A prospective, single-arm, open-label, non-randomized, phase IIa trial of a nonavalent prophylactic HPV vaccine to assess immunogenicity of a prime and deferred-booster dosing schedule among 9-11 year-old girls and boys - clinical protocol.

BACKGROUND: Human papillomavirus (HPV) vaccines are indicated for the prevention of cancers and genital warts caused by vaccine-covered HPV types. Although the standard regimen requires a two or three-dose vaccine series, there is emerging data suggesting that a single dose of the bivalent or quadrivalent HPV vaccine generates persistently positive antibody titers. No similar data is yet available for the nonavalent HPV vaccine, currently the only HPV vaccine available in the United States. The overall objective of our study is to assess the stability and kinetics of antibody titers for 24 months following a single dose of the nonavalent HPV vaccine among preteen girls and boys. METHODS: This is a prospective, single-arm, open-label, non-randomized, Phase IIa trial among 9-11 year-old girls and boys to determine the immunogenicity after a single dose of the nonavalent HPV vaccine (GARDASIL® 9) over 24 months, with a deferred booster dose at 24 months and an optional booster at 30 months after the first dose. Participants provide blood specimens at 6, 12, 18, 24, and 30 months after the first dose. Serologic geometric mean titers (GMT) of the nine vaccine types (HPV 16/18/ 6/11/31/33/45/52/58) will be measured at each time point. The primary objective is to determine the stability of type-specific serologic GMT of HPV16 and HPV18 between the 6- vs. 12-month, 12- vs. 18-month, and 18- vs. 24-month visits. Secondary objectives are to determine the stability of type-specific serologic GMT of the other HPV types (HPV 6/11/31/33/45/52/58) between the visits and to assess safety and reactogenicity after each vaccine dose. DISCUSSION: Single dose HPV vaccination could simplify the logistics and reduce costs of HPV vaccination in the US and across the world. This study will contribute important immunogenicity data on the stability and kinetics of type-specific antibody titers and inform feasibility of the single dose HPV vaccination paradigm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02568566 . Registered on October 6, 2015.

Vaccination against HPV and view of new possibilities.

OBJECTIVE: Overview of available information on current vaccination options against HPV and possibilities for further development. DESIGN: Review article. SETTINGS: Clinic of Gynecology and Obstetrics, University Hospital in Ostrava; Clinic of Gynecology and Obstetrics, General University Hospital in Prague. METHODS AND RESULTS: Three prophylactic vaccines have been developed against HPV infection and are all now avaliable in Czech Repulbic; nonavalent (Gardasil 9), quadrivalent vaccine (Silgard) and bivalent vaccine (Cervarix). Therapeutic vaccines, designed to induce regression of existing HPV-associated lesions, are in development and not yet clinically available. CONCLUSION: All three avaliable prophylactic vaccines show high efficacy in prevention of vaccine-specific HPV-type infection. The highest degree of protection is achieved in the population of HPV-naive women.

Will cervical screening remain cost-effective in women offered the next generation nonavalent HPV vaccine? Results for four developed countries.

A next generation nonavalent human papillomavirus (HPV) vaccine ("HPV9 vaccine") is being introduced in several countries. The aims of this study were to evaluate whether cervical screening will remain cost-effective in cohorts offered nonavalent vaccines and if so, to characterize the optimal number of screening tests. We used a dynamic model of HPV vaccination and cervical screening to evaluate the cost-effectiveness of strategies involving varying numbers of primary HPV tests per lifetime for cohorts offered the nonavalent vaccine as 12 year-olds. For each of four countries-the USA, New Zealand (NZ), Australia and England-we considered local factors including vaccine uptake rates (USA/NZ uptake ∼50%; Australia/England uptake >70%), attributable fractions of HPV9-included types, demographic factors, costs and indicative willingness-to-pay (WTP) thresholds. Extensive probabilistic sensitivity analysis was performed. We found that, in the USA, four screens per lifetime was the most likely scenario, with 34% probability of being optimal at WTP US$50,000/LYS, increasing to 84% probability at US$100,000/LYS. In New Zealand, five screens per lifetime was the most likely scenario, with 100% probability of being optimal at NZ$42,000/LYS, given the assumptions used. In Australia, two screens per lifetime was the most likely scenario, with 62% probability of being optimal at AU$50,000/LYS. In England, four screens per lifetime was the most likely scenario, with 32% probability of being optimal at GB£20,000/LYS, increasing to 96% probability at GB£30,000/LYS. We conclude that some cervical screening will remain cost-effective, even in countries with high vaccination coverage. However, the optimal number of screens may vary between countries.

