Comparison of humoral and cellular immune responses between ChAd-BNT heterologous vaccination and BNT-BNT homologous vaccination following the third BNT dose: A prospective cohort study.

Introduction: The differential immune responses after two additional BNT162b2 (BNT) booster doses between ChAdOx1 nCoV-10 (ChAd)-primed and BNT-primed groups have not been elucidated. The aim of this study was to compare vaccine-induced humoral and cellular immune responses and evaluate breakthrough infection between the two vaccination strategies. Methods: In 221 healthy subjects (111 in the ChAd group), longitudinal immune responses were monitored at 3, 4, and 6 months after the 2nd dose and 1, 3, and 6 months after the 3rd dose. Humoral immunity was measured by two fully automated chemiluminescent immunoassays (Elecsys and Abbott) and a surrogate virus neutralization test (sVNT). Cellular immunity was assessed by two interferon-γ (IFN-γ) release assays (QuantiFERON SARS-CoV-2 and Covi-FERON). Results: After the 2nd dose of BNT vaccination, total antibody levels were higher in the ChAd group, but IgG antibody and sVNT results were higher in the BNT group. Following the 3rd dose vaccination, binding antibody titers were significantly elevated in both groups (ChAD-BNT; 15.4 to 17.8-fold, BNT-BNT; 22.2 to 24.6-fold), and the neutralizing capacity was increased by 1.3-fold in both cohorts. The ChAd-BNT group had lower omicron neutralization positivity than the BNT-BNT group (P = 0.001) at 6 months after the 3rd dose. Cellular responses to the spike antigen also showed 1.7 to 3.0-fold increases after the 3rd dose, which gradually declined to the levels equivalent to before the 3rd vaccination. The ChAd cohort tended to have higher IFN-γ level than the BNT cohort for 3-6 months after the 2nd and 3rd doses. The frequency of breakthrough infection was higher in the ChAd group (44.8%) than in the BNT group (28.1%) (P = 0.0219). Breakthrough infection induced increased humoral responses in both groups, and increase of cellular response was significant in the ChAd group. Discussion: Our study showed differential humoral and cellular immune responses between ChAd-BNT-BNT heterologous and BNT-BNT-BNT homologous vaccination cohorts. The occurrence of low antibody levels in the ChAd-primed cohort in the humoral immune response may be associated with an increased incidence of breakthrough infections. Further studies are needed on the benefits of enhanced cellular immunity in ChAd-primed cohorts.