Effectiveness of various human papillomavirus vaccination strategies: A community randomized trial in Finland.

INTRODUCTION: We conducted a community-randomized trial (NCTBLINDED) in Finland to assess gender-neutral and girls-only vaccination strategies with the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18)vaccine. METHODS: Girls and boys (12-15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04-HPV-16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04-HPV-16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV-16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04-HPV-16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co-primary objectives were overall effectiveness following gender-neutral or girls-only vaccination. RESULTS: Of 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: -19.0, 51.1; P = 0.232) with gender-neutral vaccination. Following girls-only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04-HPV-16/18 vaccine was high in both sexes. CONCLUSIONS: This study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.

Human papillomavirus vaccine efficacy against invasive, HPV-positive cancers: population-based follow-up of a cluster-randomised trial.

BACKGROUND: Human papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that vaccination provides HPV-type-specific protection against invasive cancer. METHODS: Individually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002-2005. HPV vaccine cohorts comprised originally 16-17 year-old HPV 16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18-19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts. FINDINGS: During a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p<0.05). INTERPRETATION: Vaccination is effective against invasive HPV-positive cancer. TRIAL REGISTRATION NUMBER: NCT00122681, Post-results; NCT00169494, Post-results; NCT00092534, Post-results.

Gender-neutral vaccination provides improved control of human papillomavirus types 18/31/33/35 through herd immunity: Results of a community randomized trial (III).

With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective effectiveness (PE) against high-risk HPV infections by HPV type and vaccination strategy in a community-randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender-neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (Arm B) and gender-neutral HBV vaccination (Arm C). Entire 1992-1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20-30% and 45% coverage in 2007-2010. During 2010-2014, 11,396 cervicovaginal samples were collected from 13,545 18.5-year-old attendees. HPV typing was performed by a high-throughput PCR. VE was calculated for HPV vaccinated women and HE for non-HPV-vaccinated women, using the HBV vaccinated, for HE all non-HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate-weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86-94% and 30-66%, respectively. Only the gender-neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort-increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender-neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender-neutral vaccination-enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.

Impact of gender-neutral or girls-only vaccination against human papillomavirus-Results of a community-randomized clinical trial (I).

Human papillomavirus (HPV) vaccine is efficacious but the real-life effectiveness of gender-neutral and girls-only vaccination strategies is unknown. We report a community-randomized trial on the protective effectiveness [(PE) = vaccine efficacy (VE) + herd effect (HE)] of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (11 communities) or Arm C) gender-neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992-95 were invited in 2007-09. Virtually all (99%) 12- to 15-year-old participating males (11,662) and females (20,513) received three doses resulting in uniform 20-30% male and 50% female vaccination coverage by birth cohort. Four years later (2010-14) 11,396 cervicovaginal samples obtained from 18.5 year-old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non-vaccine types consistent with cross-protection were highest in those born 1994-95 for HPV45 (VEA 82.8%; VEB 86.1%) and for HPV31 (VEA 77.6%, VEB 84.6%). The HEs in the non HPV-vaccinated were statistically significant in those born 1994-95 for HPV18 (HEA 51.0%; 95% CI 8.3-73.8, HEB 47.2%; 6.5-70.2) and for HPV31/33 in arm A (HEA 53.7%; 22.1-72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PEA 58.1%; 45.1-69.4; PEB 55.7%; 42.9-66.6). PE estimates against HPV31/33 were higher by the gender-neutral vaccination (PEA 60.5%; 43.6-73.4; PEB 44.5%; 24.9-60.6). In conclusion, while gender-neutral strategy enhanced the effectiveness of HPV vaccination for cross-protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638.

Human Papillomavirus (HPV) Prevalence in Male Adolescents 4 Years After HPV-16/18 Vaccination.

We assessed human papillomavirus (HPV) prevalence among HPV-16/18-vaccinated and unvaccinated Finnish male adolescents participating in chlamydia screening 4 years after vaccination with AS04-adjuvanted HPV-16/18 vaccine in 2007-2009. Previously vaccinated (n = 395) or unvaccinated (n = 149) male adolescents were enrolled in 12 municipalities. First-void urine samples were tested for HPV types 6, 11, 16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 66, and 68, and prevalence rates for HPV-16/18, and HPV-11/16/18/31/33/45 were reduced profoundly (0% vs 2.1% [P = .02] and 0.8% vs 5.3 [P = .002], respectively). Overall HPV DNA prevalence was also significantly reduced among HPV-16/18-vaccinated (4.1%) compared with unvaccinated subjects (10.1%) (P = .01). In this post hoc study, a highly significant reduction in HPV prevalence 4 years after vaccination suggests that the bivalent HPV-16/18 vaccine has protective efficacy in men.

