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Review 1: "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"

The reviewer emphasizes the need for major revision for clarity and depth around the study's primary objective/rationale, the misleading label of "healthy" given high prevalence of obesity and comorbidities, and high baseline D-dimer levels likely obscuring changes post-booster.

Published onJul 03, 2024
Review 1: "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"
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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
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
Description

Abstract BaSiS (Booster After Sisonke Study) 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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: Patel et al present a comparison of the D-dimer levels before and after the booster dose of COVID-19 vaccination, in a population of relatively healthy young individuals who had received the first dose of Ad26.COV2.S in the context of the BaSiS (Booster After Sisonke Study) study.

The study is a secondary analysis of a previous study not powered to detect differences in the thromboembolic risk of the participants. Therefore we suggest the manuscript should undergo major revision.

  1. The study fails to convey a clear message. The rationale of the study should be stated more clearly, i.e. determining if the booster dose of COVID-19 vaccination increases D-dimer levels, that are a marker of an ongoing thrombotic state.

  2. The authors do not detect a significant difference in the D-dimer levels of the participants before and after the booster, because the baseline D-dimer levels of the subjects enrolled were very high. The authors should consider exploring other easy to measure parameters that could be indicative of a pro-thrombotic state, maybe the platelet count or soluble markers of platelet of platelet activation, such as the PF4 levels.

  3. The greatest value of the study is that it is based in a resource-limited country. The population studied should be defined better:

    • it shouldn’t be defined healthy as it includes a large fraction of individuals that are obese and with other comorbidities.

    • the ethnicity should be emphasised since subjects of black ethnicity are usually at higher risk of thrombosis.

    • how much time has passed from the priming Ad26.COV2.S dose to the time of the enrolment should be included if possible.

    • considering the known relationship between estrogens and thrombotic events, It would be interesting to compare the state of the art with the data on women using hormonal and non-hormonal contraceptives.

Writing style and format:

  • The authors switch between US and British English. The language format should be uniform throughout the manuscript.

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