Tři adenoviry používané jako vektory k výrobě vakcín COVID-19 se vážou na destičkový faktor 4 (PF4), protein, který se podílí na patogenezi poruch srážení krve.
Adenovirus based COVID-19 vakcíny such as Oxford/AstraZeneca’s ChAdOx1 use the weakened and genetically modified version of common cold virus adenovirus (a DNA virus) as vector for expression of viral protein of novel coronavirus nCoV-2019 in the human body. The expressed viral protein in turn act as antigen for development of active immunity. The adenovirus used is replication incompetent meaning it cannot replicate in human body but as vector it provides an opportunity for translation of incorporated gene encoding Spike protein (S) of novel koronavirus1. Other vectors such as human adenoviry type 26 (HAdV-D26; used for Janssen COVID vaccine), and human adenoviry type 5 (HAdV-C5) have also been used to generate vakcíny against SARS-CoV-2.
Vakcína Oxford/AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) byla shledána účinnou v klinických studiích a byla schválena regulačními orgány v několika zemích (obdržela schválení MHRA ve Spojeném království dne 30. prosince 2020). Na rozdíl od jiné vakcíny COVID-19 (mRNA vakcína), která byla v té době dostupná, se předpokládalo, že má relativní výhodu, pokud jde o skladování a logistiku. Brzy se stala základní vakcínou v boji proti pandemii na celém světě a významně přispěla k ochraně lidí na celém světě proti COVID-19.
However, a possible link between AstraZeneca’s COVID-19 vaccine and blood clot was suspected when about 37 cases of rare event of blood clots were reported (out of more than 17 million people vaccinated) in the EU and Britain. In light of this possible side effect, subsequently, Pfizer’s or Moderna’s mRNA Vakcíny were recommended2 for use in those under 30. But how rare clotting disorders such as thrombocytopenia syndrome (TTS), a condition resembling heparin-induced thrombocytopenia (HIT) seen in people administered with AstraZeneca COVID-19 vaccine which uses the ChAdOx1 (chimpanzee adenoviry Y25) vector is caused and the underlying mechanism involved, remained unclear.
A recent study published in Science Advances by Alexander T. Baker et al. demonstrates that the three adenoviry used as vectors to produce SARS-CoV-2 vakcíny, bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT as well as TTS.
Using a technique known as SPR (Surface Plasmon Resonance), it was shown that PF4 binds not only with pure vector preparations of these vectors, but also with vakcíny derived from these vectors, with similar affinity. This interaction is due to the presence of strong electropositive surface potential in PF4 which helps in binding to the overall strong electronegative potential on the adenoviral vectors. In case of administration of the ChAdOx1 covid vaccine, the vaccine injected into the muscle may leak into the bloodstream, leading to formation of ChAdOx1/PF4 complex as described above. In rare cases, the body recognizes this complex as foreign virus and triggers formation of PF4 antibodies. The release of PF4 antibodies further leads to aggregation of PF4, thereby forming blood clots, lead to further complications and in certain cases, death of the patient. This has so far resulted in 73 deaths out of the nearly 50 million vaccine doses of AstraZeneca vaccine that have been given in the UK.
Pozorovaný účinek TTS je výraznější po první dávce vakcíny spíše než po druhé dávce, což naznačuje, že protilátky anti-P4 nemusí být dlouhodobé. Komplex ChAdOx-1/PF4 je inhibován přítomností heparinu, který hraje klíčovou roli v HIT. Heparin se váže na více kopií proteinu P4 a tvoří agregáty s protilátkami anti-P4, které stimulují aktivaci krevních destiček a nakonec vedou ke krevním sraženinám.
These rare life-threatening events suggest that there is a need to engineer carrier viry in such a manner, so as to avoid any interactions with cellular proteins that can lead to SARs (Severe Adverse Reactions), thereby leading to death of the patient. Furthermore, one can look at alternative strategies to design vakcíny based on protein sub-units rather than DNA.
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Zdroje:
- Vakcína Oxford/AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) shledána účinnou a schválená. Vědecký Evropan. Zveřejněno 30. prosince 2020. Dostupné na http://scientificeuropean.co.uk/covid-19/oxford-astrazeneca-covid-19-vaccine-chadox1-ncov-2019-found-effective-and-approved/
- Soni R. 2021. Možná souvislost mezi vakcínou COVID-19 společnosti AstraZeneca a krevními sraženinami: Mladším 30 let bude podána mRNA vakcína Pfizer nebo Moderna. Vědecký Evropan. Publikováno 7. dubna 2021. Dostupné na http://scientificeuropean.co.uk/covid-19/possible-link-between-astrazenecas-covid-19-vaccine-and-blood-clots-under-30s-to-be-given-pfizers-or-modernas-mrna-vaccine/
- Baker AT, et al 2021. ChAdOx1 interaguje s CAR a PF4 s důsledky pro trombózu se syndromem trombocytopenie. Vědecké pokroky. Vol 7, Issue 49. Publikováno 1. prosince 2021. DOI: https//doi.org/10.1126/sciadv.abl8213
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