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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
Authors:Peggy J de Vos van Steenwijk  Mariette I E van Poelgeest  Tamara H Ramwadhdoebe  Margriet J G Löwik  Dorien M A Berends-van der Meer  Caroline E van der Minne  Nikki M Loof  Linda F M Stynenbosch  Lorraine M Fathers  A Rob P M Valentijn  Jaap Oostendorp  Elisabeth M Osse  Gert Jan Fleuren  Linda Nooij  Marjolein J Kagie  Bart W J Hellebrekers  Cornelis J M Melief  Marij J P Welters  Sjoerd H van der Burg  Gemma G Kenter
Institution:1. Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands
2. Department of Clinical Oncology, Leiden University Medical Center, Building 1, K1-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
3. Department of Clinical Pharmacology and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
4. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
6. Department of Obstetrics and Gynecology, Medical Centrum Haaglanden, The Hague, The Netherlands
7. Department of Obstetrics and Gynecology, Haga Teaching Hospital, The Hague, The Netherlands
5. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
8. ISA Pharmaceuticals, Leiden, The Netherlands
9. Center of Gynecologic Oncology Amsterdam, Amsterdam, The Netherlands
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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