Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent. Here we show, through studies in mouse models lacking antibodies but maintaining functional B cells and lymphoid organs, that immunity conferred by prior infection or mRNA vaccination can protect against SARS-CoV-2 challenge independently of antibodies. Our findings, using three distinct models inclusive of a novel human/mouse ACE2 hybrid, highlight that CD8⁺ T cells are essential for combating severe infections, whereas CD4⁺ T cells contribute to managing milder cases, with interferon-γ having an important function in this antibody-independent defense. These findings highlight the importance of T cell responses in vaccine development, urging a broader perspective on protective immunity beyond just antibodies.

疫苗降低了严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的发病率和死亡率，但新出现的变种对其有效性提出了挑战。更新疫苗的流行方法以抗体反应为目标，假设抗体反应是疫苗接种或感染后的主要防御机制。然而，这种观点可能会忽视 T 细胞的作用，特别是当抗体水平较低或不存在时。在这里，我们通过对缺乏抗体但保留功能性 B 细胞和淋巴器官的小鼠模型进行研究表明，先前感染或 mRNA 疫苗接种所赋予的免疫力可以独立于抗体而抵御 SARS-CoV-2 的攻击。我们的研究结果使用了包括新型人/小鼠 ACE2 混合体在内的三种不同模型，结果强调 CD8 ⁺ T 细胞对于对抗严重感染至关重要，而 CD4 ⁺ T 细胞有助于治疗较轻的病例，而干扰素-γ 在这种不依赖于抗体的防御。这些发现强调了 T 细胞反应在疫苗开发中的重要性，敦促人们对保护性免疫产生更广泛的认识，而不仅仅是抗体。