Reactogenicity and Immunogenicity of BNT162b2 in Subjects Having Received a First Dose of ChAdOx1s: Initial Results of a Randomised, Adaptive, Phase 2 Trial (CombiVacS)

Abstract

Background: There are no immunological data on SARS-CoV-2 heterologous vaccinations schedules in humans. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, Astra Zeneca). Methods: We did a phase 2, open-label, adaptive, randomised, controlled clinical trial on adults under 60 years old, vaccinated with a single dose of ChAdOx1-S between 8 and 12 weeks before screening, and no history of SARS-CoV-2 infection (EudraCT No. 2021-001978-37 and NCT04860739). Participants were randomly assigned (2:1) to receive BNT162b2 (0.3 mL, single intramuscular injection) or observation. The primary outcomes were 7-day reactogenicity and 14-day anti-spike IgG response, measured by immunoassays covering SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibodies functionality and cellular immune response were assessed using a pseudovirus neutralization assay and IFN-gamma immunoassay, respectively. Findings: Between April 24 and April 30, 2021, 676 individuals were randomized (n=450 intervention group, n=226 control group) at 5 sites in Spain, and 663 (441 and 222, respectively) completed the study up to day 14 (mean age 44 [SD 9], 56·5% female). In the intervention group, geometric mean titres (GMT) of IgG-RBD increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 (7371·53; 8161·96) at day 14 (p < 0·0001). IgG against trimeric spike-protein increased from 98·4 [85.69–112.99] to 3684·87 [3429·87–3958·83]). 100% participants exhibited neutralizing antibodies 14 days after BNT162b2 administration, in comparison to 34.1% at enrolment. A 4-fold increase in cellular immune response was also observed. Reactions were predominantly mild (68·3%) or moderate (29·9%), and consisted more frequently on injection site pain (88·2%), induration (35·5%), headache (44·4%) and myalgia (43·3%). No serious adverse events were reported. Interpretation: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response with an acceptable and manageable reactogenicity profile. Clinical Trial Registration Details: EudraCT No. 2021-001978-37 and NCT04860739. Funding Information: Funded by Instituto de Salud Carlos III (ISCIII). Declaration of Interests: CB is the Deputy General Manager of the ISCIII. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GSK, Daiichi-Sankyo, Janssen and Farmalider, outside of the submitted work. The other authors declare no competing interests. Ethics Approval Statement: All the participants provided written informed consent before enrolment. The trial complies with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved by the Spanish Agency of Medicines and Healthcare Products (AEMPS) and by the Ethics Committee at University Hospital La Paz.