Vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
will hopefully terminate the pandemic of coronavirus disease 2019 (COVID-19) and several
vaccines are now available. The European Medical Agency has approved four vaccines[1] for the prevention of symptomatic COVID-19: two messenger RNA (mRNA)–based vaccines
(mRNA BNT162b2-BioNTech/Pfizer and mRNA-1273-Moderna) encoding the spike protein antigen
of SARS-CoV-2 and two recombinant adenoviral vector–based vaccines (ChAdOx1-AstraZeneca
and Ad26.COV2.S -Janssen) encoding the spike glycoprotein of SARS-CoV-2.
In Europe since March 2021, ∼100 patients[2] with venous thromboses at unusual sites (cerebral venous sinus thrombosis and splanchnic
vein thrombosis) in combination with moderate-to-severe thrombocytopenia were observed
in individuals within 1 month from the vaccination with the ChAdOx1 nCoV-19 COVID-19
vaccine.[3]
[4]
[5] Similar complications have also been reported after vaccination with the Ad26.COV2.S
Janssen COVID-19 vaccine.[6]
[7] Known as vaccine-induced immune thrombotic thrombocytopenia (VITT) or thrombosis
with thrombocytopenia syndrome,[8] the condition presents with thromboses, often at unusual sites, low platelet count,
high D-dimer, and high levels of anti-platelet factor 4 (anti-PF4) antibodies,[4]
[9]
[10] which are otherwise usually seen in patients with heparin induced thrombocytopenia
or autoimmune HIT.[11] It is currently unknown what triggers the formation of these antibodies after vaccination
against COVID-19.
Recent findings, especially considering the clinical profile, suggest the production
of two types of antibodies, as described elsewhere.[11] These different types of antibodies, analogous to the reference monoclonal IgG2bK (designated KKO) and anti-PF4 (designated RTO) antibodies monoclonal antibodies,[11] are directed against overlapping, yet different epitopes of human PF4. KKO-like
antibodies were found to induce an autoimmune response in heparin-treated patients
that results in thrombocytopenia and a prothrombotic state, while RTO-like antibodies
do not promote platelet activation and thrombosis.[11] This response was observed in ChAdOx1 n-CoV-19-vaccinated people and might be occurring
in COVID-19 patients as well, since a prothrombotic state with thrombocytopenia was
observed in patients with thrombotic complications of the pulmonary and gastroenteric
districts.[12]
Considering this background, human PF4 (hPF4; Reference Sequence: NG032897) and surface
spike glycoprotein (Reference Sequence: YP_009724390.1) have been downloaded from
NCBI genome database and manually edited using BioEdit.[13] Subsequently Swiss-Model[14] and HHpred[15] online web-tools have been used to identify eventual aminoacidic domains showing
homology or similarity between the two protein structures. For this purpose, the BepiPred
2.0 online tool has been used to survey eventual common B cells epitopes.[16] The performed analyses did not show any statistically significant homologies or
similarities between the hPF4 and the spike glycoprotein structures and no potentially
overlapping B cell epitope was found. These results suggest that probably the molecular
mimicry between the hPF4 and the SARS-CoV-2 spike protein is not responsible for the
prothrombotic events associated with VITT. However, binding experiments with KKO monoclonal
antibody against the spike by using both surface plasmon resonance and immunoprecipitation
should be performed to confirm this evidence.
Previous articles have highlighted how SARS-CoV-2 can directly activate platelets
and trigger procoagulant events. Moreover, they suggested the possibility of cross-reactivity
between antivector antibodies and PF4.[17] Probably this rare emergent autoimmune response can be induced by the cross-reaction
with the adenovirus that brings viral DNA and PF4 together in the extracellular space
inducing a possible reaction with antigen presenting cells.[17] This potentially explains why thrombotic complications in patients vaccinated with
mRNA-lipid nanoparticle are less frequent compared with adenovirus as vaccine vector.
Further investigations are needed to clarify the safety of adenoviral vector vaccines
in patients with risk factors for thrombosis or chronic thrombocyte disorders.[17]
