延迟强化成本刺激可提高小鼠 mRNA 疫苗的疗效。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-17 DOI:10.1172/JCI183973
Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
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引用次数: 0

摘要

mRNA 疫苗已在 COVID-19 大流行期间显示出疗效,目前正在对多种疾病进行研究。然而,人们对免疫反应的持久性仍然存在担忧,而且接种疫苗的个体中突破性感染的发生率很高,这凸显了改进 mRNA 疫苗的必要性。在这项研究中,我们研究了通过 TNF 受体超家族成员 4-1BB 加强成本刺激对 mRNA 疫苗诱导的免疫反应的影响。我们首先用 mRNA 疫苗免疫小鼠,然后在接种后的不同时间点用 4-1BB costimulatory 抗体强化 4-1BB 通路。与之前的研究一致,在接种当天加强4-1BB成本刺激并不会大幅提高疫苗反应。然而,在疫苗接种后第4天(4-1BB表达水平最高)加强4-1BB成本刺激,可显著改善CD8 T细胞应答,增强对病原体挑战的保护。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 TNF 受体超家族中另一种激动分子 OX40 的时间依赖效应。这些研究结果表明,延迟加强成本刺激可能会产生免疫学益处,为开发更有效的 mRNA 疫苗治疗传染病和癌症提供了启示。
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Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice.

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.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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