Três adenovírus usados como vetores para produzir vacinas COVID-19, ligam-se ao fator plaquetário 4 (PF4), uma proteína implicada na patogênese dos distúrbios da coagulação.
Adenovirus based COVID-19 vacinas such as Oxford/AstraZeneca’s ChAdOx1 use the weakened and genetically modified version of common cold vírus adenovirus (a DNA vírus) 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 coronavírus1. Other vectors such as human adenovírus type 26 (HAdV-D26; used for Janssen COVID vaccine), and human adenovírus type 5 (HAdV-C5) have also been used to generate vacinas against SARS-CoV-2.
A vacina Oxford / AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) foi considerada eficaz em ensaios clínicos e foi aprovada pelos reguladores em vários países (foi aprovada pela MHRA no Reino Unido em 30 de dezembro de 2020). Ao contrário da outra vacina COVID-19 (vacina de mRNA) disponível na época, pensava-se que ela tinha uma vantagem relativa em termos de armazenamento e logística. Logo ela se tornou a vacina básica na luta contra a pandemia em todo o mundo e fez contribuições significativas na proteção de pessoas em todo o mundo contra a 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 Vacinas 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 adenovírus 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 adenovírus used as vectors to produce SARS-CoV-2 vacinas, 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 vacinas 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 vírus 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.
O efeito TTS observado é mais proeminente após a primeira dose da vacina, em vez da segunda dose, sugerindo que os anticorpos anti-P4 podem não ser duradouros. O complexo ChAdOx-1 / PF4 é inibido pela presença de heparina que desempenha um papel fundamental no HIT. A heparina se liga a várias cópias da proteína P4 e forma agregados com anticorpos anti-P4 que estimulam a ativação plaquetária e, em última análise, levam à formação de coágulos sanguíneos.
These rare life-threatening events suggest that there is a need to engineer carrier vírus 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 vacinas based on protein sub-units rather than DNA.
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Fontes:
- Vacina Oxford / AstraZeneca COVID-19 (ChAdOx1 nCoV-2019) considerada eficaz e aprovada. Científico europeu. Publicado em 30 de dezembro de 2020. Disponível em http://scientificeuropean.co.uk/covid-19/oxford-astrazeneca-covid-19-vaccine-chadox1-ncov-2019-found-effective-and-approved/
- Soni R. 2021. Possível ligação entre a vacina COVID-19 da AstraZeneca e os coágulos sanguíneos: menores de 30 anos receberão a vacina de mRNA da Pfizer ou Moderna. Científico europeu. Publicado em 7 de abril de 2021. Disponível em 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/
- Padeiro AT, et al 2021. ChAdOx1 interage com CAR e PF4 com implicações para trombose com síndrome de trombocitopenia. Science Advances. Vol 7, Issue 49. Publicado em 1 de dezembro de 2021. DOI: https // doi.org / 10.1126 / sciadv.abl8213
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