: 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.
Broadly cross-reactive mRNA COVID-19 vaccine encoding trimeric RBDs and NSP12 mitigates immune imprinting / De Chiara, A., Giachino, C., Pirillo, M.F., Campanile, A., Pellino, E., Gallinaro, A., Froechlich, G., Falce, C., Scognamiglio, A., Totaro, S., Liguori, M.V., Peltrini, R., De Simone, A., Capone, S., Pietro, Z., Negri, D., Cara, A., Nicosia, A., Sasso, E.. - In: MOLECULAR THERAPY NUCLEIC ACIDS. - ISSN 2162-2531. - 37:2(2026). [10.1016/j.omtn.2026.102918]
Broadly cross-reactive mRNA COVID-19 vaccine encoding trimeric RBDs and NSP12 mitigates immune imprinting
Giachino C.;Pellino E.;Gallinaro A.;Froechlich G.;Totaro S.;Liguori M. V.;De Simone A.;Nicosia A.;Sasso E.
Ultimo
2026
Abstract
: 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
