Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T cell immune memory is critical for continued protection against severe COVID-19. We examined T cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T cell memory responses in healthcare workers in South Africa (n = 39) who were vaccinated and experienced at least one SARS-CoV-2 infection. Spike-specific T cells are highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant nucleocapsid and membrane-specific T cells are detectable in most participants. The bulk of SARS-CoV-2-specific T cell responses have an early-differentiated phenotype, explaining their persistent nature. Overall, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的持续进化已经产生了在全球占主导地位的重组 Omicron 谱系 (XBB.1)，以及超突变变体 (BA.2.86) 的出现。在这种情况下，持久且交叉反应的 T 细胞免疫记忆对于持续防御严重的 COVID-19 至关重要。自 Omicron 首次出现以来大约 1.5 年，我们检查了 T 细胞对 SARS-CoV-2 的反应。我们描述了南非医护人员 (n = 39) 接种疫苗并至少经历过一次 SARS-CoV-2 感染后的持续 CD4+ 和 CD8+ 尖峰特异性 T 细胞记忆反应。刺突特异性 T 细胞与所有测试的 Omicron 变体（包括 BA.2.86）具有高度交叉反应性。在大多数参与者中都可以检测到丰富的核衣壳和膜特异性 T 细胞。大多数 SARS-CoV-2 特异性 T 细胞反应具有早期分化的表型，这解释了它们的持久性。总体而言，混合免疫导致在大流行开始 3.5 年后明显出现刺突和非刺突 T 细胞的积累，并保留了对高度突变的 SARS-CoV-2 变体的识别。