title: Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia.
abstract: BACKGROUND
  Vulvar intraepithelial neoplasia is a chronic disorder caused by high-risk types of human papillomavirus (HPV), most commonly HPV type 16 (HPV-16). Spontaneous regression occurs in less than 1.5% of patients, and the rate of recurrence after treatment is high.
  
  
  METHODS
  We investigated the immunogenicity and efficacy of a synthetic long-peptide vaccine in women with HPV-16-positive, high-grade vulvar intraepithelial neoplasia. Twenty women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia were vaccinated three or four times with a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7 in incomplete Freund's adjuvant. The end points were clinical and HPV-16-specific T-cell responses.
  
  
  RESULTS
  The most common adverse events were local swelling in 100% of the patients and fever in 64% of the patients; none of these events exceeded grade 2 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute. At 3 months after the last vaccination, 12 of 20 patients (60%; 95% confidence interval [CI], 36 to 81) had clinical responses and reported relief of symptoms. Five women had complete regression of the lesions, and HPV-16 was no longer detectable in four of them. At 12 months of follow-up, 15 of 19 patients had clinical responses (79%; 95% CI, 54 to 94), with a complete response in 9 of 19 patients (47%; 95% CI, 24 to 71). The complete-response rate was maintained at 24 months of follow-up. All patients had vaccine-induced T-cell responses, and post hoc analyses suggested that patients with a complete response at 3 months had a significantly stronger interferon-gamma-associated proliferative CD4+ T-cell response and a broad response of CD8+ interferon-gamma T cells than did patients without a complete response.
  
  
  CONCLUSIONS
  Clinical responses in women with HPV-16-positive, grade 3 vulvar intraepithelial neoplasia can be achieved by vaccination with a synthetic long-peptide vaccine against the HPV-16 oncoproteins E6 and E7. Complete responses appear to be correlated with induction of HPV-16-specific immunity.
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands. g.g.kenter@lumc.nl
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: A Rob P M
authors.initials: AR
authors.lastname: Valentijn
authors.forename: Margriet J G
authors.initials: MJ
authors.lastname: Lowik
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Berends-van der Meer
authors.forename: Annelies P G
authors.initials: AP
authors.lastname: Vloon
authors.forename: Farah
authors.initials: F
authors.lastname: Essahsah
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Fathers
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Jan Wouter
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Amon R
authors.initials: AR
authors.lastname: Wafelman
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
mesh_terms: D000328:Adult; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000628:therapy* / Q000821:virology; D005260:Female; D005620:Freund's Adjuvant; D052162:Human papillomavirus 16 / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology / Q000628:therapy*; D053918:Papillomavirus Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D012097:Repressor Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D014614:Vaccines, Synthetic; D014846:Vulvar Neoplasms / Q000628:therapy* / Q000821:virology; D055815:Young Adult
chemical_list: D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; D014614:Vaccines, Synthetic; C059731:oncogene protein E7, Human papillomavirus type 16; D005620:Freund's Adjuvant