Thrombocytopenia and splenic platelet directed immune responses after intravenous ChAdOx1 nCov-19 administration
Recently a rare and novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged:
thrombosis with thrombocytopenia syndrome (TTS)
Low platelets, clot formation at unusual sites and platelet-activating PF4-polyanion antibodies (reminiscent of heparin-induced thrombocytopenia).
In vitro and in vivo models
We show that intravenous but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation.
After intravenous injection, these aggregates are phagocytosed by macrophages in the spleen
This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets.
Our work contributes to the understanding of TTS and highlights accidental intravenous injection as potential mechanism for post-vaccination TTS.
Hence, safe intramuscular injection, with aspiration prior to injection, could be a potential preventive measure when administering adenovirus-based vaccines.
Consistent results with mice and human platelets
Vaccines are routinely administered intramuscularly (i.m.) and trigger immune responses mainly in the draining lymph nodes
Based on our finding that adenoviral vaccine binds to blood platelets, we hypothesized that accidental intravenous injection of adenoviral vaccine might lead to platelet-adenovirus aggregate formation with platelet activation
The decline in platelet count was dose-dependent and correlated directly with adenovirus-positive platelets circulating in the blood one hour after i.v. injection
Intravenous but not i.m. injection of ChAdOx1 nCov-19 resulted in a strong increase in platelet-adenovirus aggregates
Medizinische Klinik und Poliklinik I University Hospital Ludwig-Maximilian University Munich, Germany
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany
Medizinische Klinik und Poliklinik III University Hospital Ludwig-Maximilian University Munich, Germany
Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific, Institute, Milan, Italy.
Previous peer reviewed evidence
Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits, (Journal of Gene Medicine, 1999)
The systemic administration of a therapeutic dose of 5 x 10(11) infectious particles/kg (infusion time 20 min) led to an average reduction of 80-90% in the platelet count within 48 h.
Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance, (Blood, 2007)
Thrombocytopenia has been consistently reported following the administration of adenoviral gene transfer vectors.
The virus activates platelets and induces platelet-leukocyte aggregate formation.
Polyethylene glycol modification of adenovirus reduces platelet activation, endothelial cell activation, and thrombocytopenia, (Human gene therapy, 2007)
Thrombocytopenia is one of the complications for in vivo administration of adenovirus serotype 5 (Ad5) vectors after intravenous injection.
Platelet-adenovirus vs. inert particles interaction: effect on aggregation and the role of platelet membrane receptors, (Platelets, 2013)
Virus mediated gene therapy applications are still challenged by the resultant thrombocytopenia and the mechanism(s) of platelet-foreign particles interaction remains unclear.
Pseudotyping Serotype 5 Adenovirus with the Fiber from Other Serotypes Uncovers a Key Role of the Fiber Protein in Adenovirus 5-Induced Thrombocytopenia, (Human gene therapy, 2016)