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. 2025 Aug 25.
doi: 10.1038/s41551-025-01478-6. Online ahead of print.

A modular vaccine platform for optimized lipid nanoparticle mRNA immunogenicity

Zhenhao Fang #  1   2   3 , Valter S Monteiro #  4 , Changin Oh  1 , Kawthar Al Janabi  1   2   3   5 , Luciano Romero  1   2   3   5 , Nabihah Ahsan  1   2   3   5 , Luojia Yang  1   2   3   6 , Lei Peng  1   2   3 , Daniel DiMaio  1   7   8   9 , Carolina Lucas  10   11   12 , Sidi Chen  13   14   15   16   17   18   19   20   21
Affiliations

A modular vaccine platform for optimized lipid nanoparticle mRNA immunogenicity

Zhenhao Fang et al. Nat Biomed Eng. .

Abstract

Certain messenger RNA antigens in mRNA vaccines elicit an insufficient immune response due to challenges in cell surface translocation (CST) of the antigens. Here we develop a modular vaccine platform (MVP) to enhance the immunogenicity of challenging mRNA antigens by optimizing antigen expression and presentation. MVPs enable the modular assembly of chimeric antigens. Our platform comprises diverse modules capable of generating >2,500 combinations with any antigen and displaying distinct antigen epitopes on the cell surface. We quantify the CST efficacy of various modules using multiple antigens, including the mpox virus (MPXV) proteins A29, M1R and A35R, and compare chimeric antigen surface expression in multiple cell lines. Using MPXV as a model, we identify optimal modules that enhance the CST of multiple MPXV antigens, improving the immune response of lipid nanoparticle mRNAs and protecting against lethal viral challenge. With these effective CST modules, we further demonstrate the generalizability of MVP by optimizing additional mRNA antigens, including the human papillomavirus 16 proteins E6 and E7 and the varicella zoster virus glycoprotein gE. This platform is applicable to any antigen of interest, facilitating the development of mRNA vaccines against challenging targets.

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Conflict of interest statement

Competing interests: S.C. is a (co)founder of EvolveImmune Therapeutics, Cellinfinity Bio, MagicTime Medicine and Chen Consulting, all unrelated to this study. A patent application related to this study has been filed by Yale University. The patent titled ‘Compositions and Methods for Enhancement of mRNA Vaccine Performance and Vaccination Against Mpox’ (PCT International Appl. No. PCT/US2023/081090) covers the related biotechnology. The other authors declare no competing interests.

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