<b>Broadly cross-reactive mRNA COVID-19 vaccine encoding trimeric RBDs and NSP12 mitigates immune imprinting</b>

Journal article

The continuous evolution of SARS-CoV-2 variants, driven by mutations in the spike protein undermines viral recognition by antibodies elicited through prior infection or vaccination with the ancestral Wuhan strain. Original antigenic sin of SARS-CoV-2 ancestral virus or vaccine led to a weakened neutralizing antibody response against successive variants upon administration of an updated vaccine. On the contrary, T cells retain cross-reactivity thanks to the high density of conserved epitopes. We designed mRNA vaccines encoding single-chain heterotrimers of the receptor-binding domain (RBD) natural variants of interest (VOI), (RBD-VOI) and of phylogenetically informed consensus representing the major variant lineages RBD-consensus (RBD-Cons). We demonstrate a broad neutralizing activity against omicron subvariants and mitigated immune imprinting when RBD-Cons was used as a booster after conventional Wuhan spike priming. To enhance cellular immunity, we designed a second mRNA vaccine component encoding the viral polymerase NSP12 able to induce a cross-reactive T cell response to be combined with the heterotrimeric RBD vaccine. Our results offer a rational strategy for next-generation, imprinting-resistant vaccines.

Authors: De Chiara, A; Giachino, C; Pirillo, MF; Campanile, A; Pellino, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Molecular Therapy: Nucleic Acids
• Volume: 37
• Issue: 2
• Pages: 102918
• Article number: 102918
• Publication date: 2026-03-25
• Acceptance date: 2026-03-23
• DOI: 10.1016/j.omtn.2026.102918
• EISSN: 2162-2531
• ISSN: 2162-2531
• Pmid: 42023032
• Language: English
• Keywords: Rbd Trimer; Sars-cov-2; Mrna Vaccine; Omicron; Mt: Clinical Applications; Cross-neutralization; Antigenic Sin