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

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 ND(50), 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 ND(50), 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.