Vaccine-induced immune thrombotic thrombocytopenia is mediated by a stereotyped clonotypic antibody

Abstract

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare thromboembolic complication of adenoviral-vectored SARS-CoV2 vaccines, mediated by antibodies directed against platelet factor 4 (PF4). Given their causal role in VITT, identification of the molecular composition of anti-PF4 antibodies is crucial for developing better diagnostics and treatments. Here, we utilised a novel proteomic workflow to analyse the immunoglobulin variable (IgV) region composition of anti-PF4 antibodies at the level of the secreted proteome. Serum anti-PF4 IgG antibodies from five patients with VITT triggered by ChAdOx1 nCoV-19 vaccination were affinity purified by PF4-coupled magnetic beads and sequenced by mass spectrometry. We revealed a single IgG heavy (H)-chain species paired with a single lambda light (L)-chain species in all five unrelated patients. Remarkably, all L-chains were encoded by the identical IGLV3-21*02 gene subfamily with identical L-chain third complementarity determining region (LCDR3) lengths. Moreover, striking stereotypic features were also identified in heavy-chains anti-PF4 antibodies characterised by identical HCDR3 length and homologous sequences. In summary, we unravelled the molecular signature of highly stereotyped clonotypic anti-PF4 antibodies, indicating shared pathways of antibody production in VITT patients. These discoveries are critical to understand the molecular basis of this serious condition and develop novel therapies aimed at removing pathogenic clones.

Understanding thrombosis with thrombocytopenia syndrome after COVID-19 vaccination

“…Of note, the recent work performed by Tom Gordon 24 unveiling the molecular signature of stereotyped clonotypic anti-PF4 antibodies in five VITT patients supports the hypothesis that VITT may develop in patients with a defined genetic background. The ethnicity component was deemed a key element to be further explored.…”

“…As VITT occurs starting from 5 days post-vaccine administration, the anti-PF4 B cell response does not align with the notions of the conventional immunological response post primary antigen exposure and appears to be a secondary immune response. Recently, the molecular signature of clonotypic anti-PF4 antibodies was identified in five patients, defined as a single IgG heavy (H)-chain species paired with a single lambda light (L)-chain species, and all L-chains were encoded by the identical IGLV3-21*02 gene subfamily 24 . These results may reveal a shared pathway of antibody production in VITT patients and could point to a possible genetic predisposition at the basis of the syndrome.…”

Vaccine-induced immune thrombotic thrombocytopenia

“…Furthermore, VITT antibodies appear to have lambda light chains exclusively [ 13 ]. In another recent mass spectrometry-based study, Wang et al demonstrated that 5/5 VITT patients had anti-PF4 immunoglobulins containing lambda light chains encoded by the IGLV3-21*02 gene subfamily with identical light chain complementarity determining region lengths [ 24 ]. IgG heavy chains paired exclusively with lambda light chains likely highlight a common developmental pathway in VITT antibody production [ 13 , 24 ].…”

“…In another recent mass spectrometry-based study, Wang et al demonstrated that 5/5 VITT patients had anti-PF4 immunoglobulins containing lambda light chains encoded by the IGLV3-21*02 gene subfamily with identical light chain complementarity determining region lengths [ 24 ]. IgG heavy chains paired exclusively with lambda light chains likely highlight a common developmental pathway in VITT antibody production [ 13 , 24 ]. Lastly, antibodies in VITT appear to be more persistent relative to HIT, with anti-PF4 antibodies capable of stimulating platelet activation for several months after acute presentation and remaining detectable by enzyme-linked immunosorbent assay (ELISA) up to nine months or more [ [25] , [26] , [27] , [28] , [29] ] ( Fig.…”

Public Health Management of the COVID-19 Pandemic in Australia: The Role of the Morrison Government

“…Deaths associated with AstraZeneca were rare and primarily associated with a very rare genetic condition [ 224 ], but were nevertheless widely reported [ 225 , 226 , 227 , 228 ], contributing to vaccine hesitancy. The regulator [ 229 ], supported by the scientific community [ 230 ], attempted to reduce concerns, stressing the very small risk of death from vaccination.…”