Heterologous ChAdOx1 and Bnt162b2 vaccination induces strong neutralizing antibody responses against SARS-CoV-2 including delta variant with tolerable reactogenicity

Abstract

Objectives: We assessed humoral responses and reactogenicity following the heterologous vaccination compared to the homologous vaccination groups.

Methods: We enrolled healthcare workers (HCWs) who were either vaccinated with ChAdOx1 followed by BNT162b2 (heterologous group) or 2 doses of ChAdOx1 (ChAdOx1 group) or BNT162b2 (BNT162b2 group). Immunogenicity was assessed by measuring antibody titers against receptor-binding domain (RBD) of SARS-CoV-2 spike protein in all participants and neutralizing antibody titer in 100 participants per group. Reactogenicity was evaluated by a questionnaire-based survey.

Results: We enrolled 499 HCWs (ChAdOx1, n = 199; BNT162b2, n = 200; heterologous ChAdOx1/BNT162b2, n = 100). The geometric mean titer of anti-receptor-binding domain antibody at 14 days after the booster dose was significantly higher in the heterologous group (11 780.55 binding antibody unit (BAU)/mL [95% CI, 10 891.52-12 742.14]) than in the ChAdOx1 (1561.51 [95% CI, 1415.03-1723.15]) or BNT162b2 (2895.90 [95% CI, 2664.01-3147.98]) groups (both p < 0.001). The neutralizing antibody titer of the heterologous group (geometric mean ND₅₀, 2367.74 [95% CI, 1970.03-2845.74]) was comparable to that of the BNT162b2 group (2118.63 [95% CI, 1755.88-2556.32]; p > 0.05) but higher than that of the ChAdOx1 group (391.77 [95% CI, 326.16-470.59]; p < 0.001). Compared with those against wild-type SARS-CoV-2, the geometric mean neutralizing antibody titers against the Delta variant at 14 days after the boosting were reduced by 3.0-fold in the heterologous group (geometric mean ND₅₀, 872.01 [95% CI, 685.33-1109.54]), 4.0-fold in the BNT162b2 group (337.93 [95% CI, 262.78-434.57]), and 3.2-fold in the ChAdOx1 group (206.61 [95% CI, 144.05-296.34]). The local or systemic reactogenicity after the booster dose in the heterologous group was higher than that of the ChAdOx1 group but comparable to that of the BNT162b2 group.

Discussion: Heterologous ChAdOx1 followed by BNT162b2 vaccination with a 12-week interval induced a robust humoral immune response against SARS-CoV-2, including the Delta variant, that was comparable to the homologous BNT162b2 vaccination and stronger than the homologous ChAdOx1 vaccination, with a tolerable reactogenicity profile.

Keywords: BNT162b2; COVID-19; ChAdOx1; Heterologous vaccination; SARS-CoV-2.

Fig. 1

Study flowchart.

Fig. 2

Local and systemic reactions. Reactogenicity of each vaccination regime was presented as the sum of symptom scores. (A) Reactogenicity of each vaccination group. (B) Reactogenicity according to sex group. Horizontal bars represent mean, and error bars represent 95% CI. ^ap <0.05, ^bp < 0.001. Abbreviations: ns, non-significant p value.

Fig. 3

Anti-RBD antibody titers and neutralizing antibody titers against wild-type SARS-CoV-2. (A) Anti-RBD antibody titers before and 2 weeks after booster dose. (B) Anti-RBD antibody titers by group related to time after first dose. (C) Neutralizing antibody titers before and 2 weeks after booster dose. (D) Neutralizing antibody titers by group related to time after first dose. (E) Schematic showing the dosing strategies and blood sampling time points. The red solid line indicates the mean titer, and the error bar depicts the 95% CI. The black dotted line in 3A and 3B indicates the limitation of detection (0.98 binding antibody unit /mL). ^ap < 0.05, ^bp < 0.001, ^cp < 0.0001. Abbreviations: ns, non-significant p value.

Fig. 4

Neutralizing antibody response against SARS-CoV-2 variants. Horizontal bars represent mean values. Error bars represent standard error of the mean. Neutralizing titers (ND₅₀) and reduced folds compared to wild type are shown for each column.