American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant SurgeonsJul 27, 2026

CD8 T-cell mRNA vaccines targeting viral proteins to prevent BK polyomavirus disease after kidney transplant

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 28, 2026

Abstract

BK polyomavirus (BKPyV) threatens kidney transplant outcomes by causing premature allograft failure.

Insufficient BKPyV-specific immunity is linked to the onset and persistence of BKPyV-DNAemia and nephropathy.
Cytotoxic CD8 T-cells targeting immunodominant 9mer-epitopes in the viral large tumor-antigen (LTag) are associated with protective immunity.
Vaccination strategies aimed at increasing LTag-specific T-cells were developed by reducing LTag to 143 residues and focusing on four clusters of immunodominant 9mers.
Transfection of human monocytes with LTAG1-mRNA and LTAG2-mRNA resulted in the expected immunogen sizes of 13.9kD and 15.2kD.
Higher CD8 T-cell responses were observed with LTAG2-mRNA compared to LTAG1-mRNA, indicating a robust effector memory phenotype.
LTag5-expanded T-cells demonstrated BKPyV-specific interferon-γ expression and cytotoxicity, suggesting effective immunogenic potential.

Simplified

BK polyomavirus (BKPyV) continues to threaten kidney transplantation outcomes by directly or indirectly causing premature allograft failure. Insufficient BKPyV-specific immunity underlies the onset and duration of BKPyV-DNAemia and nephropathy. BKPyV-specific T-cells have been correlated with protection and include cytotoxic CD8 T-cells targeting immunodominant 9mer-epitopes encoded in the viral large tumor-antigen (LTag). To develop vaccines increasing LTag-specific T-cells, we reduced the 695 amino acid-long LTag to 143 residues or less, comprising four clusters of immunodominant 9mers presented by 54 HLA-alleles. Prediction algorithms allowed to improve global coverage, AAY-linker placement, proteasomal processing, and solubility. Using a human cell culture vaccination model, transfection of adherent monocytes with LTAG1-mRNA and LTAG2-mRNA demonstrated the expected 13.9kD and 15.2kD immunogens, respectively. LTAG2-mRNA induced higher CD8 T-cell responses than LTAG1-mRNA, with an interferon-γ-positive CD62L-CD45RA-effector memory phenotype and cytotoxicity for BKPyV-replicating primary human renal tubular epithelial cells. We tested three additional candidates (LTAG3-mRNA, LTAG4-mRNA, LTAG5-mRNA) by changing AAY-linkers and extending immunogenic regions. The encoded immunogens were expressed and increased upon proteasome inhibitor treatment. LTag5-expanded T-cells showed BKPyV-specific interferon-γ expression and cytotoxicity. Our results demonstrate novel approaches to design modular mRNA-based vaccine candidates for clinical development of non-secreted antigens using BKPyV as a paradigm of non-enveloped DNA viruses.

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Competing interests

Competing interests Authors MMW, OMF, AG, KM, MW, and TS declare that they have no competing interests. HHH has received speaker honoraria from Astellas, Biotest, Eurofins, and Takeda, and consultant honoraria from Allovir, Anocca, Astra-Zeneca, Memo Therapeutics, Moderna, and Roche Diagnostics.

PubMed

CD8 T-cell mRNA vaccines targeting viral proteins to prevent BK polyomavirus disease after kidney transplant

Abstract

Full Text

Funding

Competing interests

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