High prevalence of human papillomaviruses in Ghanaian pregnant women.

Data about the prevalence of human papillomaviruses (HPV) in African women with normal and abnormal cervical cytology are still scarce. Current HPV vaccines contain HPV types, which mainly represent the HPV epidemiology of industrial countries. As further developments of HPV vaccines are going on, it is necessary to regard regional differences in HPV type prevalence to ensure optimal protection by the vaccine. Vaginal swabs of Ghanaian pregnant women, routinely collected before delivery to rule out bacterial infections causing early onset sepsis, were screened for 12 high-risk (HR), 13 probably/possibly (pHR), and 18 low-risk (LR) HPV types. Most pregnant women come for delivery to the hospital. This was considered as appropriate possibility to have an unselected group of women. HPV DNA were detected in 55/165 women (33.3, 95 % CI 26.3-41.1 %). Thirty-four out of fifty-five (61.8, 95 % CI 47.7-74.3 %) of HPV-positive women were infected with HR and/or pHR HPV types. The five most prevalent HR or pHR HPV types were HPV-52 and HPV-67 (7 women each, 4.2, 95 % CI 1.9-8.9 %), HPV-53 (six women, 3.6, 95 % CI 1.5-8.1 %), HPV-45 (five women, 3.0, 95 % CI 1.1-7.3 %), and HPV-18 (four women, 2.4, 95 % CI 0.8-6.5 %), respectively. HPV-16 was found in two women only (1.2, 95 % CI 0.2-4.8 %). Future HPV vaccine research may devote special interest to HPV-67 and HPV-53 provided further studies confirm their high prevalence in the general population of Sub-Saharan African countries. The true carcinogenic potential of HPV-67, which is a member of species alpha9 including HPV-16, and so far categorized as pHR, should be clarified.

Safety and Immunogenicity of the Nonavalent Human Papillomavirus Vaccine in Women Living with HIV.

BACKGROUND: The objectives were to evaluate the safety and immunogenicity of the nonavalent human papillomavirus (nHPV) vaccine in adult Spanish women living with HIV (WLHIV); the prevalence of anal and cervical dysplasia and nHPV vaccine genotypes in the anus and cervix; and risk factors for high-risk HPV (HR-HPV) infection in anal mucosa. METHODS: In this single-center, open-arm, non-randomized clinical trial, the nHPV vaccine was administered at 0, 2, and 6 months to WLHIV enrolled between February 2020 and November 2023, measuring vaccine antibody titers pre-vaccination and at 2, 6, and 7 months after the first dose. Cervical and anal cytology and HPV PCR genotyping studies were performed. Women with abnormal cytology and/or anal or cervical HPV infection at baseline underwent high-resolution anoscopy and/or colposcopy. RESULTS: A total of 122 participants were included with mean age of 49.6 years: 52.5% smoked; 10.7% had anal-genital condylomatosis; 38.5% were infected by HR-HPV in the anus and 25.4% in the cervix, most frequently HPV 16; 19.1% had anal intraepithelial neoplasia 1-(AIN1); and 3.1% had cervical intraepithelial neoplasia 1 and 2 (CIN1/CIN2). Vaccine administration did not modify viral-immunological status (CD4 [809 ± 226.8 cells/uL vs. 792.35 ± 349.95; p = 0.357]) or plasma HIV load (3.38 ± 4.41 vs. 1.62 ± 2.55 cop/uL [log]; p = 0.125). Anti-HPV antibodies ([IQR: 0-0] vs. 7.63 nm [IQR: 3.46-19.7]; p = 0.0001) and seroconversion rate (8.2% vs. 96.7% [p = 0.0001]) were increased at 7 versus 0 months. There were no severe vaccine-related adverse reactions; injection-site pain was reported by around half of the participants. HR-HPV infection in the anus was solely associated with a concomitant cervix infection (HR 5.027; 95% CI: 1.009-25.042). CONCLUSIONS: nHPV vaccine in adult WLHIV is immunogenic and safe.

