Clot Twist – D-dimer analysis of healthy adults receiving heterologous or homologous booster COVID-19 vaccine after a single prime dose of Ad26.COV2.S in a phase II randomised open-label trial, BaSiS

BaSiS ( B ooster A fter Si sonke S tudy) is a prospectively enrolled open-label trial in which healthy adults, with controlled co-morbidities and no prior thrombosis, who received a single Ad26.COV2.S prime vaccination primarily through the Sisonke phase IIIB open label implementation study in South Africa. An exploratory objective evaluated the clotting profiles of participants who were enrolled across 4 sites in South Africa and randomised 1:1:1:1 to receive one of full-dose Ad26.COV2.S, half-dose Ad26.COV2.S, full-dose Comirnaty or half-dose Comirnaty booster. D-dimer testing (INNOVANCE®D-Dimer Assay), as a coagulopathy marker, was conducted pre-booster (baseline) and 2 weeks post-booster. The median age among 285 participants was 42.2 years (IQR:35.5-48.7), 235/285 (82.5%) were female, 269/285 (94.4%) were Black African. Of the 40.4% (115/285) people living with HIV (PLHIV), 79.1% (91/115) were well-controlled on antiretroviral therapy. At baseline, 39.3% (112/285) had elevated d-dimers; all asymptomatic. Females and obese participants were significantly more likely to have elevated baseline d-dimers (OR=4.17; 95% CI:1.88 to 9.26 and OR=2.64; 95% CI:1.57 to 4.43, respectively). Of 169 with normal baseline d-dimers, 29 (17.2%) became elevated 2 weeks post-booster: median increase 0.23µg/ml (IQR:0.15-0.42); those receiving full-dose Comirnaty exhibited lower risk of d-dimer elevation post vaccination, compared to other booster vaccination arms (OR:0.26; 95% CI:0.07 to 0.98). PLHIV experienced significantly higher median increases compared to HIV uninfected participants (0.43 vs 0.17, p=0.004). Elevated d-dimers in asymptomatic, low-risk adults were unexpectedly common but were not associated with thromboembolism, supporting the rationale of using d-dimers only if clinically indicated. Trial Registration: South African Clinical Trails Register number DOH-27-012022-7841. ### Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: FP, MD: Support for the present manuscript - Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program (INV-030570) and the Wellcome Trust (226137/Z/22/Z); SAMRC. Both paid to institution. Grants/ contracts - Received grant funding from Janssen to conduct the following clinical trials: Ensemble study (3UM1 AI068614-14SI), Sherpa Study (96867), Sisonke 1 study (96833), Horizon 1 (VAC31518COV2004), Horizon 2 (VAC31518COV3006). Received grant funding from Pfizer to conduct the following clinical trials:C4591015. All paid to institution. SS, JLR: Support for the present manuscript - SAMRC (paid to institution), South African National Department of Health (SA NDoH) - Sponsor of Comirnaty, Janssen Pharmaceuticals - Sponsor of Janssen Ad26.COV2.S. Grants/ contracts - CDC, BMGF, Wellcome Trust, EU, EDCTP. All paid to institution. LF: Support for the present manuscript - Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program (INV-030570) and the Wellcome Trust (226137/Z/22/Z); SAMRC. Both paid to institution. Participation on a Data Safety Monitoring Board or Advisory Board: MIGHTY-MO Study (DSMB Chair), Petite-DTG study (DSMB Member). Leadership or fiduciary role: IMPAACT Therapeutic Scientific Committee PLM: Support for the present manuscript - Bill and Melinda Gates Foundation; SAMRC. Both paid to institution. AS: Support for the present manuscript - Bill and Melinda Gates Foundation. Sub-award to institution. BFJ: Consulting fees - Sanofi, Aspen, AstraZeneca, Zyquis. Payment for expert testimony - Medicolegal cases of thrombosis problems Support for attending meetings and/or travel: Aspen - To attend ESC and teach on return ### Clinical Trial DOH-27-012022-7841 ### Funding Statement This study was funded by: SAMRC (South African Medical Research Council) - https://www.samrc.ac.za/ Sponsor of Comirnaty: South African National Department of Health SA NDoH - https://www.health.gov.za/ Sponsor of Janssen Ad26.COV2.S: Janssen Pharmaceuticals - https://www.janssen.com/ SAMRC played a role in study design, decision to publish, and preparation of the manuscript. SA NDoH and Janssen Pharmaceuticals did not play any additional roles beyond vaccine sponsorship. FP, MD: Support for the present manuscript - SAMRC. Paid to institution. SS, JLR: Support for the present manuscript - SAMRC (paid to institution), South African National Department of Health (SA NDoH) - Sponsor of Comirnaty, Janssen Pharmaceuticals - Sponsor of Janssen Ad26.COV2.S. LF: Grants/ contracts - SAMRC. PLM: Support for the present manuscript - Bill and Melinda Gates Foundation; SAMRC. Both paid to institution. AS: Support for the present manuscript - Bill and Melinda Gates Foundation. Sub-award to institution. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The BaSiS study was approved by Wits University's Human Research Ethics Committee (Reference no 211001B), Biomedical Research Ethics Committee (Reference no BREC/00003487/2021), University of Cape Town (UCT) Faculty of Health Sciences Human Research Ethics Committee (Reference no 680/2021) and the South African Health Products Regulatory Authority (SAHPRA Reference no 20210423). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes