Vaccination against HPV-16 Oncoproteins for Vulvar Intraepithelial Neoplasia

TLDR

Vulvar intraepithelial neoplasia, primarily caused by HPV‑16, has a spontaneous regression rate below 1.5 % and a high recurrence rate after treatment. The study examined the immunogenicity and efficacy of a synthetic long‑peptide vaccine targeting HPV‑16 oncoproteins E6 and E7 in women with high‑grade vulvar intraepithelial neoplasia. Twenty patients received three to four injections of a mixture of long peptides from HPV‑16 E6 and E7 formulated in incomplete Freund's adjuvant, with clinical response and HPV‑16‑specific T‑cell activation as endpoints. At 3 months post‑vaccination, 60 % of patients showed clinical response, with 25 % achieving complete regression and HPV‑16 clearance in most; by 12 months, 79 % responded and 47 % had complete regression, a rate sustained to 24 months, and stronger HPV‑16‑specific IFN‑γ CD4⁺/CD8⁺ T‑cell responses correlated with complete remission.

Abstract

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.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.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.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.