T cell responses play an important role in protection against beta-coronavirus infections, including SARS-CoV-2, where they associate with decreased COVID-19 disease severity and duration. To enhance T cell immunity across epitopes infrequently altered in SARS-CoV-2 variants, we designed BNT162b4, an mRNA vaccine component that is intended to be combined with BNT162b2, the spike-protein-encoding vaccine. BNT162b4 encodes variant-conserved, immunogenic segments of the SARS-CoV-2 nucleocapsid, membrane, and ORF1ab proteins, targeting diverse HLA alleles. BNT162b4 elicits polyfunctional CD4⁺ and CD8⁺ T cell responses to diverse epitopes in animal models, alone or when co-administered with BNT162b2 while preserving spike-specific immunity. Importantly, we demonstrate that BNT162b4 protects hamsters from severe disease and reduces viral titers following challenge with viral variants. These data suggest that a combination of BNT162b2 and BNT162b4 could reduce COVID-19 disease severity and duration caused by circulating or future variants. BNT162b4 is currently being clinically evaluated in combination with the BA.4/BA.5 Omicron-updated bivalent BNT162b2 (NCT05541861).

T 细胞反应在预防 β 冠状病毒感染（包括 SARS-CoV-2）方面发挥着重要作用，它们与减少 COVID-19 疾病严重程度和持续时间有关。为了增强 T 细胞对 SARS-CoV-2 变体中不常改变的表位的免疫，我们设计了 BNT162b4，这是一种 mRNA 疫苗成分，旨在与 BNT162b2（刺突蛋白编码疫苗）结合使用。BNT162b4 编码 SARS-CoV-2 核衣壳、膜和 ORF1ab 蛋白的变异保守的免疫原性片段，针对不同的 HLA 等位基因。BNT162b4 单独或与 BNT162b2 共同给药时，可在动物模型中引发针对不同表位的多功能 CD4 ⁺和 CD8 ⁺ T 细胞反应，同时保留尖峰特异性免疫。重要的是，我们证明 BNT162b4 可以保护仓鼠免受严重疾病的侵害，并在受到病毒变体攻击后降低病毒滴度。这些数据表明，BNT162b2 和 BNT162b4 的组合可以减少由循环或未来变异引起的 COVID-19 疾病严重程度和持续时间。BNT162b4 目前正在与 BA.4/BA.5 Omicron 更新的二价 BNT162b2 (NCT05541861) 结合进行临床评估。