Tri adenovirusa koji se koriste kao vektori za proizvodnju cjepiva protiv COVID-19, vežu se na faktor trombocita 4 (PF4), protein koji je uključen u patogenezu poremećaja zgrušavanja.
Adenovirus based COVID-19 cjepiva 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 koronavirusa1. Other vectors such as human adenovirusa type 26 (HAdV-D26; used for Janssen COVID vaccine), and human adenovirusa type 5 (HAdV-C5) have also been used to generate cjepiva against SARS-CoV-2.
Oxford/AstraZeneca cjepivo protiv COVID-19 (ChAdOx1 nCoV-2019) utvrđeno je učinkovitom u kliničkim ispitivanjima i dobilo je odobrenje od strane regulatora u nekoliko zemalja (dobilo ga je odobrenje od strane MHRA u UK-u 30. prosinca 2020.). Za razliku od drugog cjepiva protiv COVID-19 (mRNA cjepiva) dostupnog u to vrijeme, smatralo se da ovo ima relativnu prednost u smislu skladištenja i logistike. Ubrzo je postalo glavno cjepivo u borbi protiv pandemije diljem svijeta i dalo značajan doprinos u zaštiti ljudi diljem svijeta od 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 cjepiva 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 adenovirusa 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 adenovirusi used as vectors to produce SARS-CoV-2 cjepiva, 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 cjepiva 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.
Vidljivi TTS učinak je izraženiji nakon prve doze cjepiva, a ne druge doze, što sugerira da anti-P4 protutijela možda neće biti dugotrajna. Kompleks ChAdOx-1/PF4 inhibira prisutnost heparina koji igra ključnu ulogu u HIT-u. Heparin se veže na više kopija proteina P4 i stvara agregate s anti-P4 antitijelima koja stimuliraju aktivaciju trombocita i u konačnici dovode do krvnih ugrušaka.
These rare life-threatening events suggest that there is a need to engineer carrier virusi 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 cjepiva based on protein sub-units rather than DNA.
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Izvori:
- Oxford/AstraZeneca cjepivo protiv COVID-19 (ChAdOx1 nCoV-2019) proglašeno učinkovitim i odobreno. Znanstveni europski. Objavljeno 30. prosinca 2020. Dostupno na http://scientificeuropean.co.uk/covid-19/oxford-astrazeneca-covid-19-vaccine-chadox1-ncov-2019-found-effective-and-approved/
- Soni R. 2021. Moguća veza između AstraZenecinog cjepiva protiv COVID-19 i krvnih ugrušaka: mlađi od 30 godina trebaju dobiti Pfizerovo ili Modernino mRNA cjepivo. Znanstveni europski. Objavljeno 7. travnja 2021. Dostupno 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, dr. 2021. ChAdOx1 stupa u interakciju s CAR i PF4 s implikacijama za trombozu sa sindromom trombocitopenije. Napredak znanosti. Vol 7, Broj 49. Objavljeno 1. prosinca 2021. DOI: https//doi.org/10.1126/sciadv.abl8213
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