Dataset Information

ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome.

ABSTRACT: Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.

SUBMITTER: Baker AT

PROVIDER: S-EPMC8635433 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome.

Baker Alexander T AT Boyd Ryan J RJ Sarkar Daipayan D Teijeira-Crespo Alicia A Chan Chun Kit CK Bates Emily E Waraich Kasim K Vant John J Wilson Eric E Truong Chloe D CD Lipka-Lloyd Magdalena M Fromme Petra P Vermaas Josh J Williams Dewight D Machiesky LeeAnn L Heurich Meike M Nagalo Bolni M BM Coughlan Lynda L Umlauf Scott S Chiu Po-Lin PL Rizkallah Pierre J PJ Cohen Taylor S TS Parker Alan L AL Singharoy Abhishek A Borad Mitesh J MJ

Science advances 20211201 49

Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstr ...[more]

PMID: 34851659

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Project description:Several vaccine-induced thrombotic thrombocytopenia syndrome (VITTS) cases have been reported after the ChAdOx1 nCov-19 vaccination. The current study systematically reviewed the reported post-ChAdOx1 nCoV-19 vaccination thrombotic thrombocytopenia cases. Their laboratory and clinical features, as well as the diagnostic and therapeutic measures, were investigated. Online databases were searched until 25 August 2021. Studies reporting post-ChAdOx1 nCov-19 vaccination thrombotic thrombocytopenia syndrome (TTS) were included. Overall, 167 cases (21-77 years old) from 53 publications were included showing a female dominance of 1.75 times. About 85% of the cases exhibited the primary symptoms within the first two weeks post-vaccination. Headache was the most common initial symptom (>44.2%), and hemorrhage/thrombotic problems (22.46%), as well as discoordination/weakness/numbness/ hemiparesis/cyanotic toes (19.6%), were the most prevalent uncommon initial symptoms. Prothrombin time (PT), D-dimers, and C-reactive protein were the most remarkable increased laboratory parameters in 50.6%, 99.1%, and 55.6% of cases, respectively. In comparison, platelet and fibrinogen were the most remarkable decreased laboratory parameters in 92.7% and 50.5% of cases, respectively. Most VITT cases presented with cerebral venous thrombosis/cerebral venous sinus thrombosis, supraventricular tachycardia, transverse sinus/cerebral thrombosis, pulmonary embolism, and cerebral hemorrhage. Anti-PF4 antibody measurement through immunoassays and functional assays were positive in 86.2% and 73% of cases, respectively. About 31% of the cases died. Early diagnosis and proper therapeutic measures are important in ChAdOx1 nCov-19 vaccine-induced VITTS patients. Therefore, experts are recommended to know the corresponding clinical and laboratory features, as well as diagnostic methods. Elucidation of the pathophysiologic mechanism of ChAdOx1 nCov-19 vaccine-induced TTS deserves further investigation.

Project description:BackgroundPost-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management.MethodsWe searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated.FindingsWe identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets.ConclusionsThe reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome.

Project description:BackgroundThrombosis with thrombocytopenia syndrome (TTS) associated with viral vector COVID-19 vaccines, including ChAdOx1-S (AstraZeneca AZD1222) vaccine, can result in significant morbidity and mortality. We report the clinicopathological features of TTS following ChAdOx1-S vaccination and summarise the case outcomes in Australia.MethodsIn this cohort study, patients diagnosed with TTS in Australia between 23 March and 31 December 2021 were identified according to predefined criteria. Cases were included if they met the Therapeutic Goods Administration (TGA) probable and confirmed case definitions and were reclassified using Centres for Disease Control and Prevention (CDC) definition for analysis. Data were collected on patient baseline characteristics, clinicopathological features, risk factors, treatment and outcomes.FindingsA total of 170 TTS cases were identified, with most occurring after the first dose (87%) of ChAdOx1-S. The median time to symptom onset after vaccination and symptom onset to admission was 11 and 2 days respectively. The median age of cases was 66 years (interquartile range 55-74). All except two patients received therapeutic anticoagulation and 66% received intravenous immunoglobulin. Overall, 85.3% of cases were discharged home after a median hospitalisation of 6 days, 9.4% required ongoing rehabilitation and 5.3% died. Eight deaths were related to TTS, with another dying from an unrelated condition while receiving treatment for TTS. Deaths occurred more commonly in those classified as Tier 1 according to the CDC definition and were associated with more severe thrombocytopenia and disease-related haemorrhage.InterpretationTTS, while rare, can be severe and have catastrophic outcomes in some individuals. In Australia, the mortality rate was low compared to that reported in other high-income countries. Almost all received therapeutic anticoagulation with no bleeding complications and were successfully discharged. This emphasises the importance of community education and an established pathway for early recognition, diagnosis and treatment of TTS.FundingAustralian Commonwealth Department of Health and Aged Care. H.A Tran, N. Wood, J. Buttery, N.W. Crawford, S.D. Chunilal, V.M. Chen are supported by Medical Research Future Funds (MRFF) grant ID 2015305.

Dataset Information

ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome.

Publications

ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome.

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