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Prophylactic human papillomavirus (HPV) vaccines against cervical cancer were successfully developed; however, challenges such as high cost and low compliance still remain to be overcome. In addition, because many HPV types can cause cervical cancer, antigens of multiple HPV types are needed to achieve broad protection. In this study, a bivalent single-injection HPV vaccine was designed in which virus-like particles (VLPs) of HPV 16 L1 and HPV 18 L1 were used as antigens. A recently developed drug carrier that uses tannic acid/polyethylene glycol films as the erodible layer was employed to accomplish multiple pulsatile releases of the antigens. Monovalent single-injection vaccines for HPV 16 and HPV 18 were first designed. A bivalent single-injection vaccine was then obtained by simply mixing the two monovalent vaccines. The bivalent vaccine provided protection against both HPV types. More importantly, it elicited both humoral and cellular immune responses as potent as those elicited by the corresponding multiple dose vaccine because of their similar release profile of antigens. Cross-reactivity was observed between HPV 16 and 18 in terms of cellular immune responses, while no cross-reactivity was found in terms of humoral immune responses. Note that other multivalent single-injection vaccines could be designed in the same way. These vaccines are expected to help prevent cervical cancer because of their broad protection, enhanced compliance and lowered vaccination cost.

Background: The Costa Rica HPV Vaccine Trial provided initial evidence that 1 dose of the bivalent human papillomavirus (HPV) vaccine induces stabilizing antibody levels that may provide extended protection against HPV-16/18 infections. We report antibody seropositivity and stability 11 to 16 years after vaccination., Methods: We invited a random subset of Costa Rica HPV Vaccine Trial participants (n = 398) who had received 3 doses and all women (n = 203) who had received 1 dose at 18 to 25 years of age to follow-up visits 11, 14, and 16 years after vaccination. We calculated HPV-16 and HPV-18 seropositivity and assessed change in enzyme-linked immunosorbent assay antibody levels 11 to 16 years after vaccination among 500 participants., Results: By year 16, 99.4% (95% confidence interval [CI] = 96.8% to 100.0%) and 100.0% (95% CI = 98.9% to 100.0%) of 1-dose and 3-dose recipients, respectively, were HPV-16 seropositive and 98.8% (95% CI = 95.9% to 99.9%) and 100% (95% CI = 98.9% to 100.0%) of 1-dose and 3-dose recipients, respectively, were HPV-18 seropositive. Between years 11 and 16, women who had received 3 doses had a small but statistically significant decrease in the geometric mean concentration for HPV-16 of ‒12.4% (95% CI = ‒16.3% to ‒8.4%) and HPV-18 of ‒13.4% (95% CI = ‒17.2% to ‒9.4%). Among women who had received 1 dose, the decrease was statistically significant for HPV-16 at ‒8.9 (95% CI = ‒14.2% to ‒3.1%) but nonsignificant for HPV-18. Geometric mean concentration ratios of 3:1 dose (year 16) were 3.0 and 2.2 for HPV-16 and HPV-18, respectively., Conclusions: HPV-16/18 seropositivity remained exceedingly high 16 years after vaccination. Over 5 years, small declines in antibodies were observed. Women should have protection for at least 20 years and likely much longer at the observed rate of decline., (Published by Oxford University Press 2024.)

Background: The World Health Organization has endorsed single-dose human papillomavirus (HPV) vaccination, but data on the impact on HPV prevalence in high HIV burden settings are limited., Methods: A single-dose bivalent HPV vaccine was delivered to adolescent girls in grade 10 in a schools-based campaign in 1 district in South Africa. Impact on HPV 16 and 18 prevalence was evaluated using repeat cross-sectional surveys. A clinic-based survey in girls aged 17-18 years established HPV 16 and 18 prevalence in a prevaccine population (n = 506, including 157 living with HIV) in 2019 and was repeated in the same age group and sites in a single-dose eligible population in 2021 (n = 892, including 117 with HIV). HPV DNA was detected on self-collected vaginal swabs using the Seegene Anyplex II HPV 28. Population impact was estimated overall and by HIV status using prevalence ratios adjusted for differences in sexual behavior between surveys., Results: Single-dose vaccination campaign coverage was 72% (4807 of 6673) of eligible girls attending high school (n = 66) in the district. HPV 16 and 18 prevalence was 35% lower in the postvaccine survey overall (adjusted prevalence ratio = 0.65, 95% confidence interval [CI] = 0.51 to 0.83; P < .001) and 37% lower in those living with HIV (adjusted prevalence ratio = 0.63, 95% CI = 0.41 to 0.95; P  = .026). No protective effect was seen for nonvaccine oncogenic HPV types 33, 35, 39, 51, 52, 56, 58, 59, or 68 overall (adjusted prevalence ratio = 1.14, 95% CI = 1.03 to 1.26; P = .011) or in those living with HIV (adjusted prevalence ratio = 1.00, 95% CI = 0.83 to 1.21. P = 0.99)., Conclusion: These data provide reassuring evidence of single-dose impact on population-level HPV 16 and 18 prevalence in a South African population, irrespective of HIV status., (© The Author(s) 2024. Published by Oxford University Press.)

