Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine^1,2, European health authorities recommended that patients under the age of 55 years who received one dose of ChAdOx1-S-nCoV-19 receive a second dose of the Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here we show that the heterologous ChAdOx1-S-nCoV-19 and BNT162b2 combination confers better protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the homologous BNT162b2 and BNT162b2 combination in a real-world observational study of healthcare workers (n = 13,121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody responses, but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential correlated with increased frequencies of switched and activated memory B cells that recognize the SARS-CoV-2 receptor binding domain. The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immunocompromised individuals.

在对阿斯利康 ChAdOx1-S-nCoV-19 疫苗^1,2产生严重不良反应后，欧洲卫生当局建议接受一剂 ChAdOx1-S-nCoV-19 的 55 岁以下患者接受第二剂辉瑞BNT162b2 疫苗作为加强剂。然而，这种疫苗接种方案的有效性和免疫原性尚未经过正式测试。在这里，我们表明，在真实世界的医疗保健观察研究中，异源 ChAdOx1-S-nCoV-19 和 BNT162b2 组合比同源 BNT162b2 和 BNT162b2 组合对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染具有更好的保护作用工人 ( n = 13,121)。为了了解潜在机制，我们对每种疫苗组合所赋予的抗尖峰免疫进行了纵向调查。两种组合都诱导了强烈的抗尖峰抗体反应，但来自异种接种疫苗的个体的血清显示出更强的中和活性，而与 SARS-CoV-2 变体无关。这种增强的中和电位与识别 SARS-CoV-2 受体结合域的转换和激活记忆 B 细胞的频率增加有关。与 BNT162b2 疫苗相比，ChAdOx1-S-nCoV-19 疫苗在初免剂量后诱导的 IgG 反应较弱，但 T 细胞反应更强，这可以解释两种疫苗在联合使用时的互补性。因此，异源疫苗接种方案可能特别适用于免疫功能低下的个体。