Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination

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.

Keywords: HPV-16/18 AS04-adjuvanted vaccine; cervical cancer; efficacy; human papillomavirus (HPV); immunogenicity; long-term protection; pre-cancer; safety.

Figure 1. Flow of participants HPV-001: NCT00689741; HPV-007: NCT00120848; HPV-023: NCT00518336. ATP = according-to-protocol. The ATP cohort for primary analysis of efficacy included all women for whom differential treatment effect on efficacy was likely (i.e., those meeting all eligibility criteria in HPV-001, HPV-007 and HPV-023), complying with the procedures defined in the respective study protocol, and for whom data concerning efficacy endpoint measures were available. The ATP immunogenicity cohort included all evaluable women (i.e., those meeting all eligibility criteria, complying with the procedures defined in the protocol, and fulfilling requirements for analysis) for whom data concerning immunogenicity were available. M0 = Month 0 = time of randomization; M18 = Month 18 (18 mo after the first dose of vaccine); M33 = Month 33 (33 mo after the first dose); M76 = Month 76 (76 mo after the first dose); M77 = Month 77 (77 mo after the first dose); M113 = Month 113 (113 mo after the first dose).

Figure 2. Reverse cumulative distribution curves for HPV-16/18 incident infection (A) and HPV-16/18 6-mo persistent infection (B) in cervical samples (ATP efficacy cohort). Combined analysis of initial and follow-up studies (HPV-001/007/023). Vaccine = HPV-16/18 vaccine group. Placebo = placebo group. VE = vaccine efficacy, with 95% confidence interval.

Figure 3. Seropositivity rates and geometric mean titers for anti-HPV-16 (A) and anti-HPV-18 (B) antibodies, measured by ELISA (ATP immunogenicity cohort). ATP immunogenicity cohort = women who met all eligibility criteria (all had received 3 doses of vaccine or placebo), complied with study procedures in the current and preceding studies, and had data available for at least one vaccine antibody blood sample. Data are shown for the women enrolled in the Brazilian centers for the initial, first follow-up, and current studies. Histogram bars show the GMT and corresponding 95% Confidence intervals (CI). ELISA = enzyme-linked immunosorbent assay; HPV = HPV-16/18 vaccine group; Placebo = placebo group; PRE = pre-vaccination; PII = post dose II; PIII = post dose III; M = Month. EL.U/mL = ELISA units/mL. Figures above the bars are the seropositivity rates for the corresponding timepoint. Horizontal line represents the IgG antibody level in women from a phase III efficacy study (HPV-008, NCT00122681) who had cleared a natural infection before enrolment. IgG GMTs corresponding to natural infection in study HPV-008 were 29·8 EL.U/mL (95% CI: [28·5 to 31·0]) for HPV-16 and 22·6 EL.U/mL (95% CI: [21·6 to 23·6]) for HPV-18; measured by ELISA.

Figure 4. Seropositivity rates and geometric mean titers for (A) anti-HPV-16 and (B) anti-HPV-18 antibodies, measured by PBNA (ATP immunogenicity cohort). ATP cohort for immunogenicity = women who met all eligibility criteria (all had received 3 doses of vaccine or placebo), complied with study procedures in the current and preceding studies, and had data available for at least one vaccine antibody blood sample. Data are shown for a subset of the women enrolled in the Brazilian centers for the initial, first follow-up, and current studies. Histogram bars show the GMT and corresponding 95% Confidence intervals (CI). PBNA = Pseudovirion-Based Neutralisation Assay; PRE = pre-vaccination; PII = post dose II; PIII = post dose III; M = Month. Figures above the bars are the seropositivity rates for the corresponding timepoint. Horizontal line represents the IgG antibody level in women from a phase III efficacy study (HPV-010, NCT00423046) who had cleared a natural infection before enrolment. IgG GMTs corresponding to natural infection in study HPV-010 were 180·1 ED₅₀ (95% CI: [153·3 to 211·4]) for HPV-16 and 137·3 ED₅₀ (95% CI: [112·2 to 168·0]) for HPV-18; measured by PBNA).

Figure 5. Anti-HPV-16 antibody responses predicted by the modified power-law (A), piece-wise model (B), and their comparison (C), up to 20 y. GMT = geometric mean titer; EL.U/mL = ELISA units/mL; Natural infection = mean antibody titers associated with natural infection were obtained from women enrolled in a Phase III efficacy study (HPV-008, NCT00122681).

Figure 6. Anti-HPV-18 antibody responses predicted by the modified power-law (A), piece-wise model (B), and their comparison (C), up to 20 y. GMT = geometric mean titer; EL.U/mL = ELISA units/mL; Natural infection = mean antibody titers associated with natural infection were obtained from women enrolled in a Phase III efficacy study (HPV-008, NCT00122681).