Persistent infection with high-risk human papillomavirus (HPV) types can lead to the development of cancer in HPV-infected tissues, including the cervix, oropharynx, anus, penis, vagina, and vulva. While current HPV vaccines cover approximately 90 % of cervical cancers, nearly 10 % of cases associated with HPV types not included in the vaccines remain unaddressed, notably HPV59. This study describes the development of a chimeric virus-like particle (VLP) targeting HPV18/45/59, proposed as a vaccine candidate for high-risk HPV type (HPV59) currently lacking commercial vaccines. Given that the majority of neutralizing antibody epitopes are located on the surface loops, we engineered a strategic swap of these loops between the closely related HPV18 and HPV45. This methodology was then extended to incorporate surface loops of HPV59, resulting in the lead candidate construct of the H18-45BCEF-59HI chimeric VLP with two surface loops swapping from HPV45 to HPV18. Characterization confirmed that H18-45BCEF-59HI closely resembled the wild-type (WT) backbone types in particle size and morphology, as verified by Transmission Electron Microscopy (TEM), High-Performance Size-Exclusion Chromatography (HPSEC), and Analytical Ultracentrifugation (AUC), and demonstrated similar thermal stability as evidenced by Differential Scanning Calorimetry (DSC). Immunization studies in mice with the chimeric VLPs assessed their immunogenicity, revealing that the H18-45EF-59HI chimeric VLP exhibited optimal cross-neutralization. Additionally, when produced in a Good Manufacturing Practice (GMP)-like facility, the H18-45BCEF-59HI VLP was selected as a promising vaccine candidate for the prevention of HPV18/45/59 infection. This study not only offers a potential solution to the current vaccination gap but also provides a foundational approach for the design of vaccines targeting viruses with multiple subtypes or variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Bivalent human papillomavirus HPV16/18-AS04 vaccine (Cervarix, GSK) offers direct protection against HPV16/18. Results from randomised controlled trials showed cross protective effects and suggested that declines in some closely related HPV types could be expected in a population with high vaccination coverage., Aim: To evaluate the evidence for cross-protection afforded by HPV16/18-AS04 from post-implementation surveillance in England, and how this complements clinical trial data and post-implementation observations in other countries., Methods: Evidence of cross-protection in young women offered vaccination with HPV16/18-AS04 was gathered from HPV surveillance in England. Data from clinical trials and other post-implementation studies were reviewed., Results: Surveillance using anonymised residual specimens in England found declines of 52.3%, 67.4% and 33.3% against grouped HPV-31/33/45 in 16-18, 19-21, and 22-24 year olds, respectively. Additionally, type-specific analysis found that the prevalence of HPV31 declined to below 1% across all age groups. Cross-protection has been monitored and maintained for over 10 years since the introduction of the vaccination programme. Cross-protection against HPV6/11 was not found in English surveillance outcomes., Conclusion: Surveillance of type-specific infections in vaccine-eligible populations in England has generated clear evidence of cross-protective effects from HPV16/18-AS04 vaccination against high-risk HPV 31/33/45 infections, consistent with other post-implementation observations and confirming and in some ways exceeding expectations from clinical trials., Competing Interests: Declaration of competing interest ANT, VW and EG are employed by GSK. ANT may hold shares. sVW and EG hold shares in GSK. BB was a former GSK employee and he may hold company shares. VW is listed as inventor of patented unrelated vaccines. These authors declare no other financial and non-financial relationships and activities. The Blood Safety, Hepatitis, Sexually Transmitted Infections (STI) and HIV Service at UKHSA has provided GSK with post-marketing surveillance reports on HPV infections; a cost recovery charge is made for these reports. All other authors have no further conflict of interests. Funding statement: GlaxoSmithKline Biologicals SA took in charge all costs associated with the development and publishing of this manuscript., (Copyright © 2024 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate human papillomavirus (HPV) vaccine effectiveness in a cohort of Korean women infected with HPV., Methods: From 2010 to 2021, Korean women aged 20-60 years who diagnosed HPV-positive atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion were recruited from 6 hospitals. HPV vaccine effectiveness was estimated by observing the differences in pathological and clinical information and experimental results-prevalence, viral load (VL), physical state (PS), and HPV16/18 infection duration-between the vaccinated