Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia.
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.
Kenter
Gemma G
GG
Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands. g.g.kenter@lumc.nl
Welters
Marij J P
MJ
Valentijn
A Rob P M
AR
Lowik
Margriet J G
MJ
Berends-van der Meer
Dorien M A
DM
Vloon
Annelies P G
AP
Essahsah
Farah
F
Fathers
Lorraine M
LM
Offringa
Rienk
R
Drijfhout
Jan Wouter
JW
Wafelman
Amon R
AR
Oostendorp
Jaap
J
Fleuren
Gert Jan
GJ
van der Burg
Sjoerd H
SH
Melief
Cornelis J M
CJ
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
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