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The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study

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Abstract

The capacity of a low-dose HPV16 synthetic long-peptide vaccine (HPV16-SLP) to induce an HPV16-specific T-cell response as well as to establish long-term immunologic memory in patients with low-grade abnormalities of the cervix was determined in a placebo-controlled, double-blinded phase II study. In addition, the effect of a booster vaccination after 1 year was evaluated. Patients received either the HPV16-SLP or a placebo at the start of the study. After 1 year, the vaccinated patients were again randomized to receive the HPV16-SLP or a placebo. Patients were followed for 2 years. HPV16-specific T-cell responses were determined in pre- and post-vaccination blood samples by ELISPOT, proliferation assay and cytokine assays. We show that the HPV16-specific T-cell responses detected after vaccination are clearly due to vaccination and that reactivity was maintained for at least 2 years. Interestingly, a booster vaccination after 1 year especially augmented the HPV16-specific Th2 response. Furthermore, pre-existing immunity to HPV16 was associated with a stronger response to vaccination and with more side effects, reflected by flu-like symptoms. We conclude that two low-dose injections of HPV16-SLP can induce a strong and stable HPV16-specific T-cell response that lasts for at least 1 year. If booster vaccination is required, then polarizing adjuvant should be added to maintain the Th1 focus of the vaccine-induced T-cell response.

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Acknowledgments

This study was financially supported by The Netherlands Organization for Health Research and Development (ZonMW 92003425).

Conflict of interest

This study has been conducted by the Leiden University Medical Center (LUMC), which holds a patent on the use of synthetic long peptides as vaccine (US 7.202.034). Cornelis J.M. Melief and Sjoerd H. van der Burg are named as inventors on this patent. The LUMC does not share the financial benefit from this patent with its employees. Cornelis J.M. Melief has been employed part-time (75 %) since January 20, 2008, by ISA Pharmaceuticals, which exploits this long-peptide vaccine patent, and has been granted options on ISA Pharmaceuticals stock. All other authors declare that they have no conflict of interest.

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Author notes

  1. Gemma G. Kenter

    Present address: Center of Gynecologic Oncology Amsterdam, Amsterdam, The Netherlands

Authors and Affiliations

  1. Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands

    Peggy J. de Vos van Steenwijk, Mariette I. E. van Poelgeest, Margriet J. G. Löwik, Dorien M. A. Berends-van der Meer & Gemma G. Kenter

  2. Department of Clinical Oncology, Leiden University Medical Center, Building 1, K1-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Tamara H. Ramwadhdoebe, Caroline E. van der Minne, Nikki M. Loof, Linda F. M. Stynenbosch, Marij J. P. Welters & Sjoerd H. van der Burg

  3. Department of Clinical Pharmacology and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Lorraine M. Fathers, A. Rob P. M. Valentijn & Jaap Oostendorp

  4. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Elisabeth M. Osse & Gert Jan Fleuren

  5. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    Cornelis J. M. Melief

  6. Department of Obstetrics and Gynecology, Medical Centrum Haaglanden, The Hague, The Netherlands

    Linda Nooij & Marjolein J. Kagie

  7. Department of Obstetrics and Gynecology, Haga Teaching Hospital, The Hague, The Netherlands

    Bart W. J. Hellebrekers

  8. ISA Pharmaceuticals, Leiden, The Netherlands

    Cornelis J. M. Melief

Authors
  1. Peggy J. de Vos van Steenwijk
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  2. Mariette I. E. van Poelgeest
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  3. Tamara H. Ramwadhdoebe
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  4. Margriet J. G. Löwik
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  5. Dorien M. A. Berends-van der Meer
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  6. Caroline E. van der Minne
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  8. Linda F. M. Stynenbosch
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  14. Linda Nooij
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  17. Cornelis J. M. Melief
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  18. Marij J. P. Welters
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  19. Sjoerd H. van der Burg
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Corresponding author

Correspondence to Sjoerd H. van der Burg.

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de Vos van Steenwijk, P.J., van Poelgeest, M.I.E., Ramwadhdoebe, T.H. et al. The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study. Cancer Immunol Immunother 63, 147–160 (2014). https://doi.org/10.1007/s00262-013-1499-2

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  • DOI: https://doi.org/10.1007/s00262-013-1499-2

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