and unvaccinated groups., Results: HPV16/18 prevalence declined from 18.5% to 11.8% as vaccination rates increased from 14.3% to 60.7% in the 1,757 registered cohort women. DNA analysis from 96 samples collected from the participants, indicated that HPV vaccination reduced HPV16 VL by 6 times and increased E2/E6 ratio for both HPV16 and HPV18 by 1.4 and 5 times, respectively. The HPV16 infection rate-lasting more than 18 months from 31.0% to 21.6%-and the HPV18 infection rate-lasting more than 12 and less than 24 months from 35.5% to 21.1%-were reduced by vaccination. We found VL and the infection duration to be directly proportional. Moreover, HPV vaccination reduced not only the VL to 1/4 in both the persistence and clearance groups but also the persistence rate from 90% (27/30) to 70.6% (12/17) in HPV16., Conclusion: HPV vaccination reduced the prevalence and duration of infection and kept the PS in an episomal form for both HPV16 and HPV18. The tendency of persistence VL to be higher than clearance in the unvaccinated group implies that the vaccine's effect of reducing VL in HPV16 may lower the risk of progression to cervical cancer by shortening the infection duration., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Human papillomavirus (HPV) proteins may elicit antibody responses in the process toward HPV-related malignancy. However, HPV seroepidemiology in noncervical HPV-related cancers remains poorly understood, particularly in populations with a high prevalence of human immunodeficiency virus (HIV). Using a glutathione S-transferase-based multiplex serology assay, antibodies against E6, E7 and L1 proteins of HPV16 and HPV18 were measured in sera of 535 cases of noncervical HPV-related cancers (anal (n = 104), vulval (n = 211), vaginal (n = 49), penile (n = 37) and oropharyngeal (n = 134)) and 6651 non-infection-related cancer controls, from the Johannesburg Cancer Study that recruited Black South African with newly diagnosed cancer between 1995 and 2016. Logistic and Poisson regression models were used to calculate adjusted odds ratios (aOR) and prevalence ratios (aPR) and 95% confidence intervals (CI) in cases versus controls. HPV16 E6 was more strongly associated with noncervical HPV-related cancers than HPV16 L1 or E7, or HPV18 proteins: anal (females (HPV16 E6 aOR = 11.50;95%CI:6.0-22.2), males (aOR = 10.12;95%CI:4.9-20.8), vulval (aOR = 11.69;95%CI:7.9-17.2), vaginal (aOR = 10.26;95%CI:5.0-21), penile (aOR = 18.95;95%CI:8.9-40), and oropharyngeal (females (aOR = 8.95;95%CI:2.9-27.5), males (aOR = 3.49;95%CI:1.8-7.0)) cancers. HPV16-E6 seropositivity ranged from 24.0% to 35.1% in anal, vulval, vaginal and penile cancer but was significantly lower (11.2%) in oropharyngeal cancer. After adjustment for HIV, prevalence of which increased from 22.2% in 1995-2005 to 54.1% in 2010-2016, HPV16 E6 seropositivity increased by period of diagnosis (aPR for 2010-2016 vs. 1995-2006 = 1.84;95%CI:1.1-3.0). Assuming HPV16 E6 seroprevalence reflects HPV attributable fraction, the proportion of certain noncervical-HPV-related cancers caused by HPV is increasing over time in South Africa. This is expected to be driven by the increasing influence of HIV., (© 2024 International Agency for Research on Cancer. International Agency for Research on Cancer retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8 + T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections., Competing Interests: Declaration of interests S.C., J.W., W.Z., and Y.D. are co-inventors on pending patent applications related to the HPV-associated mRNA vaccine. H.L., H.Z., H.C., Y.W., T.Z., Y.C., Q.W., J.Z., C.H., Y.D., and W.Z. are employees of RinuaGene Biotechnology Co., Ltd., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Given low seroconversion rates following human papillomavirus (HPV) infection, fixed external cutoffs may lead to errors in estimating HPV seroprevalence. We evaluated finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) among unvaccinated, sexually active, HPV-exposed women to determine study-specific HPV16 and HPV18 seropositivity thresholds. We included 399 women (aged 18-24 years) enrolled in the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study between 2005 and 2011 in Montreal, Canada. Participants' blood samples from up to six visits spanning 2 years were tested by multiplex serology for antibodies [median fluorescence intensity (MFI)] specific to bacterially expressed HPV16 and HPV18 L1 glutathione S-transferase fusion proteins. We applied FMM and GBTM to baseline and longitudinal antibody titer measurements, respectively, to define HPV type-specific seronegative and seropositive distributions. Study-specific thresholds were generated as five standard deviations above the mean seronegative antibody titers, mimicking cutoffs (HPV16: 422 MFI; HPV18: 394 MFI) derived from an external population of sexually inactive, HPV DNA-negative Korean women (aged 