Background More than ten years have elapsed since human papillomavirus (HPV) vaccination was implemented. We performed a systematic review and meta-analysis of the population-level impact of female-only HPV vaccination on HPV infections, anogenital wart diagnoses (AGW) and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination. Methods We updated our prior review (01/01/2007-28/02/2014), by searching Medline and Embase (01/02/2014-11/10/2018) for studies that examined changes, between pre-and post-vaccination periods, in HPV infections, AGW, or CIN2+. We stratified all analyses by sex, age, and years since HPV vaccination introduction. We used random-effects models to estimate pooled relative risks and performed subgroup analysis to identify the main sources of heterogeneity. Findings We identified 65 eligible articles conducted in 14 high-income countries. After 5-8 years of vaccination, HPV-16/18, AGW, and CIN2+ decreased significantly by about 80%, 70%, and 50% among girls aged 15-19 years and by 65%, 55%, and 30% among women aged 20-24 years. Significant cross-protection and herd effects were also observed. HPV-31/33/45 decreased significantly by 50% among girls aged 15-19 years and AGW decreased significantly by 30-50% among boys/men aged 15-24 years. After 5-8 years of vaccination, countries with multi-cohort vaccination and high coverage (≥50%) had greater reductions in AGW, 44 and 85 percentage points among girls and boys aged 15-19 years, respectively, than countries with single-cohort vaccination and/or low vaccination coverage. Interpretation Our meta-analysis, including data from >60 million individuals from 14 high-income countries, shows a substantial impact of female-only HPV vaccination programs on AGW among girls/women and boys/men, and HPV infections and CIN2+ among girls/women. In addition, programs with multi-cohort vaccination and high vaccination coverage lead to greater and faster direct impact and herd effects. CONTRIBUTIONS MD, MB, and MCB conceived the study. MD, EB and NP did the literature search and performed the analysis. MB and MCB participated in the analysis. MD and MB co-drafted the first version of the article.

Key words: HPV; human papillomavirus; DNA; mRNA; PreTect HPV-Proofer; NASBA; PCR; ASCUS; LSIL Cytological cervical cancer screening programs have been successful in reducing the incidence of cervical cancer, even though a single conventional Papanicolaou (Pap) smear is only moderately accurate and does not achieve concurrent high sensitivity and specificity. 1,2 The management of women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) is problematic because only a small proportion will progress to cervical intraepithelial neoplasia (CIN) 3 and invasive cervical carcinoma (ICC). Histologically verified CIN has been found in 10 -60% of women with an ASCUS diagnosis, with CIN2/3 present in more than 5%. 3-11 Pap smear follow-up of women with an ASCUS smear fails to identify all women at higher risk of CIN2ϩ, suggesting that cervical cancer screening programs might benefit from implementing new diagnostic tests in the triage of women with equivocal Pap smears. 12 Infection with high-risk (HR) types of HPV is necessary for the development of ICC 13-16 and the expression of the E6/E7 oncogenes is necessary for conversion to and maintenance of malignancy in cervical tissue. [17][18][19] Therefore, detection of the E6/E7 mRNA of HR-HPV types might serve as a better risk evaluation factor than mere DNA detection for the development of high-grade squamous intraepithelial lesion (HSIL) and ICC. 20 The combination of cytology and HPV testing seems to save additional life at a reasonable cost compared to Pap testing alone. 21,22 Detection of E6/E7 mRNA can be achieved by using the commercial PreTect HPV-Proofer assay (NorChip AS, Klokkarstua, Norway), that utilizes nucleic acid sequence based amplification (NASBA).The aim of our study was to assess whether a positive HPV mRNA or DNA test at the time of an ASCUS or LSIL Pap-smear identifies women diagnosed with a histological CIN2ϩ after 2 years of follow-up. Material and methods Study subjectsThe study subjects comprise a subgroup from 4,136 women older than 30 years of age that visited a selection of gynecologists in Oslo, Norway, and have been tested in 2001 for the presence of HPV DNA by Gp5ϩ/6ϩ consensus PCR and E6/E7 transcripts by real-time multiplex NASBA (PreTect HPV-Proofer, NorChip AS) in addition to cytology. 35 PreTect HPV-Proofer detects mRNA from HPV types 16, 18, 31, 33 and 45, whereas Gp5ϩ/6ϩ consensus PCR detects HPV DNA from the L1 region in Ͼ20 HPV types. We included all women with an index Pap smear diagnosis of ASCUS or LSIL (n ϭ 77). The index Pap smear refers to the smear taken together with the HPV testing. Information on Pap smears in the 10-year period before the inclusion in our study was obtained from CRN registers. Former abnormal smears mean any smear that is not normal or unsatisfactory and has been taken before the index smear in 2001. Follow-upSeventy-seven women were followed up for 24 months in the registers of the Cancer Registry of Norway (CRN) with subsequent Pap smears...

Background Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. Patients and methods We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6–11 years, range = 0–40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). Results HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1–155.4) in whites and 17.2-fold (95% CI 1.7–170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years ( N = 24), 20–30 years ( N = 148), 10–20 years ( N = 228), and <10 years ( N = 301 cases) ( p -trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. Conclusions The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Background: The quadrivalent human papillomavirus (qHPV) vaccine prevented vaccine HPV type-related infection and disease in young women in the 4-year FUTURE II efficacy study (NCT00092534). We report long-term effectiveness and immunogenicity at the end of 14 years of follow-up after enrollment in FUTURE II. Methods: Young women (16À23 years of age) from Denmark, Iceland, Norway, and Sweden who received three qHPV vaccine doses during the randomized, double-blind, placebo-controlled FUTURE II base study were followed for effectiveness for an additional 10 years through national registries. Tissue samples including but not limited to those collected during organized cervical cancer screening programs were obtained from regional biobanks to be adjudicated for histopathology diagnosis and tested for HPV DNA. The observed incidence of HPV16/18-related high-grade cervical dysplasia (primary outcome) was compared with recent historical background incidence rates in an unvaccinated population. Serum was collected at years 9 and 14 to assess antibody responses. Findings: No cases of HPV16/18-related high-grade cervical dysplasia were observed in the per-protocol effectiveness population (N = 2121; 24,099¢0 person-years of follow-up) during the entire study. Vaccine effectiveness of 100% (95% CI 94¢7À100) was demonstrated for 12 years, with a trend toward continued protection through 14 years post-vaccination. Seropositivity rates at study conclusion were >90% (HPV6/11/16) and 52% (HPV18) using competitive Luminex immunoassay, and >90% (all four HPV types) using the more sensitive IgG Luminex immunoassay. Interpretation: Vaccination of young women with qHPV vaccine offers durable protection against HPV16/18-related high-grade cervical dysplasia for 12 years, with a trend toward continued protection through 14 years post-vaccination, and induces sustained HPV6/11/16/18 antibody responses for up to 14 years post-vaccination. There was no evidence of waning immunity, suggesting no need for a booster dose during that period.

V501-015.