High Prevalence of Non-Vaccinated Oncogenic Human Papillomavirus Genotypes in High-Grade Squamous Intraepithelial Lesions of the Cervix: Thought-Provoking Results of a Detailed HPV Genotype Analysis.

Identification of HPV infection is usually performed on cytological specimens, despite the often transient virus types. HPV profile analysis of pathologically confirmed lesions can also be performed on formalin-fixed paraffin-embedded (FFPE) cone samples and should be taken as standard during follow-up. We compared HPV profiles of cytological and FFPE specimens of women diagnosed with HSIL. Archived PAP smears and FFPE cones from 49 patients were processed. For genotyping, the HPV Direct Flow CHIP test was used. All samples were positive. HPV profile agreement of the two sample types was 84.16-100%. Mono-infections occurred in 12.24% and 61.22% in PAP smears and FFPE specimens, respectively; while multi-infections were detected in 87.76% and 38.78%, respectively. The most abundant genotypes were HPVs 16, 31, and 51/33. Of all infections, 56.25% and 64.93% were caused by nonavalent vaccinated type (VT) HPVs; while 50.69% and 38.96% belonged to non-nonavalent VT HPVs, in PAP smears and FFPE specimens, respectively. Our results confirmed the importance of HPV genotyping of FFPE cone samples. We also confirmed a remarkable presence of non-vaccinated HPV types in HSIL cases indicating the importance of vaccine development.

Monitoring human papillomavirus prevalence among young Australian women undergoing routine chlamydia screening.

INTRODUCTION: Australia has recently implemented major changes in cervical cancer prevention policies including introduction of primary human papillomavirus (HPV) screening starting at age 25, and replacement of the quadrivalent HPV vaccine with the nonavalent vaccine in the national school-based program. We assessed the feasibility and utility of conducting HPV testing in residual clinical specimens submitted for routine Chlamydia trachomatis screening, as a means of tracking HPV vaccine program impact among young sexually active women. METHODS: De-identified residual specimens from women aged 16-24 years submitted for chlamydia testing were collected from three pathology laboratories in Victoria and New South Wales. Limited demographic information, and chlamydia test results were also collected. Patient identifiers were sent directly from the laboratories to the National HPV Vaccination Program Register, to obtain HPV vaccination histories. Samples underwent HPV genotyping using Seegene Anyplex II HPV 28 assay. RESULTS: Between April and July 2018, 362 residual samples were collected, the majority (60.2%) of which were cervical swabs. Demographic data and vaccination histories were received for 357 (98.6%) women (mean age 21.8, SD 2.0). Overall, 65.6% of women were fully vaccinated, 9.8% partially, and 24.7% unvaccinated. The majority (86.0%) resided in a major city, 35.9% were classified in the upper quintile of socioeconomic advantage and chlamydia positivity was 7.8%.The prevalence of quadrivalent vaccine-targeted types (HPV6/11/16/18) was 2.8% (1.5-5.1%) overall with no differences by vaccination status (p = 0.729). The prevalence of additional nonavalent vaccine-targeted types (HPV31/33/45/52/58) was 19.3% (15.6-23.8%). One or more oncogenic HPV types were detected in 46.8% (95% CI 41.6-52.0%) of women. CONCLUSIONS: HPV testing of residual chlamydia specimens provides a simple, feasible method for monitoring circulating genotypes. Applied on a larger scale this method can be utilised to obtain a timely assessment of nonavalent vaccine impact among young women not yet eligible for cervical screening.

Cost-effectiveness of HPV vaccination for adults through age 45 years in the United States: Estimates from a simplified transmission model.

