Alexander T. Baker, Ryan J. Boyd, Daipayan Sarkar, John Vant, Alicia Teijeira
Crespo, Chloe D. Truong, Emily Bates, Eric Wilson, Chun Kit Chan, Magdalena
Lipka-Lloyd, Petra Fromme, Marius Bolni Nagalo, Meike Heurich, Dewight
Williams, Po-Lin Chiu, Pierre J. Rizkallah, Alan L. Parker, Abhishek
Singharoy, and Mitesh J. Borad.
ChAdOx1 interacts with CAR and PF4 with implications for
thrombosis with thrombocytopenia syndrome.
Science Advances, 7:eabl8213, 2021.
BAKE2021-AS
Adenovirus derived vectors, based on chimpanzee adenovirus Y25
(ChAdOx1) and human adenovirus type 26 are proving critical in
combatting the 2019 SARS-CoV-2 pandemic. Following emergency use
authorisation, scale up in vaccine administration has inevitably
revealed vaccine related adverse effects; too rare to observe even in
large Phase-III clinical trials. These include vaccine-induced
thrombotic thrombocytopenia (VITT), an ultra-rare adverse event in
which patients develop life-threatening blood clots 5-24 days
following vaccination. To investigate vector-host interactions of
ChAdOx1 underpinning VITT we solved the structure of the ChAdOx1
capsid by CryoEM, and the structure of the primary receptor tropism
determining fiber-knob protein by crystallography. These structural
insights have enabled us to unravel key protein interactions involved
in ChAdOx1 cell entry and a possible means by which it may generate
misplaced immunity to platelet factor 4 (PF4), a protein involved in
coagulation. We use in vitro cell binding assays to show that the
fiber-knob protein uses coxsackie and adenovirus receptor (CAR) as a
high affinity binding partner, while it does not form a stable
interface with CD46. Computational simulations identified a putative
mechanism by which the ChAdOx1 capsid interacts with PF4 by binding in
the spaces between hexon proteins, with downstream implications for
the causes of VITT.
