Researchers Discover Why a Rare Blood Clot Occurs After COVID-19 Vaccination

Researchers have discovered why the unusual side effect of a blood clot that impacted some recipients of the Oxford/AstraZeneca and Johnson & Johnson COVID-19 vaccines occurred, which could help vaccine developers produce safer vaccines based on the same technology, preventing the same issues occurring in the future. The blood clot, known as vaccine-induced immune thrombocytopenia and thrombosis (VITT), is a rare prothrombotic complication that occurs after adenoviral vector-based vaccination against coronavirus disease 2019; in rare cases, it can also occur after natural adenovirus infection.

In the study, the researchers used antibody proteomics to determine the amino acid sequences of anti-PF4 antibodies from 21 patients with VITT and sequenced the genes encoding the immunoglobulin light-chain hypervariable region from 100 patients with VITT. To identify an adenoviral trigger, they used the antigen-binding fingerprints of anti-PF4 and anti–adenovirus protein antibodies to identify a shared serum clonotype and, subsequently, used adenovirus protein peptides and recombinant anti-PF4 VITT antibodies to map the mimicking linear epitope.

They found that genomic and proteomic profiling of VITT antibodies shared immunoglobulin light-chain allele, IGLV3-21*02 or *03, harboring a critical somatic hypermutation, K31E. Only antibodies purified against adenoviral core protein VII (pVII) contained anti-PF4 species matching the VITT fingerprint; antibodies against intact virions or other adenoviral proteins did not. Cross-reactive IgGs were mapped to a basic linear epitope on pVII. A pathogenic anti-PF4 VITT antibody, back-mutated to germline (K31), lost its prothrombotic activity in vitro and in vivo and preferentially bound pVII, a finding that directly supported the role of the hypermutation in the antigenic shift from adenovirus pVII to PF4.

According to the researchers, the results indicate that VITT occurs when, in persons with immunoglobulin light-chain allele IGLV3-21*02 or *03, a specific somatic hypermutation develops that affects antibodies that recognize a specific epitope on the adenoviral core protein pVII, which results in misdirection of antibody targeting toward PF4.