Medicines and Healthcare Products said it had investigated at least 79 cases of strokes and coagulation events related to the vaccine, at least 18 of them fatal.)

However, EMA does not recommend restricting the vaccine to specific age groups. And the ever-changing COVID-19 statistics support this position. Based on the available data, the risk of serious harm from the vaccine for people aged 20 to 29 in the UK is around 1.1 out of 100,000, says David Spiegelhalter, a statistician at the University of Cambridge. Their risk of being admitted to intensive care due to COVID-19 in the next 16 weeks ranges from 0.8 in 100,000 to about 6.9 in 100,000, depending on their risk of exposure to the virus.

“In this kind of gradual slide of benefit-risk balance, there is no sudden point at which it becomes safe or unsafe,” says Spiegelhalter. “It’s a judgment.” But for now, the numbers suggest that the vaccine is a net benefit to the vast majority, even for young people. Being vaccinated also provides protection to other people, says Spiegelhalter: ‘I think this is an aspect that is not emphasized enough. ”

Local circumstances can change the picture. In Australia, where there is currently no COVID-19, the calculation may go differently than in Europe. (The country has recommended that people under 50 receive another vaccine if possible.) The availability of alternatives is also an important consideration. European countries have ordered doses from many different companies, but others do not have the luxury. More than 30 million doses of Vaxzevria have been administered to more than 100 countries through the COVAX plant, led by the World Health Organization and GAVI, the Vaccine Alliance.

Halve the dose

EMA instructed AstraZeneca “to look at their existing data from closed clinical trials to see if it can provide any further information on possible mechanisms, risk factors, etc.,” EMA Peter Arlett told a news conference on April 7. It also asked two academic groups, one led by Utrecht University and the other by Erasmus University in Rotterdam, to look at risk factors for thrombosis in COVID-19 disease and vaccination. ‘We would expect results to start from that [studies] over the next few months, ”says Arlett.

Greinacher and his collaborator, Rolf Marschalek, a molecular biologist at the University of Frankfurt, are also asking for tests of a simple solution: halve the dose of Vaxzevria. In AstraZeneca’s Phase III trial in the UK, a small number of people accidentally received a lower dose and had fewer side effects in general; perhaps the lower dose will be less likely to cause the kind of strong inflammation that also increases PF4 antibodies, the researchers say. And unexpectedly, people are slightly better protected, perhaps because high levels of inflammation can actually block the formation of antibodies, Marschalek says. “Part of the problem may be that they are just overdosing on the vaccine,” says Greinacher.

The fact that more common side effects occur less frequently at half a dose does not mean that they are the same for the very rare side effects, warns Cox. But if the feeling is good, a terrible blow to one of the world’s most important weapons against the pandemic could be good news: the stock of the vaccine could vaccinate twice as many people – with fewer side effects.