tetano
Editor, Senior Moderator
Mol Ther
. 2026 Jun 15:S1525-0016(26)00504-6.
doi: 10.1016/j.ymthe.2026.06.027. Online ahead of print.
Increasing Intrinsic Protein Disorder Improves CD8+ Immunogenicity for a SARS CoV2 Vaccine Candidate Antigen
Li Wan[SUP] 1 [/SUP], Bingxian Xie[SUP] 2 [/SUP], Masahiro Shuda[SUP] 1 [/SUP], Maura E O'Malley[SUP] 3 [/SUP], Carlos J Camacho[SUP] 3 [/SUP], Greg M Delgoffe[SUP] 2 [/SUP], Yuan Chang[SUP] 4 [/SUP], Patrick S Moore[SUP] 5 [/SUP]
Affiliations
CD8+ T cell targeting of the conserved SARS CoV2 RNA-dependent RNA polymerase (RdRp, nsp12) may offer a means for cross-protection against diverse coronavirus strains. Native RdRp, however, displays primary sequence immunoevasion (PSI) that inhibits in cis RdRp-derived peptide presentation on MHC I . We show that this is related to the highly-ordered nature of RdRp, which can be reversed by dividing RdRp into two intrinsically disordered, complementary sub-fragments (RdRp[SUP]Frag[/SUP]). RdRp[SUP]Frag[/SUP] possesses nearly all of the native peptide epitopes found in the full-length protein. Using a syngeneic MC38 cancer cell mouse model, cellular RdRp[SUP]Frag[/SUP] expression suppressed tumor growth and markedly increased specific tumor-infiltrating effector T lymphocytes as measured by tetramer assays. mRNA vaccination with WA-1 strain RdRp[SUP]Frag[/SUP] elicited more potent CD8+ T cell responses than native WA-1 strain RdRp mRNA but did not significantly prevent acute Omicron SARS CoV2 early infection in transgenic hamster challenge studies. These findings suggest highly-ordered protein evolution may be an unrecognized PSI mechanism used by viruses to evade T cell recognition. Increasing antigen intrinsic disorder by protein subfragmentation may improve antigenicity for antiviral or antitumor vaccine candidates.
. 2026 Jun 15:S1525-0016(26)00504-6.
doi: 10.1016/j.ymthe.2026.06.027. Online ahead of print.
Increasing Intrinsic Protein Disorder Improves CD8+ Immunogenicity for a SARS CoV2 Vaccine Candidate Antigen
Li Wan[SUP] 1 [/SUP], Bingxian Xie[SUP] 2 [/SUP], Masahiro Shuda[SUP] 1 [/SUP], Maura E O'Malley[SUP] 3 [/SUP], Carlos J Camacho[SUP] 3 [/SUP], Greg M Delgoffe[SUP] 2 [/SUP], Yuan Chang[SUP] 4 [/SUP], Patrick S Moore[SUP] 5 [/SUP]
Affiliations
- PMID: 42298822
- DOI: 10.1016/j.ymthe.2026.06.027
CD8+ T cell targeting of the conserved SARS CoV2 RNA-dependent RNA polymerase (RdRp, nsp12) may offer a means for cross-protection against diverse coronavirus strains. Native RdRp, however, displays primary sequence immunoevasion (PSI) that inhibits in cis RdRp-derived peptide presentation on MHC I . We show that this is related to the highly-ordered nature of RdRp, which can be reversed by dividing RdRp into two intrinsically disordered, complementary sub-fragments (RdRp[SUP]Frag[/SUP]). RdRp[SUP]Frag[/SUP] possesses nearly all of the native peptide epitopes found in the full-length protein. Using a syngeneic MC38 cancer cell mouse model, cellular RdRp[SUP]Frag[/SUP] expression suppressed tumor growth and markedly increased specific tumor-infiltrating effector T lymphocytes as measured by tetramer assays. mRNA vaccination with WA-1 strain RdRp[SUP]Frag[/SUP] elicited more potent CD8+ T cell responses than native WA-1 strain RdRp mRNA but did not significantly prevent acute Omicron SARS CoV2 early infection in transgenic hamster challenge studies. These findings suggest highly-ordered protein evolution may be an unrecognized PSI mechanism used by viruses to evade T cell recognition. Increasing antigen intrinsic disorder by protein subfragmentation may improve antigenicity for antiviral or antitumor vaccine candidates.