Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial

Abstract

Background To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). Methods We did a phase 2, open-label, randomised, controlled trial on adults aged 18–60 years, vaccinated with a single dose of ChAdOx1-S 8–12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov ( NCT04860739 ), and is ongoing. Findings Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84–85·33) at baseline to 7756·68 BAU/mL (7371·53–8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69–112·99) to 3684·87 BAU/mL (3429·87–3958·83). The interventional:control ratio was 77·69 (95% CI 59·57–101·32) for RBD protein and 36·41 (29·31–45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. 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. Funding Instituto de Salud Carlos III. Translations For the French and Spanish translations of the abstract see Supplementary Materials section.

Optimising SARS-CoV-2 vaccination schedules

“…In The Lancet , Xinxue Liu and colleagues 2 present results for four of the eight intervention groups of the Com-COV clinical trial, showing that the immunological response of double-dose ChAdOx1 nCoV-19 (AstraZeneca; hereafter referred to as ChAd) is statistically lower than any other schedule including BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT) and ChAd at 28 days post boost dose, with a 28-day prime–boost interval. In addition, their findings support previous published data from an academic study done by the Instituto de Salud Carlos III, of which I was an investigator and author, 3 suggesting that a heterologous schedule based on the sequential administration of ChAd and BNT could be highly immunogenic, and perhaps more immunogenic than homologous schedules based on ChAd. In addition, Liu and colleagues show that double-dose BNT is more potent in inducing a humoral response than the BNT–ChAd permutation.…”

“…The Com-COV trial, like the CombiVacS trial, 3 was not able to identify very low-frequency adverse events. Of course, no phase 2 study is able to do so.…”

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

“…Our results for the ChAd/BNT schedule build on preliminary data from a Spanish randomised trial, in which 18–60-year-olds received a dose of BNT 2–3 months after priming with ChAd and showed a 37-fold increase in SARS-CoV-2 anti-spike IgG at 14 days post boost, higher than the 22-fold increase at 7 days and 19-fold increase at 28 days post boost in this study. 13 Potential explanations for these differences include the longer prime-boost interval, the different sampling timepoints, and a younger population in the Spanish study. 13 Fold increases in the cellular response were, however, similar (four-fold in the Spanish study versus 3·7-fold in this study).…”

“… 13 Potential explanations for these differences include the longer prime-boost interval, the different sampling timepoints, and a younger population in the Spanish study. 13 Fold increases in the cellular response were, however, similar (four-fold in the Spanish study versus 3·7-fold in this study). Early results from a prospective cohort study in Germany, which compared health-care workers immunised with BNT/BNT at a 3-week interval or ChAd/BNT at an 8–12 week interval, showed similar concentrations of binding antibody at 3 weeks post boost and higher cellular responses in the ChAd/BNT recipients.…”

“…Nevertheless, preclinical studies support evaluation of this approach, 11 , 12 and results from a randomised study in Spain suggested an increase in binding and neutralising antibody after boosting ChAd-primed participants with BNT, compared with not having a boost dose. 13 Additionally, early results from an observational study in Germany show that humoral responses are similar in the cohort receiving BNT/BNT at a 3-week interval to those receiving ChAd/BNT at a 10-week interval, with cellular responses appearing to be higher in the ChAd/BNT cohort. 14 However, we have previously reported that heterologous schedules incorporating ChAd and BNT are more reactogenic than their homologous schedules.…”