Polish Scientists Unveil Groundbreaking Mechanism to Boost mRNA Vaccine Efficiency
In a landmark study published in Nature on April 16, 2025, researchers from the International Institute of Molecular and Cell Biology in Warsaw (IIMCB) have revealed a novel biological mechanism that significantly enhances the stability and efficacy of mRNA-based therapies, including vaccines. This research marks a pivotal advancement in the understanding of mRNA molecules’ lifecycle within human cells and holds immense potential to revolutionize treatments against infectious diseases and cancer.
The global spotlight on mRNA technology during the COVID-19 pandemic underscored its transformative power, yet it also highlighted inherent limitations—most notably, the inherent instability of mRNA molecules. Unlike DNA, mRNA is transient by nature, rapidly degrading inside cells, which limits the duration its therapeutic instructions can be executed. This instability, although not compromising safety, curtails the effectiveness and longevity of mRNA-based drugs. The Polish team’s research focused on the molecular underpinnings that dictate this stability, with particular attention to the poly(A) tail—a string of adenine nucleotides appended to mRNA molecules.
The poly(A) tail is crucial because it safeguards mRNA from premature degradation and modulates its translation efficiency into proteins. Despite its importance, the detailed dynamics of poly(A) tail changes, especially in synthetic mRNA used in vaccines, had remained elusive. Using cutting-edge nanopore sequencing technology, the researchers directly examined the sequence and length of poly(A) tails in the mRNA used in the two dominant COVID-19 vaccines: Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax.
Nanopore sequencing, distinct from traditional methods, allows the direct, real-time reading of RNA molecules, including their poly(A) tails, without conversion to complementary DNA. This technological leap enabled the team to observe how mRNA’s poly(A) tails evolve once inside cells post-vaccination—a process previously impossible to monitor with such precision. To analyze the extensive data generated by nanopore sequencing, the scientists developed bespoke computational software, expertly engineered to track and interpret the metabolism of therapeutic mRNA molecules at unprecedented resolution.
One of the most groundbreaking discoveries was the identification of the enzyme TENT5A as a critical player in enhancing mRNA stability. Contrary to prior assumptions that poly(A) tails only shorten over time, TENT5A actively adds adenines to elongate these tails within cells. This re-adenylation process effectively ‘resets the clock’ on mRNA degradation, allowing the molecule to persist and function for extended periods. "We liken it to flipping over an hourglass," explains Dr. Paweł Krawczyk, a computational biologist involved in the study. "By extending the poly(A) tail, TENT5A buys extra time for the mRNA to produce proteins—boosting vaccine efficacy."
Functionally, the enzyme TENT5A’s activity translates into longer-lasting antigen production. After mRNA from vaccines is taken up by immune cells, it directs these cells to produce viral proteins that stimulate the immune system. By prolonging this protein synthesis phase, TENT5A amplifies the immune system’s ability to recognize and combat the actual virus upon exposure.
Delving deeper, the team pinpointed macrophages—a type of immune cell responsible for engulfing pathogens and cellular debris—as the key cell type where this poly(A) tail extension takes place. Upon vaccine administration, macrophages at the injection site internalize lipid-encapsulated mRNA and rely on TENT5A to stabilize these messenger molecules. Crucially, experiments showed that macrophages deficient in TENT5A exhibit reduced capacity to sustain antigen production, leading to diminished vaccine efficacy.
This insight dramatically reshapes the understanding of immune response mechanics in mRNA vaccination. Macrophages not only serve as frontline defenders but also as essential bio-factories whose enzymatic machinery can profoundly influence therapeutic outcomes. "Our findings underscore the centrality of macrophages and their enzymatic environment in shaping the durability of mRNA therapeutics," notes Dr. Seweryn Mroczek.
Despite this breakthrough, the researchers emphasize that mRNA biology remains a complex frontier. The dynamics of mRNA metabolism, interactions with cellular enzymes, and the implications for diverse cell types require further exploration. Capitalizing on their foundational work, the IIMCB team plans to advance this research through the Virtual Research Institute, supported by the Polish Science Fund, aiming to innovate next-generation mRNA medicines with optimized stability and therapeutic profiles.
The collaborative nature of the work reflects the vibrant scientific ecosystem at Warsaw’s Ochota Campus, bringing together expertise from the International Institute of Molecular and Cell Biology, the University of Warsaw’s Faculties of Biology and Physics, the Medical University of Warsaw, and the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences. This interdisciplinary synergy was vital in navigating the intricate molecular details unraveled in the study.
This publication marks a historic milestone—not only for its scientific content but also for its provenance. It is the first exclusive life sciences article authored solely by Polish institutions to appear in Nature in the 21st century. Prof. Andrzej Dziembowski, the project’s lead, reflects on the arduous journey to publication, initiated in mid-2021 amid the pandemic. Rigorous reviews and successive data submissions culminated in this widely recognized scientific contribution.
Looking beyond the laboratory, the study has already catalyzed educational innovation. The University of Warsaw’s Faculty of Medicine is launching a Master’s program titled Biological Therapeutics in the 2025/2026 academic year. Co-founded by IIMCB, this program aims to nurture the next generation of scientists and biotechnologists equipped to develop and implement mRNA-based therapies, bridging fundamental research and clinical application.
Ultimately, this research illuminates new paths to leverage the body’s own enzymatic toolkit—specifically TENT5A—to engineer mRNA molecules that are not only safe but functionally superior. Such advancements could lead to vaccines and therapies that require fewer doses, last longer, and are more robust against emerging variants and diseases. With mRNA technology poised to shape the future of medicine, the Polish team’s work stands as a beacon of scientific excellence and innovation on the global stage.
Subject of Research:
mRNA stability and enhancement mechanisms in therapeutic applications, focusing on the role of enzyme TENT5A in poly(A) tail elongation.
Article Title:
Re-adenylation by TENT5A enhances efficacy of SARS-CoV-2 mRNA vaccines
News Publication Date:
April 16, 2025
Web References:
DOI: 10.1038/s41586-025-08842-1
Image Credits:
International Institute of Molecular and Cell Biology in Warsaw (IIMCB)
Keywords:
mRNA vaccines, poly(A) tail, TENT5A enzyme, mRNA stability, SARS-CoV-2, nanopore sequencing, macrophages, mRNA therapeutics, immunology, vaccine efficacy, RNA biology, molecular biology
