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Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice
Sarah Sanchez, … , Slim Fourati, Pablo Penaloza-MacMaster
Sarah Sanchez, … , Slim Fourati, Pablo Penaloza-MacMaster
Published October 21, 2024
Citation Information: J Clin Invest. 2024;134(24):e183973. https://doi.org/10.1172/JCI183973.
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Research Article Immunology Article has an altmetric score of 19

Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice

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Abstract

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.

Authors

Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster

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Figure 2

CD8+ T cell subset differentiation after reinforcing 4-1BB costimulation.

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CD8+ T cell subset differentiation after reinforcing 4-1BB costimulation...
Experimental outline was similar to that in Figure 1A. On day 7 after vaccination, splenic CD8+ T cells were MACS sorted. Subsequently, live CD8+CD44+KbVL8 tetramer+ cells were FACS-purified to approximately 99% purity and used for bulk RNA-seq. (A) PCA shows transcriptional clustering. (B) Heatmap showing row-standardized expression of selected proliferation and apoptotic genes. (C) Heatmap showing row-standardized expression of selected cell cycle (top) and kinesins (bottom) genes. (D) Heatmap showing row-standardized expression of selected activation genes. (E) Heatmap showing row-standardized expression of selected effector genes. (F) GSEA plot showing enrichment of effector genes. (G) Validation of gene expression results at the protein level. Representative FACS plots showing the frequencies of virus-specific CD8+ T cells (KbVL8+) that differentiate into effector, effector memory, and central memory T cell subsets. (H) Pie diagrams showing CD8+ T cell subsets. (I–K) Numbers of central memory, effector memory, and effector CD8+ T cells. All data are from tetramer+ (KbVL8+) cells from spleen. RNA-seq data are from 1 experiment, with n = 4 per group. Data in panel H are from 1 representative experiment, with n = 4 per group; the experiment was performed twice with similar results. All other data are from 2 experiments, with n = 4–5 per group/experiment. Indicated P values in I–K were calculated by the Mann-Whitney test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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