Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Oosterhuis, Koen; Öhlschläger, Peter; van den Berg, Joost H.; Toebes, Mireille; Gomez, Raquel; Schumacher, Ton N.; Haanen, John B.

Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

Dateien

Oehlschlaeger_etal.pdfGröße: 5.33 MBDownloads: 733

Datum

2011

Autor:innen

Oosterhuis, Koen

Öhlschläger, Peter

van den Berg, Joost H.

Toebes, Mireille

Gomez, Raquel

Schumacher, Ton N.

Haanen, John B.

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie
Zukunftskolleg

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

International Journal of Cancer. 2011, 129(2), pp. 397-406. ISSN 0020-7136. eISSN 1097-0215. Available under: doi: 10.1002/ijc.25894

Zusammenfassung

To allow vaccination irrespective of HLA type, DNA vaccines encoding full-length antigens are required. However, here, we demonstrate that the immunogenicity of DNA vaccines encoding the full-length human papillomavirus (HPV) type 16 E7 and E6 proteins is highly reduced compared to vaccines encoding only the immunodominant epitope. Furthermore, the low remaining immunogenicity is essentially lost for both E7 and E6 when a nononcogenic "gene-shuffled" variant is utilized. To address these issues, we tested whether alterations in transgene design can restore the immunogenicity of full-length and gene-shuffled DNA vaccines. Remarkably, genetic fusion of E7 with tetanus toxin fragment C (TTFC) resulted in a dramatic increase in immunogenicity both for the full-length and the gene-shuffled version of E7. Moreover, the TTFC fusion vaccines were more immunogenic than a vaccine encoding a fusion of E7 and mycobacterial heat shock protein-70, which has recently been tested in a clinical trial. Interestingly, vaccination with these TTFC fusion vaccines also resulted in extremely persistent T-cell responses. The E7-specific CD8+ T cells induced by TTFC fusion vaccines were functional in terms of IFN-γ production, formation of immunological memory, in vivo cytolytic activity and tumor eradication. Finally, we show that genetic fusion with TTFC also improves the immunogenicity of a gene-shuffled E6 DNA vaccine. These data demonstrate that genetic fusion with tetanus toxin fragment C can dramatically improve the immunogenicity of full-length and gene-shuffled DNA vaccines. The DNA fusion vaccines developed here will be evaluated for the treatment of HPV-positive carcinomas in future studies.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

DNA vaccination, CD8+, T cells, HPV 16, tetanus toxin fragment C, genetic fusion

Zitieren

ISO 690

OOSTERHUIS, Koen, Peter ÖHLSCHLÄGER, Joost H. VAN DEN BERG, Mireille TOEBES, Raquel GOMEZ, Ton N. SCHUMACHER, John B. HAANEN, 2011. Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7. In: International Journal of Cancer. 2011, 129(2), pp. 397-406. ISSN 0020-7136. eISSN 1097-0215. Available under: doi: 10.1002/ijc.25894

BibTex

@article{Oosterhuis2011-07-15Precl-16487,
  year={2011},
  doi={10.1002/ijc.25894},
  title={Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7},
  number={2},
  volume={129},
  issn={0020-7136},
  journal={International Journal of Cancer},
  pages={397--406},
  author={Oosterhuis, Koen and Öhlschläger, Peter and van den Berg, Joost H. and Toebes, Mireille and Gomez, Raquel and Schumacher, Ton N. and Haanen, John B.}
}

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Universitätsbibliographie

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