DNA and modified vaccinia Ankara prime–boost vaccination generates strong CD8+ T cell responses against minor histocompatibility antigen HA‐1

• Published in: British journal of haematology Vol. 195; no. 3; pp. 433 - 446
• Main Authors: Eldershaw, Suzy A., Pearce, Hayden, Inman, Charlotte F., Piper, Karen P., Abbotts, Ben, Stephens, Christine, Nicol, Samantha, Croft, Wayne, Powell, Richard, Begum, Jusnara, Taylor, Graham, Nunnick, Jane, Walsh, Donna, Sirovica, Mirjana, Saddique, Shamyla, Nagra, Sandeep, Ferguson, Paul, Moss, Paul, Malladi, Ram
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2021
• Subjects: Adult; Aged; Allografts; Antigens; Antigens, Neoplasm - immunology; CD8 antigen; Cytotoxicity; Cytotoxicity, Immunologic; Deoxyribonucleic acid; DNA; DNA vaccines; Epitopes - immunology; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Graft vs Leukemia Effect - immunology; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; HLA-A2 Antigen - immunology; Humans; Immunization; Immunogenicity; Immunogenicity, Vaccine; Immunologic Memory; immunotherapy; Leukemia; Lymphocytes; Lymphocytes T; Male; Middle Aged; Minor histocompatibility antigens; Minor Histocompatibility Antigens - immunology; Oligopeptides - immunology; Peptides; Peptides - immunology; Receptors, Antigen, T-Cell, alpha-beta - immunology; Stem cell transplantation; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; Vaccination; vaccines; Vaccines, Attenuated; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use; Vaccinia; Vaccinia virus - immunology; Viral Vaccines - immunology; Viral Vaccines - therapeutic use; Ankara Turkey; Turkey; DNA vaccines; vaccines; stem cell transplantation; immunotherapy
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.17495

Summary Allogeneic immune responses underlie the graft‐versus‐leukaemia effect of stem cell transplantation, but disease relapse occurs in many patients. Minor histocompatibility antigen (mHAg) peptides mediate alloreactive T cell responses and induce graft‐versus‐leukaemia responses when expressed on patient haematopoietic tissue. We vaccinated nine HA‐1‐negative donors against HA‐1 with a ‘prime–boost’ protocol of either two or three DNA ‘priming’ vaccinations prior to ‘boost’ with modified vaccinia Ankara (MVA). HA‐1‐specific CD8+ T cell responses were observed in seven donors with magnitude up to 1·5% of total CD8+ T cell repertoire. HA‐1‐specific responses peaked two weeks post‐MVA challenge and were measurable in most donors after 12 months. HA‐1‐specific T cells demonstrated strong cytotoxic activity and lysed target cells with endogenous HA‐1 protein expression. The pattern of T cell receptor (TCR) usage by HA‐1‐specific T cells revealed strong conservation of T cell receptor beta variable 7‐9 (TRBV7‐9) usage between donors. These findings describe one of the strongest primary peptide‐specific CD8+ T cell responses yet recorded to a DNA–MVA prime–boost regimen and this may reflect the strong immunogenicity of mHAg peptides. Prime–boost vaccination in donors or patients may prove of substantial benefit in boosting graft‐versus‐leukaemia responses.