Ten-year follow-up of human papillomavirus vaccine efficacy against the most stringent cervical neoplasia end-point-registry-based follow-up of three cohorts from randomized trials.

OBJECTIVE: Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+). METHODS: We report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials' end. RESULTS: During the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88). CONCLUSIONS: Ten years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects. TRIAL REGISTRATION NUMBER: NCT01393470.

Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women.

Vaccination against oncogenic human papillomavirus (HPV) types is one key intervention for cervical cancer prevention. This follow-up study assessed the persistence of the systemic and mucosal immune responses together with the safety profile of the HPV-16/18 AS04-adjuvanted vaccine administered to young women aged 10-25 years. Serum and cervicovaginal secretion (CVS) samples were collected at prespecified time-points during the 48-month follow-up period. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay (ELISA). At Month 48, all subjects remained seropositive for serum anti-HPV-16 and -18 antibodies. As previously observed, anti-HPV-16 and -18 antibodies levels (ELISA Units/mL) were higher in subjects vaccinated at the age of 10-14 years (2862.2 and 940.8) compared to subjects vaccinated at the age of 15-25 years (1186.2 and 469.8). Moreover, anti-HPV-16 and -18 antibodies in CVS were still detectable for subjects aged 15-25 years (84.1% and 69.7%, respectively). There was a strong correlation between serum and CVS anti-HPV-16 and -18 antibodies levels (correlation coefficients = 0.84 and 0.90 at Month 48, respectively) supporting the hypothesis of transudation or exudation of serum immunoglobulin G antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women induces long-term systemic and mucosal immune response and has a clinically acceptable safety profile up to 4 years after the first vaccine dose.

Correlation between levels of human papillomavirus (HPV)-16 and 18 antibodies in serum and cervicovaginal secretions in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine.

This pooled analysis of data from four Phase III clinical trials was undertaken to assess the correlation between levels of anti-human papillomavirus (HPV)-16/18 antibodies in serum and cervicovaginal secretions (CVS) in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Serum and CVS samples were collected from a subset of women aged 10-65 years (N=350) at pre-specified time-points from 7 to 36 months post-vaccination. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay. Pearson correlation coefficients between serum and CVS antibody levels, standardized for total immunoglobulin G, were calculated at each time-point in women with detectable antibodies in both serum and CVS. All subjects had seroconverted at Month 7 and remained seropositive through Month 36 for both antigens. Geometric mean titers of anti-HPV-16/18 antibodies in serum were substantially higher at all time-points than those in a control group of women who had cleared a natural HPV infection in another trial. In women with detectable antibodies in both serum and CVS, good correlation was seen between HPV-16/18 antibody levels at all time-points (Pearson correlation coefficient: 0.84-0.92 for HPV-16 and 0.90-0.91 for HPV-18). The strong correlation between levels of HPV-16/18 antibodies in serum and CVS up to 36 months post-vaccination in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine supports transudation of serum antibodies as the mechanism by which antibodies are introduced into CVS. These CVS antibodies may play a role in the protective efficacy of this vaccine.

Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10-18 years.

PURPOSE: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix) has been shown to be well-tolerated and immunogenic in females aged 10 to 55 years, and up to 100% effective for the prevention of HPV-16/18 infection and associated precancerous cervical lesions in females aged 15 to 25 years. This study is the first to evaluate the immunogenicity and safety of the vaccine in males. METHODS: Healthy males aged 10 to 18 years were randomized (2:1 ratio) to receive HPV-16/18 AS04-adjuvanted vaccine (n = 181) or hepatitis B virus (HBV) control vaccine (n = 89) at 0, 1, and 6 months, and were followed for 7 months. RESULTS: All initially seronegative subjects in the HPV-16/18 group seroconverted for HPV-16 and 18 (ELISA) at month 2. At month 7, all subjects were seropositive, and the HPV-16 and -18 antibody levels were, respectively, four- and twofold higher than at month 2. The anti-HPV-16 and -18 antibody responses for males aged 10 to 18 years and 10 to 14 years, respectively, were higher than those reported for females aged 15 to 25 years and 10 to 14 years, respectively, in a previous study. The reactogenicity profiles of the HPV-16/18 AS04 and HBV vaccines were similar, except that pain and swelling at the injection site were more common in the HPV-16/18 group. However, vaccine-related symptoms did not affect compliance with the three-dose course, which was equally high (97%) in both groups. CONCLUSIONS: The HPV-16/18 AS04-adjuvanted vaccine is immunogenic and well tolerated in boys aged 10 to 18 years. However, further data on the potential public health benefits of vaccination of boys are required before any recommendations can be made.

Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant.

PURPOSE: In female individuals 15-25-years of age, the AS04-containing human papillomavirus (HPV)-16/18 vaccine is highly immunogenic and provides up to 100% protection against HPV-16/18 persistent infection and associated cervical lesions up to 4.5 years. Optimal cervical cancer prevention will require prophylactic vaccination against oncogenic HPV 16 and 18 before the onset of sexual activity in early adolescent girls. To establish the feasibility of vaccination in girls 10-14 years of age, we compared the immunogenicity and safety in early adolescent female individuals to those 15-25 years in whom vaccine efficacy has been demonstrated. METHODS: We enrolled 773 female participants aged 10-14 years and 15-25 years to receive the HPV-16/18 L1 VLP AS04 vaccine, which was administered at months 0, 1, and 6. Serum samples were collected at months 0 and 7; antibodies to HPV 16 and 18 VLPs were measured by enzyme-linked immunosorbent assay. Vaccine safety was assessed at 7 or 30 days after each dose; serious adverse events were recorded during the entire study period. RESULTS: Both age groups achieved 100% seroconversion for HPV 16 and 18. Participants in the group aged 10-14 years were not only noninferior to those 15-25 years in terms of HPV 16 and 18 seroconversion rates but also had approximately twice as high geometric mean titers. The vaccine was generally safe and well tolerated. CONCLUSIONS: These findings suggest that HPV vaccination during early adolescence is generally safe, well tolerated, and highly immunogenic. The observed higher antibody titers in the group 10-14 years of age are likely to result in longer antibody persistence. Overall, these data support the implementation of prophylactic HPV vaccination in this age group.

Enrolment of 22,000 adolescent women to cancer registry follow-up for long-term human papillomavirus vaccine efficacy: guarding against guessing.

Human papillomaviruses (HPVs, most notably types 16 and 18) cause cervical carcinoma, the second most common cancer among women. Vaccination of adolescents against HPV16/18 might prevent large proportion of cervical and other anogenital cancers. However, because of ethical reasons this cannot be proven by clinical studies. To determine the long-term vaccine efficacy (VE) of HPV16/18 virus-like-particle (VLP) vaccine against cervical carcinoma in situ (CIS+) and invasive cervical carcinoma, the following three population-based cohorts of adolescent women have been enrolled: (1) women vaccinated with the HPV vaccine; (2) women vaccinated with hepatitis A control vaccine; and (3) unvaccinated control women. These cohorts will be passively followed for cumulative incidence of CIS+ endpoints by population-based cancer registry. Overall 24,046 16- to 17-year-old adolescent women from 18 cities in Finland were invited between May 2004 and June 2005 to participate in a phase III trial with bivalent HPV16/18 VLP vaccine. A total of 58,996 18- to 19-year-old women were invited in May 2005 to participate as unvaccinated controls. Women who reported their willingness to participate in an HPV vaccination trial had they been 1-2 years younger were eligible. Cumulative incidence (CI) of CIS+ in our cohorts over 15 years is approximately 0.45%. VE of 70% against CIS+ with 80% power requires 3357-3189 HPV16/18 vaccine recipients, 3357-3189 other vaccine recipients, and 6714-9567 unvaccinated controls. We have now enrolled 2404 HPV16/18 vaccine recipients, 2404 hepatitis A-vaccine recipients, and 5130 unvaccinated controls. This enrolment in addition to our earlier enrolment in another phase III trial guarantees enough power so that by 2020 we can ultimately provide data on the efficacy of HPV16/18 vaccination against CIS+.