Sanchez Sarah, Dangi Tanushree, Awakoaiye Bakare, Lew Min Han, Irani Nahid, Fourati Slim, Penaloza-MacMaster Pablo
Department of Microbiology-Immunology, and.
Department of Medicine, Division of Allergy and Immunology, Feinberg School of Medicine and Center for Human Immunobiology, Northwestern University, Chicago, Illinois, USA.
J Clin Invest. 2024 Oct 21;134(24):e183973. doi: 10.1172/JCI183973.
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.
信使核糖核酸（mRNA）疫苗在新冠疫情期间已证明其有效性，目前正针对多种疾病进行研究。然而，人们对免疫反应的持久性仍存在担忧，而且接种疫苗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。在本研究中，我们研究了通过肿瘤坏死因子受体超家族成员4-1BB增强共刺激对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，然后在接种疫苗后的不同时间点用4-1BB共刺激抗体进行治疗，以增强4-1BB信号通路。与先前的研究一致，在接种疫苗当天增强4-1BB共刺激并没有使疫苗反应得到实质性改善。然而，在接种疫苗后第4天增强4-1BB共刺激，此时4-1BB表达水平最高，导致CD8+ T细胞反应有显著改善，并增强了对病原体攻击的保护作用。在治疗性癌症疫苗模型中也观察到了类似的临床益处。我们还报告了肿瘤坏死因子受体超家族的另一个共刺激分子OX40的时间依赖性效应。这些发现表明，延迟增强共刺激可能产生免疫学益处，为开发更有效的针对传染病和癌症的mRNA疫苗提供了思路。
