Trei adenovirusuri utilizați ca vectori pentru a produce vaccinuri COVID-19, se leagă de factorul trombocitar 4 (PF4), o proteină implicată în patogeneza tulburărilor de coagulare.
Adenovirus based COVID-19 vaccinuri 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 coronavirus1. Other vectors such as human adenovirusuri type 26 (HAdV-D26; used for Janssen COVID vaccine), and human adenovirusuri type 5 (HAdV-C5) have also been used to generate vaccinuri against SARS-CoV-2.
Vaccinul Oxford/AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) a fost găsit eficient în studiile clinice și a primit aprobarea autorităților de reglementare din mai multe țări (a primit aprobarea MHRA în Regatul Unit la 30 decembrie 2020). Spre deosebire de celălalt vaccin COVID-19 (vaccin ARNm) disponibil în acea perioadă, se credea că acesta are un avantaj relativ în ceea ce privește stocarea și logistica. În curând a devenit vaccinul de bază în lupta împotriva pandemiei la nivel mondial și a adus contribuții semnificative la protejarea oamenilor din întreaga lume împotriva 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 vaccinuri 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 adenovirusuri 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 Adenovirusurile used as vectors to produce SARS-CoV-2 vaccinuri, 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 vaccinuri 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.
Efectul TTS observat este mai proeminent după prima doză de vaccin, mai degrabă decât a doua doză, sugerând că anticorpii anti-P4 ar putea să nu fie de lungă durată. Complexul ChAdOx-1/PF4 este inhibat de prezența heparinei care joacă un rol cheie în HIT. Heparina se leagă de copii multiple ale proteinei P4 și formează agregate cu anticorpi anti-P4 care stimulează activarea trombocitelor și duc în cele din urmă la cheaguri de sânge.
These rare life-threatening events suggest that there is a need to engineer carrier viruși 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 vaccinuri based on protein sub-units rather than DNA.
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Surse:
- Vaccinul Oxford/AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) a fost găsit eficient și aprobat. științific european. Publicat 30 decembrie 2020. Disponibil la http://scientificeuropean.co.uk/covid-19/oxford-astrazeneca-covid-19-vaccine-chadox1-ncov-2019-found-effective-and-approved/
- Soni R. 2021. Legătură posibilă între vaccinul AstraZeneca împotriva COVID-19 și cheaguri de sânge: sub 30 de ani li se administrează vaccinul ARNm de la Pfizer sau Moderna. științific european. Publicat 7 aprilie 2021. Disponibil la 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 interacționează cu CAR și PF4 cu implicații pentru tromboză cu sindrom de trombocitopenie. Progresele științei. Vol 7, Issue 49. Publicat 1 Dec 2021. DOI: https//doi.org/10.1126/sciadv.abl8213
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