Nove hipoteze in potencialno dobre novice v zvezi z zapleti po cepljenju z AstraZeneco

V reviji Science so bili danes objavljeni povzetki dveh študij, objavljenih v petek v reviji v New England Journal of Medicine (NEJM), ki preiskujeta možne vzroke za zaplete s krvnimi strdki po cepljenju s cepivom AstraZenece (AZ). Prva študija se nanaša na preiskavo 11 bolnikov v Nemčiji in Avstriji, druga pa na preiskavo 5 bolnikov na Norveškem. Obe študiji sta ugotovili, da so imeli bolniki nenavadna protitelesa, ki sprožijo reakcije strjevanja krvi, ki porabijo trombocite v telesu in lahko blokirajo krvne žile, kar vodi do potencialno smrtonosnih kapi ali embolij. Obe študiji ponujata različne hipoteze za ta pojav (ena je, da do povečane tvorbe protiteles pride po močnih vnetjih, ki se zgodijo po cepljenju z AZ), ki pa jih je treba še podrobneje preiskati. Rezultatov ni mogoče pričakovati v prej kot dveh mesecih.

Vendar pa avtorja prve študije (Andreas Greinacher in Rolf Marschalek) pozivata k preizkusom preproste rešitve: k prepolovitvi odmerka cepiva AZ. Do tega sta prišla na podlagi opažanja, da je v tretji fazi kliničnega preizkušanja AZ v V. Britaniji majhno število ljudi po naključju dobilo manjši odmerek in na splošno imelo manj neželenih učinkov. Njuna hipoteza je, da morda manjši odmerek manj verjetno sproži močno vnetje, ki sicer poveča tvorbo protiteles proti PF4. In nepričakovano so bili ti ljudje nekoliko bolje zaščiteni. Možna razlaga je, da morda zato, ker lahko visoka stopnja vnetja dejansko blokira nastajanje protiteles proti Covid. To bi lahko pomenilo, da so morda odmerki AZ cepiva preveliki.

Seveda gre zgolj za hipotezo, ki pa – če bi se izkazala kot resnična – s seboj potegne nepričakovane koristi. Glede na pomanjkanje cepiv, bi cepljenje s polovično dozo AZ lahko podvojilo število ljudi, ki bi lahko bili cepljeni.

What was a worrisome suspicion four weeks ago is now widely accepted: The AstraZeneca COVID-19 vaccine can, in very rare cases, cause a disorder characterized by dangerous blood clots and low platelet counts. In Europe, at least 222 suspected cases have been reported among 34 million who have received their first dose of the vaccine. More than 30 have died.

On Friday, some of the first researchers to describe the condition published 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 trigger clotting reactions, which use up the body’s platelets and can block blood vessels, leading to potentially deadly strokes or embolisms.

The symptoms resemble a rare reaction to the drug heparin, called heparin-induced thrombocytopenia (HIT), in which the immune system makes antibodies to a complex of heparin and a protein called platelet factor 4 (PF4), triggering platelets to form dangerous clots throughout the body. Sickened vaccine recipients also had antibodies to PF4, the researchers found.

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

In their paper, Greinacher and his colleagues also speculate about a possible mechanism. Vaxzevria consists of an adenovirus engineered to infect cells and prompt them to produce the virus’s spike protein. Among the 50 billion or so virus particles in each dose, some may break apart and release their DNA, Greinacher says. Like heparin, DNA is negatively charged, which would help bind it to PF4, which has a positive charge. The complex might then trigger the production of antibodies, especially when the immune system is already on high alert because of the vaccine. An immune reaction to extracellular DNA is part of an ancient immune defense triggered by severe infection or injury, Greinacher notes, and free DNA itself can signal the body to increase blood coagulation.

Alternatively, the antibodies may already be present in the patients and the vaccine may just boost them. Many healthy people harbor such antibodies against PF4, but they are kept in check by an immune mechanism called peripheral tolerance, says Gowthami Arepally, a hematologist at Duke University School of Medicine who is working as an external consultant with AstraZeneca on the issue. “When you get vaccinated, sometimes the mechanisms of peripheral tolerance get disrupted,” she says. “When that happens, does that unleash any autoimmune syndromes that you are predisposed to, like HIT?”

Early suggestions that the rare reactions may be the result of a COVID-19 infection before vaccination have not be substantiated. None of the five patients in Norway had been infected, for instance. Others have suggested that antibodies against the virus’s spike protein—which many vaccines seek to elicit—somehow cross-react with PF4. That could spell trouble for nearly all COVID-19 vaccines. But so far, there is no evidence that the messenger-RNA-based vaccines made by Pfizer/BioNtech and Moderna, which tens of millions of people have received, are causing similar clotting disorders.  

Initial studies by Greinacher’s team, posted as a preprint, don’t support that theory either. Among more than 200 patients who had recovered from COVID-19, they found only a few with antibodies that reacted to PF4, and those reacted relatively weakly. More importantly, Greinacher says, the platelet-activating antibodies isolated from VITT patients did not react to the coronavirus spike protein. At a press conference on Friday, Greinacher called the finding “fantastic news for the vaccination program.”

Pinpointing the mechanism is crucial to understanding whether other vaccines made from a modified adenovirus, which include those from Johnson & Johnson and CanSino as well as Russia’s Sputnik V, do something similar. On 9 April, EMA said it was investigating four cases of similar clotting seen in U.S. patients who had 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. The cases could be coincidence, Greinacher says, but “it’s at least very suspicious.”

Greinacher and his collaborator Rolf Marschalek, a molecular biologist at Frankfurt University, are also calling for tests of a simple solution: halving Vaxzevria’s dose. In AstraZeneca’s phase III trial in the United Kingdom, a small number of people accidentally received a lower dose and had fewer side effects in general; perhaps the lower dose is less likely to trigger the kind of strong inflammation that boosts PF4 antibodies as well, the researchers say. And unexpectedly, those people were slightly better protected, perhaps because high levels of inflammation can actually block the formation of antibodies, Marschalek says. “Part of the problem might be that they just overdose” the vaccine, Greinacher says.

The fact that more common side effects appear less frequently at half a dose does not mean the same is true for the very rare side effects, Cox cautions. But if the hunch proves correct, what looked like a terrible blow for one of the world’s most important weapons against the pandemic might be good news in disguise: Supplies of the vaccine could vaccinate twice as many people—with fewer side effects.

Vir: Science

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