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A polytope DNA vaccine elicits multiple effector and memory CTL responses and protects against human papillomavirus 16 E7-expressing tumour

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Abstract

Vaccine-induced CD8 T cells directed to tumour-specific antigens are recognised as important components of protective and therapeutic immunity against tumours. Where tumour antigens have pathogenic potential or where immunogenic epitopes are lost from tumours, development of subunit vaccines consisting of multiple individual epitopes is an attractive alternative to immunising with whole tumour antigen. In the present study we investigate the efficacy of two DNA-based multiepitope (‘polytope’) vaccines containing murine (H-2b) and human (HLA-A*0201)–restricted epitopes of the E7 oncoprotein of human papillomavirus type 16, in eliciting tumour-protective cytotoxic T-lymphocyte (CTL) responses. We show that the first of these polytopes elicited powerful effector CTL responses (measured by IFN-γ ELISpot) and long-lived memory CTL responses (measured by functional CTL assay and tetramers) in immunised mice. The responses could be boosted by immunisation with a recombinant vaccinia virus expressing the polytope. Responses induced by immunisation with polytope DNA alone partially protected against infection with recombinant vaccinia virus expressing the polytope. Complete protection was afforded against challenge with an E7-expressing tumour, and reduced growth of nascent tumours was observed. A second polytope differing in the exact composition and order of CTL epitopes, and lacking an inserted endoplasmic reticulum targeting sequence and T-helper epitope, induced much poorer CTL responses and failed to protect against tumour challenge. These observations indicate the validity of a DNA polytope vaccine approach to human papillomavirus E7–associated carcinoma, and underscore the importance of design in polytope vaccine construction.

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Acknowledgements

The work was funded by the National Health and Medical Research Council (Australia) and Queensland Cancer Fund. Dr Andreas Suhrbier provided pSTMPDV. We thank Ms Donna West and her staff for excellent animal husbandry. Publication number 207 of the Sir Alberts Sakzewski Virus Research Centre.

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Authors and Affiliations

  1. Sir Albert Sakzewski Virus Research Centre, Clinical Medical Virology Centre, Royal Children’s Hospital, University of Queensland, Herston Road, Herston, Brisbane, QLD 4029, Australia

    Tracy Doan, Karen Herd & Robert W. Tindle

  2. John Curtin School of Medical Research, Australian National University, Canberra, Australia

    Ian Ramshaw & Scott Thomson

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  1. Tracy Doan
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  2. Karen Herd
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Correspondence to Robert W. Tindle.

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Doan, T., Herd, K., Ramshaw, I. et al. A polytope DNA vaccine elicits multiple effector and memory CTL responses and protects against human papillomavirus 16 E7-expressing tumour. Cancer Immunol Immunother 54, 157–171 (2005). https://doi.org/10.1007/s00262-004-0544-6

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