Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine

Abstract

HPV-023 (NCT00518336; ClinicalTrial.gov) is a long-term follow-up of an initial double-blind, randomized (1:1), placebo-controlled study (HPV-001, NCT00689741) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities, persistence of immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine. Among the women, aged 15–25 years, enrolled in HPV-001 and who participated in the follow-up study HPV-007 (NCT00120848), a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up (HPV-023) for a total of 113 months (9.4 years). During HPV-023, anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay (ELISA) and pseudovirion-based neutralisation assay (PBNA). Cervical samples were tested for HPV DNA every 6 months, and cyto-pathological examinations were performed annually. During HPV-023, no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group. Vaccine efficacy (VE) against HPV-16/18 incident infection was 100% (95%CI: 66.1, 100). Over the 113 months (9.4 years), VE was 95.6% (86.2, 99.1; 3/50 cases in vaccine and placebo groups, respectively) against incident infection, 100% (84·1, 100; 0/21) against 6-month persistent infection (PI); 100% (61·4, 100; 0/10) against 12-month PI; 97·1% (82.5, 99.9; 1/30) against ≥ ASC-US; 95·0% (68.0, 99.9; 1/18) against ≥ LSIL; 100% (45.2, 100; 0/8) against CIN1+; and 100% (–128.1, 100; 0/3) against CIN2+ associated with HPV-16/18. All vaccinees remained seropositive to HPV-16/18, with antibody titers remaining several folds above natural infection levels, as measured by ELISA and PBNA. There were no safety concerns. To date, these data represent the longest follow-up reported for a licensed HPV vaccine.

Ten‐year immune persistence and safety of the HPV‐16/18 AS04‐adjuvanted vaccine in females vaccinated at 15–55 years of age

“…Antibody titers at Year 10 were still at least three times higher than those observed after natural infection across all age groups, and in the older age categories (≥25 years), titers were similar to or just below the plateau levels associated with long‐term efficacy 14, 22. These findings were in line with the results of the primary study and consistent with our expectations, since GMTs are known to decline with increasing age at vaccination 9.…”

“…Plateau levels (dashed lines) are 418.3  EU / mL and 242.6  EU / mL for HPV ‐16 and HPV ‐18, respectively (month 107–113 in reference study) 13, 14, 16. Natural infection levels (solid lines) are 29.8  EU / mL and 22.7  EU / mL for HPV ‐16 and HPV ‐18, respectively 15.…”

“…Secondary analyses compared the immune response of subjects to the AS04‐HPV‐16/18 vaccine in this study (NCT00947115) with the immunogenicity plateau levels measured in the efficacy study (NCT00689741) and associated long‐term follow‐up studies (NCT00120848, NCT00518336) 12, 13, 14, and the immune response measured after natural infection in subjects from the PATRICIA study (NCT00122681) 15, in which efficacy was demonstrated in women aged 15–25 years 16. GMT values from CVS samples up to 10 years after first vaccination were evaluated.…”

Six‐year multi‐centre, observational, post‐marketing surveillance of the safety of the HPV‐16/18 AS04‐adjuvanted vaccine in women aged 10–25 years in Korea

“…In other clinical trials and surveillance studies conducted in different countries such as Japan, the Netherlands and United Kingdom7, 8, 9, 10, 11, 12, 13, 14, 15, 24, 25, 26, 27, 28, 29, transient injection‐site pain lasting for less than 5 days 30 was consistently the most commonly occurring AE. The results of the present study now provide further evidence that the safety profile of the HPV‐16/18 AS04‐adjuvanted vaccine is similar when administered to women in Korea.…”

“…The vaccine has been shown to be efficacious in preventing 93.2% of high grade cervical intraepithelial neoplasia (CIN3+) in naive population with an acceptable safety profile and sustained immunogenicity 7, 8, 9, 10, 11. Post‐licensure surveillance has confirmed the safety profiles of the vaccine in many populations 12, 13, 14, 15.…”