Aunins Emily A, Phan Anthony T, Alameh Mohamad-Gabriel, Dwivedi Garima, Cruz-Morales Elisa, Christian David A, Tam Ying, Bunkofske Molly E, Peñafiel Anabel Zabala, O'Dea Keenan M, Merolle Maria, Furey Colleen, Scott Phillip, Vonderheide Robert H, Hensley Scott E, Kedl Ross M, Weissman Drew, Hunter Christopher A
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sci Immunol. 2025 Jun 6;10(108):eads1328. doi: 10.1126/sciimmunol.ads1328.
Optimizing vaccine design to induce CD8 T cell responses has been challenging, but lipid nanoparticle (LNP)-encapsulated mRNA vaccines effectively generate CD8 T cell memory. Interleukin-12 (IL-12) supports CD8 T cell expansion and acquisition of effector function, but the role of IL-12 in the generation of CD8 T responses to mRNA vaccination is unclear. Here, we determine that endogenous IL-12 is not required for CD8 T cell responses to mRNA-LNP vaccination. We assessed the adjuvant activity of an mRNA-LNP encapsulating a codon-optimized mRNA that encodes both subunits of IL-12 (LNP-IL-12). Coadministration of LNP-IL-12 with ovalbumin (OVA) mRNA-LNPs enhanced CD8 T cell expansion and effector function and expanded circulating, effector, and tissue-resident memory CD8 T cells. LNP-IL-12 increased CD8 T cell responses against SARS-CoV-2 and influenza virus antigens and improved protection against -OVA and B16F0-OVA melanoma. Thus, modification of mRNA-LNP formulations to include a cytokine mRNA provides a strategy to enhance CD8 T cell-mediated protection.
优化疫苗设计以诱导CD8 T细胞反应一直具有挑战性，但脂质纳米颗粒（LNP）包裹的mRNA疫苗能有效产生CD8 T细胞记忆。白细胞介素-12（IL-12）支持CD8 T细胞扩增并获得效应功能，但IL-12在mRNA疫苗接种诱导的CD8 T细胞反应中的作用尚不清楚。在此，我们确定内源性IL-12对于mRNA-LNP疫苗接种诱导的CD8 T细胞反应并非必需。我们评估了一种包裹编码IL-12两个亚基的密码子优化mRNA的mRNA-LNP（LNP-IL-12）的佐剂活性。将LNP-IL-12与卵清蛋白（OVA）mRNA-LNP共同给药可增强CD8 T细胞扩增和效应功能，并扩大循环、效应和组织驻留记忆CD8 T细胞。LNP-IL-12增强了针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和流感病毒抗原的CD8 T细胞反应，并改善了对OVA和B16F0-OVA黑色素瘤的保护作用。因此，对mRNA-LNP制剂进行修饰以包含细胞因子mRNA提供了一种增强CD8 T细胞介导的保护作用的策略。