INTRODUCTION: The objective of this study was to assess incremental costs and benefits of a human papillomavirus (HPV) vaccination program expanded to include "mid-adults" (adults aged 27 through 45 years) in the United States. METHODS: We adapted a previously published, dynamic mathematical model of HPV transmission and HPV-associated disease to estimate the incremental costs and benefits of a 9-valent HPV vaccine (9vHPV) program for people aged 12 through 45 years compared to a 9vHPV program for females aged 12 through 26 years and males aged 12 through 21 years. RESULTS: A 9vHPV program for females aged 12 through 26 years and males aged 12 through 21 years was estimated to cost < $10,000 quality-adjusted life year (QALY) gained, compared to no vaccination. Expanding the 9vHPV program to include mid-adults was estimated to cost $587,600 per additional QALY gained when including adults through age 30 years, and $653,300 per additional QALY gained when including adults through age 45 years. Results were most sensitive to assumptions about HPV incidence among mid-adults, current and historical vaccination coverage, vaccine price, and the impact of HPV diseases on quality of life. CONCLUSIONS: Mid-adult vaccination is much less cost-effective than the comparison strategy of routine vaccination for all adolescents at ages 11 to 12 years and catch-up vaccination for women through age 26 years and men through age 21 years.

Defining Elimination of Genital Warts-A Modified Delphi Study.

Background: Substantial declines in genital warts (GW) have been observed in countries with quadrivalent HPV vaccination programmes, with Australia showing the highest reductions due to early commencement and high vaccination coverage. There is a real potential to achieve GW elimination; however, no GW elimination definition exists. Taking Australia as a case study, we aimed to reach expert consensus on a proposed GW elimination definition using a modified Delphi process. Method: We used modelling and epidemiological data to estimate the expected number of new GW cases, from pre-vaccination (baseline) in 2006 to the year 2060 in Australian heterosexuals, men who have sex with men (MSM), and newly arrived international travellers and migrants. We used these data and the literature, to develop a questionnaire containing ten elimination-related items, each with 9-point Likert scales (1-strongly disagree; 9-strongly agree). The survey was completed by 18 experts who participated in a full day face-to-face modified Delphi study, in which individuals and then small groups discussed and scored each item. The process was repeated online for items where consensus (≥70% agreement) was not initially achieved. Median and coefficient of variation (COV) were used to describe the central tendency and variability of responses, respectively. Findings: There was a 95% participation rate in the face-to-face session, and 84% response rate in the final online round. The median item score ranged between 7.0 and 9.0 and the COV was ≤0.30 on all items. Consensus was reached that at ≥80% HPV vaccination coverage, GW will be eliminated as a public health problem in Australia by 2060. During this time period there will be a 95% reduction in population-level incidence compared with baseline, equivalent to <1 GW case per 10,000 population. The reductions will occur most rapidly in Australian heterosexuals, with 73%, 90% and 97% relative reductions by years 2021, 2030 and 2060, respectively. The proportion of new GW cases attributable to importation will increase from 3.6% in 2006 to ~49% in 2060. Interpretation: Our results indicate that the vaccination programme will minimise new GW cases in the Australian population, but importation of cases will continue. This is the first study to define GW elimination at a national level. The framework developed could be used to define GW elimination in other countries, with thresholds particularly valuable for vaccination programme impact evaluation. Funding: LK supported through an Australian Government Research Training Programme Scholarship; unconditional funding from Seqirus to support the Delphi Workshop.

Estimating the epidemiological impact and cost-effectiveness profile of a nonavalent HPV vaccine in Spain.

