Trije adenovirusi, ki se uporabljajo kot vektorji za proizvodnjo cepiv proti COVID-19, se vežejo na faktor trombocitov 4 (PF4), protein, ki je vpleten v patogenezo motenj strjevanja krvi.
Adenovirus based COVID-19 cepiva 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 adenovirus type 26 (HAdV-D26; used for Janssen COVID vaccine), and human adenovirus type 5 (HAdV-C5) have also been used to generate cepiva against SARS-CoV-2.
Cepivo Oxford/AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) je bilo ugotovljeno, da je učinkovito v kliničnih preskušanjih in so ga odobrili regulatorji v več državah (dovolil ga je MHRA v Združenem kraljestvu 30. decembra 2020). Za razliko od drugega cepiva proti COVID-19 (cepivo mRNA), ki je bilo na voljo v tistem času, se je menilo, da ima to relativno prednost v smislu skladiščenja in logistike. Kmalu je postalo osnovno cepivo v boju proti pandemiji po vsem svetu in je pomembno prispevalo k zaščiti ljudi po vsem svetu pred 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 Cepiva 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 adenovirus 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 cepiva, 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 cepiva 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.
Učinek TTS je bolj izrazit po prvem odmerku cepiva kot po drugem odmerku, kar kaže, da protitelesa proti P4 morda ne bodo dolgotrajna. Kompleks ChAdOx-1/PF4 zavira prisotnost heparina, ki ima ključno vlogo pri HIT. Heparin se veže na več kopij proteina P4 in tvori agregate s protitelesi proti P4, ki spodbujajo aktivacijo trombocitov in na koncu vodijo do krvnih strdkov.
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 cepiva based on protein sub-units rather than DNA.
***
Viri:
- Cepivo Oxford/AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) ugotovljeno, da je učinkovito in odobreno. Znanstveni evropski. Objavljeno 30. decembra 2020. Dostopno na http://scientificeuropean.co.uk/covid-19/oxford-astrazeneca-covid-19-vaccine-chadox1-ncov-2019-found-effective-and-approved/
- Soni R. 2021. Možna povezava med AstraZenecinim cepivom COVID-19 in krvnimi strdki: mlajši od 30 let, ki jim je treba dati cepivo Pfizer ali Moderna mRNA. Znanstveni evropski. Objavljeno 7. aprila 2021. Dostopno 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, sod 2021. ChAdOx1 sodeluje s CAR in PF4 s posledicami za trombozo s sindromom trombocitopenije. Napredek znanosti. Letnik 7, številka 49. Objavljeno 1. decembra 2021. DOI: https//doi.org/10.1126/sciadv.abl8213
***
