Synergistic effect of nucleoside modification and ionizable lipid composition on translation and immune responses to mRNA vaccines
Lipid nanoparticle (LNP) components can impact the safety and immunogenicity of mRNA vaccines. Here we examine the mechanisms contributing to the performance of mRNA-LNP vaccines by exploring the impact of nucleoside modifications and LNP components on translational efficiency, innate immune activation, and immunogenicity. Our data reveals several molecular and immunological parameters affected by nucleoside modification including a synergistic effect of the mRNA and ionizable lipid composition on the immune activation triggered by the mRNA-LNP formulation. Our results indicate changes in the LNP composition, independent from whether the mRNA is modified or unmodified, caused differential expression of genes associated with innate and antiviral immunity. We believe these findings offer valuable insights into mRNA vaccine function and offer strategies for enhancing vaccine efficacy and reducing the reactogenicity of next generation mRNA vaccines.
Authors
- Sudha Chivukula (ORCID: https://orcid.org/0000-0002-1832-1465)
- Brian Schanen (ORCID: https://orcid.org/0000-0001-6528-4399)
- Allison L. Dauner (ORCID: https://orcid.org/0000-0001-7346-7355)
- Alisa Zhilin-Roth
- Anusha Dias
- Azadeh Bahadoran (ORCID: https://orcid.org/0000-0002-3803-9491)
- Mihaela Babiceanu
- Robert A. Amezquita (ORCID: https://orcid.org/0000-0001-6868-7193)
- Hillary Danz
- Daniel G. Anderson (ORCID: https://orcid.org/0000-0001-5629-4798)
- Kevin F. Gilbert
- Robert Jordan Ontiveros
- Mona Motwani (ORCID: https://orcid.org/0000-0003-0912-5478)
- Christina Khoo (ORCID: https://orcid.org/0000-0001-6149-3820)
- Nicholas Clark
- Janhavi Nadkarni
- Andrew Kettring (ORCID: https://orcid.org/0000-0002-8963-4039)
- Monica Wu
- Shrirang Karve (ORCID: https://orcid.org/0000-0002-9433-3089)
- Ana Kume
- Frank DeRosa
- Shraddha Sharma
- Bin Lu (ORCID: https://orcid.org/0000-0001-7184-2211)
- Christina Lee (ORCID: https://orcid.org/0000-0002-9039-2516)
- Wei Zong (ORCID: https://orcid.org/0000-0002-7399-7687)
- Yanhua Yan (ORCID: https://orcid.org/0000-0001-5158-0517)
- Xiaobo Gu (ORCID: https://orcid.org/0000-0001-5116-2294)
- Edgar A. Reyes
- Omkar Chaudhary
- Alex Shumate
Institutions
- Orlando Health (US)
- Sanofi (France) (FR)
- Sanofi (United States) (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- npj Vaccines
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41541-025-01263-1
- Citations
- 5
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Sanofi