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 time points after vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement in vaccine responses. However, reinforcing 4-1BB costimulation on day 4 after vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement in 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.

中文翻译：

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延迟增强共刺激提高了 mRNA 疫苗在小鼠中的疗效


mRNA 疫苗在 COVID-19 大流行期间已证明有效，目前正在研究多种疾病。然而，人们对免疫反应的持久性的担忧挥之不去，接种疫苗的个体中突破性感染的高发生率凸显了改进 mRNA 疫苗的必要性。在这项研究中，我们调查了通过 4-1BB（TNF 受体超家族的成员）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 疫苗免疫小鼠，然后用 4-1BB 共刺激抗体治疗，以加强接种疫苗后不同时间点的 4-1BB 通路。与之前的研究一致，在接种疫苗当天加强 4-1BB 共刺激并未导致疫苗反应的实质性改善。然而，在接种疫苗后第 4 天，当 4-1BB 表达水平最高时，加强 4-1BB 共刺激，导致 CD8⁺ T 细胞反应的显着改善，与增强对病原体挑战的保护相关。在治疗性癌症疫苗模型中观察到类似的临床益处。我们还报道了 OX40 的时间依赖性效应，OX40 是 TNF 受体超家族的另一种共刺激分子。这些发现表明，延迟加强共刺激可能会发挥免疫学益处，为开发更有效的传染病和癌症 mRNA 疫苗提供见解。