mRNA 疫苗在 COVID-19 大流行期间已证明有效，目前正在针对多种疾病进行研究。然而，人们对免疫反应持久性的担忧依然存在，而且接种疫苗的个体中突破性感染的高发生率凸显了对改进 mRNA 疫苗的需求。在这项研究中，我们研究了通过 4-1BB（TNF 受体超家族成员）加强共刺激对 mRNA 疫苗引发的免疫反应的影响。我们首先用 mRNA 疫苗对小鼠进行免疫，然后用 4-1BB 共刺激抗体进行治疗，以在疫苗接种后的不同时间点加强 4-1BB 途径。与之前的研究一致，在疫苗接种当天加强 4-1BB 共刺激并没有导致疫苗反应的实质性改善。然而，在疫苗接种后第 4 天（此时 4-1BB 表达水平最高）加强 4-1BB 共刺激，可显着改善 CD8 T 细胞反应，从而增强对病原体攻击的保护。在治疗性癌症疫苗模型中观察到类似的临床益处。我们还报告了 OX40（TNF 受体超家族的另一种共刺激分子）的时间依赖性效应。这些发现表明，共刺激的延迟强化可能会产生免疫学益处，为开发针对传染病和癌症的更有效的 mRNA 疫苗提供了见解。

mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines. We first immunized mice with mRNA vaccines, followed by treatment with 4-1BB costimulatory antibodies to reinforce the 4-1BB pathway at different timepoints post-vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement of vaccine responses. However, reinforcing 4-1BB costimulation at day 4 post-vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement of CD8 T cell responses associated with enhanced protection against pathogen challenges. A similar clinical benefit was observed in a therapeutic cancer vaccine model. We also report time-dependent effects with OX40, another costimulatory molecule of the TNF receptor superfamily. These findings demonstrate that delayed reinforcement of costimulation may exert an immunologic benefit, providing insights for the development of more effective mRNA vaccines for infectious diseases and cancer.