Human papillomavirus (HPV) is one of the main causes of infection-related cancer. The bivalent vaccine (2vHPV) (16/18) and quadrivalent (6/11/16/18) HPV vaccine (4vHPV) have been included in the Spanish vaccination calendar since 2007. The new nonavalent HPV vaccine (9vHPV), approved in Europe in 2015, includes nine HPV types 6/11/16/18/31/33/45/52/58 and has been available in Spain since May 2017. Our study aims to estimate the epidemiological impact and the cost-effectiveness of a girls-only and a gender-neutral vaccination program with 9vHPV compared to the current vaccination program in Spain. A dynamic transmission model simulating the natural history of HPV infections was calibrated to the Spanish setting and applied to estimate costs and quality-adjusted life years (QALYs) associated with vaccination strategies using a payer perspective and a 100-year time horizon. A girls-only vaccination strategy at age 12 years with 9vHPV was found to be a cost-effective strategy compared with 4vHPV (incremental cost-effectiveness ratio (ICER) of €7,718 per QALY). Compared with girls-only vaccination with 4vHPV, gender-neutral vaccination with 9vHPV was associated with further reductions of up to 28.5% in the incidence of cervical intraepithelial neoplasia (CIN) 2/3 and 17.1% in the incidence of cervical cancer, as well as with a 14.0% reduction in cervical cancer mortality. Furthermore, a gender-neutral vaccination program with 9vHPV could potentially be cost-effective considering some parameters as head and neck protection or discount rates, leading to a reduction in the burden of HPV-related diseases in both sexes in the Spanish population.

Cost-effectiveness of nonavalent HPV vaccination among males aged 22 through 26 years in the United States.

INTRODUCTION: In the United States, routine human papillomavirus (HPV) vaccination is recommended for females and males at age 11 or 12 years; the series can be started at age 9 years. Vaccination is also recommended for females through age 26 years and males through age 21 years. The objective of this study was to assess the health impact and cost-effectiveness of harmonizing female and male vaccination recommendations by increasing the upper recommended catch-up age of HPV vaccination for males from age 21 to age 26 years. METHODS: We updated a published model of the health impact and cost-effectiveness of 9-valent human papillomavirus vaccine (9vHPV). We examined the cost-effectiveness of (1) 9vHPV for females aged 12 through 26 years and males aged 12 through 21 years, and (2) an expanded program including males through age 26 years. RESULTS: Compared to no vaccination, providing 9vHPV for females aged 12 through 26 years and males aged 12 through 21 years cost an estimated $16,600 (in 2016 U.S. dollars) per quality-adjusted life year (QALY) gained. The estimated cost per QALY gained by expanding male vaccination through age 26 years was $228,800 and ranged from $137,900 to $367,300 in multi-way sensitivity analyses. CONCLUSIONS: The cost-effectiveness ratios we estimated are not so favorable as to make a strong economic case for recommending expanding male vaccination, yet are not so unfavorable as to preclude consideration of expanding male vaccination. The wide range of plausible results we obtained may underestimate the true degree of uncertainty, due to model limitations. For example, the cost per QALY might be less than our lower bound estimate of $137,900 had our model allowed for vaccine protection against re-infection. Models that specifically incorporate men who have sex with men (MSM) are needed to provide a more comprehensive assessment of male HPV vaccination strategies.

The impact and cost-effectiveness of nonavalent HPV vaccination in the United States: Estimates from a simplified transmission model.

INTRODUCTION: The objective of this study was to assess the incremental costs and benefits of the 9-valent HPV vaccine (9vHPV) compared with the quadrivalent HPV vaccine (4vHPV). Like 4vHPV, 9vHPV protects against HPV types 6, 11, 16, and 18. 9vHPV also protects against 5 additional HPV types 31, 33, 45, 52, and 58. METHODS: We adapted a previously published model of the impact and cost-effectiveness of 4vHPV to include the 5 additional HPV types in 9vHPV. The vaccine strategies we examined were (1) 4vHPV for males and females; (2) 9vHPV for females and 4vHPV for males; and (3) 9vHPV for males and females. In the base case, 9vHPV cost $13 more per dose than 4vHPV, based on available vaccine price information. RESULTS: Providing 9vHPV to females compared with 4vHPV for females (assuming 4vHPV for males in both scenarios) was cost-saving regardless of whether or not cross-protection for 4vHPV was assumed. The cost per quality-adjusted life year (QALY) gained by 9vHPV for both sexes (compared with 4vHPV for both sexes) was < $0 (cost-saving) when assuming no cross-protection for 4vHPV and $8,600 when assuming cross-protection for 4vHPV. CONCLUSIONS: Compared with a vaccination program of 4vHPV for both sexes, a vaccination program of 9vHPV for both sexes can improve health outcomes and can be cost-saving.