已经描述了严重急性呼吸综合征冠状病毒2 (SARS-CoV-2) 感染后疫苗接种的保护血清学相关性("疫苗突破")。然而，关于疫苗突破的保护T细胞相关性一直没有完全定义清楚，尤其是CD4+和CD8+ T细胞的具体贡献。本研究在英国PITCH(医护工作者中的细胞保护免疫)队列研究中招募了279名志愿者，并在其中进行了一个套嵌案例对照研究。病例组是在Delta优势时期接种两剂疫苗后进行SARS-CoV-2 PCR或侧向流动装置(LFD)检测阳性的个体(n = 32)，而对照组是在此期间没有报告阳性检测结果，也没有在此期间实施抗核衣壳蛋白G(IgG)血清转换的个体(n = 247)。在疫苗接种之前曾感染过SARS-CoV-2与较低的疫苗突破几率相关联。在第二剂疫苗接种后28天，即突破发生之前，我们观察到未来的病例组在祖先峰(S)和受体结合结构域（RBD）特异性IgG滴度以及S1和S2特异性T细胞干扰素γ（IFNγ）反应方面较对照组更低，尽管当我们根据接种前的感染状况对个体进行分层时，这些差异并不持久。在感染前没有感染的病例组和对照组的子集中，与对照组相比，疫苗突破病例的CD4+和CD8+ IFNγ和肿瘤坏死因子（TNF）对Delta S肽的反应较低。对于CD8+反应而言，这种差异似乎是由病例组对Delta肽与祖先肽的反应降低所驱动的；而对照组则没有观察到对Delta肽的这种反应降低。我们的研究结果支持了T细胞在Delta突破感染中的保护作用。 重要性：定义SARS-CoV-2疫苗突破感染的保护相关性有助于疫苗政策的制定，包括加强剂次和未来疫苗设计。现有研究表明了保护的体液相关性，但是T细胞在保护中的作用仍不清楚。在这项研究中，我们探讨了与英国医护工作者群体中Delta变异株疫苗突破感染相关的抗体和T细胞免疫反应。我们证明了支持CD4+和CD8+ T细胞以及针对Delta疫苗突破感染的抗体的作用的证据。此外，我们的结果表明，交叉反应性T细胞在疫苗突破中可能起到了潜在的作用。

Serological correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after vaccination ("vaccine breakthrough") have been described. However, T cell correlates of protection against breakthrough are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. Here, 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK cohort study were enrolled in a nested case-control study. Cases were those who tested SARS-CoV-2 PCR or lateral flow device (LFD) positive after two vaccine doses during the Delta-predominant era (n = 32), while controls were those who did not report a positive test or undergo anti-nucleocapsid immunoglobulin G (IgG) seroconversion during this period (n = 247). Previous SARS-CoV-2 infection prior to vaccination was associated with reduced odds of vaccine breakthrough. Using samples from 28 d after the second vaccine dose, before all breakthroughs occurred, we observed future cases had lower ancestral spike (S)- and receptor binding domain-specific IgG titers and S1- and S2-specific T cell interferon gamma (IFNγ) responses compared with controls, although these differences did not persist when individuals were stratified according to previous infection status before vaccination. In a subset of matched infection-naïve cases and controls, vaccine breakthrough cases had lower CD4+ and CD8+ IFNγ and tumor necrosis factor (TNF) responses to Delta S peptides compared with controls. For CD8+ responses, this difference appeared to be driven by reduced responses to Delta compared with ancestral peptides among cases; this reduced response to Delta peptides was not observed in controls. Our findings support a protective role for T cells against Delta breakthrough infection. IMPORTANCE Defining correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine breakthrough infection informs vaccine policy for booster doses and future vaccine designs. Existing studies demonstrate humoral correlates of protection, but the role of T cells in protection is still unclear. In this study, we explore antibody and T cell immune responses associated with protection against Delta variant vaccine breakthrough infection in a well-characterized cohort of UK Healthcare Workers (HCWs). We demonstrate evidence to support a role for CD4+ and CD8+ T cells as well as antibodies against Delta vaccine breakthrough infection. In addition, our results suggest a potential role for cross-reactive T cells in vaccine breakthrough.