Effect of a COVID-19-Heterologous Vaccination Schedule on Haemostasis: A Subanalysis of the Phase 2, Multicentre, Randomised, Controlled CombiVacS Study

Background: Several cases of unusual thrombotic events and thrombocytopenia have occurred after vaccination with recombinant adenoviral vectors encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to elucidate the impact of a COVID-19 heterologous vaccination schedule including priming with an adenovirus vaccine on haemostasis and coagulation profile.Methods: Adult participants were vaccinated with a single dose of ChAdOx1-S. Between 8–12 weeks after vaccination they were randomly assigned (2:1) to receive either BNT162b2 vaccine (intervention group) or continue observation (control group).Samples drawn before and 28 days after a vaccination with BNT162b2 were analyzed for platelet count and markers of haemostasis (D-dimer, Anti-heparin PF4 antibodies, cell-free DNA, plasminogen activator inhibitor-1, thrombin generation, and serum capacity to activate platelets).Findings: Platelet count from all participants after receiving BNT162b2 was within normal range.Anti-PF4 antibodies were present in 26% and 18% of subjects from the control and intervention group, respectively, at day 28. In most cases levels of anti-PF4 antibodies were high before receiving BNT162b2. Moreover, serum from these participants did not affect activity state of platelets from healthy controls. There were no differences between groups in PAI-1 and cfDNA plasma levels. According to D-dimer plasma concentration, thrombin generation test showed that none of the participants had a procoagulant profile.Interpretation: Our data support the safety in terms of alteration of haemostasis and coagulation of the heterologous vaccination against COVID-19 infection with ChAdOx1-S and a second dose with BNT162b2.Funding Instituto de Salud Carlos III.Trial Registration Details: This study is registered with EudraCT (No. 2021-001978-37) and ClinicalTrials.gov (NCT04860739)Funding Information: This work is funded by the Instituto de Salud Carlos III, a Spanish public body assigned to the Ministry of Science and Innovation that manages and promotes public clinical research related to public health. The Spanish Clinical Trials Platform is a public network funded by the Instituto de Salud Carlos III (grant numbers PTC20/00018 and PT17/0017), the State Plan for Research, Development, and Innovation 2013–16, the State Plan for Scientific and Technical Research and Innovation 2017–20, and the Subdirectorate General for Evaluation and Promotion of Research, Instituto de Salud Carlos III, cofinanced with FEDER funds. CombiVacS was designed under the umbrella of the VACCELERATE project. VACCELERATE received funding from the EU's Horizon 2020 Research and Innovation Programme (grant agreement numbers 101037867 and 860003). The Instituto de Salud Carlos III is the Spanish partner in the VACCELERATE project. The authors thank all trial participants. The authors thank Esther Prieto for editorial assistance and writing support (employed by Hospital Universitario La Paz; funded by the Instituto de Salud Carlos III, grant number PCT20/00018).Declaration of Interests: CB-I is the deputy general manager of the Instituto de Salud Carlos III. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GlaxoSmithKline, Daiichi-Sankyo, Janssen, and Farmalider, outside of the submitted work. AMB has received fees from Janssen and Pfizer, outside of the submitted work. VJY and MTAR are principal investigators of clinical trials sponsored by Pfizer, NovoNordisk, Roche, Sanofi, SOBI, Takeda, and Grifols outside of the submitted work. RdMB reports personal fees (speaker fee) and non-financial support from ViiV and Gilead. All other authors declare no competing interests.Ethics Approval Statement: The trial complies with the principles of the Declaration of Helsinki and Good Clinical Practice, and was approved by the Spanish Agency of Medicines and Healthcare Products and by the ethics committee at La Paz University Hospital. All participants provided written informed consent before enrolment.