15-29 years). Agreement (kappa) of study-specific thresholds was evaluated against external cutoffs. Seroprevalence estimates using FMM (HPV16: 27.5%-43.2%; HPV18: 21.7%-49.5%) and GBTM (HPV16: 11.8%-11.8%; HPV18: 9.9%-13.4%) thresholds exceeded those of external cutoffs (HPV: 10.2%; HPV18: 9.7%). FMM thresholds showed slight-to-moderate agreement with external cutoffs (HPV16: 0.26%-0.46%; HPV18: 0.20%-0.56%), while GBTM thresholds exhibited high agreement (HPV16: 0.92%-0.92%; HPV18: 0.82%-0.99%). Kappa values suggest that GBTM, used for longitudinal serological data, and otherwise FMM, for cross-sectional data, are robust methods for determining the HPV serostatus without prior classification rules.IMPORTANCEWhile human papillomavirus (HPV) seropositivity has been employed as an epidemiologic determinant of the natural history of genital HPV infections, only a fraction of women incidentally infected with HPV respond by developing significant antibody levels. HPV seropositivity is often determined by a dichotomous fixed cutoff based on the seroreactivity of an external population of women presumed as seronegative, given the lack of evidence of HPV exposure. However, considering the variable nature of seroreactivity upon HPV infection, which arguably varies across populations, such externally defined cutoffs may lack specificity to the population of interest, causing inappropriate assessment of HPV seroprevalence and related epidemiologic uses of that information. This study demonstrates that finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) can be used to independently estimate seroprevalence or serve as the basis for defining study-specific seropositivity thresholds without requiring prior subjective assumptions, consequently providing a more apt internally valid discrimination of seropositive from seronegative individuals., Competing Interests: E.L.F. has served as an occasional advisor to companies involved with human papillomavirus (HPV) diagnostics (Roche, BD, Qiagen, and Gen-Probe) and HPV vaccines (Merck and GSK). His institution has received unconditional grants from Merck in aid of investigator-initiated studies. M.Z. and E.L.F. hold a patent related to the discovery "DNA methylation markers for early detection of cervical cancer", registered at the Office of Innovation and Partnerships, McGill University, Montreal, Quebec, Canada (October 2018). F.C. has received grants or free reagents through his institution from Merck Sharp and Dohme, Becton Dickinson and Roche, as well as honoraria from Merck and Roche for lectures on HPV. T.W. serves on advisory boards for MSD (Merck) Sharp & Dohme. All other authors report no potential conflicts of interest. None of the work presented in this manuscript was paid for or influenced by any of the aforementioned companies.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The Cancer Epidemiology Research Program from Catalan Institute of Oncology (ICO-IDIBELL) has received sponsorship/grants and free reagents from MSD, Roche, GSK, IDT, Hologic and Seegene, as well as structural funds from CIBERESP and the Government of Catalonia. None of these entities had any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript, nor alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 López-Codony et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Vaccination against human papillomavirus (HPV) is changing the performance of cytology as a cervical screening test, but its effect on HPV testing is unclear. We review the effect of HPV16/18 vaccination on the epidemiology and the detection of HPV infections and high-grade cervical lesions (CIN2+) to evaluate the likely direction of changes in HPV test accuracy. The reduction in HPV16/18 infections and cross-protection against certain non-16/18 high-risk genotypes, most notably 31, 33, and/or 45, will likely increase the test's specificity but decrease its positive predictive value (PPV) for CIN2+. Post-vaccination viral unmasking of non-16/18 genotypes due to fewer HPV16 co-infections might reduce the specificity and the PPV for CIN2+. Post-vaccination clinical unmasking exposing a higher frequency of CIN2+ related to non-16/18 high-risk genotypes is likely to increase the specificity and the PPV of HPV tests. The effect of HPV16/18 vaccination on HPV test sensitivity is difficult to predict based on these changes alone. Programmes relying on HPV detection for primary screening should monitor the frequency of false-positive and false-negative tests in vaccinated (younger) vs. unvaccinated (older) cohorts, to assess the outcomes and performance of their service., (© 2024. The Author(s).)

HPV vaccination with concomitant HPV-based screening of young women has been proposed for faster cervical cancer elimination. We describe the baseline results of a population-based trial of this strategy to reduce the incidence of HPV. All 89,547 women born 1994-1999 and resident in the capital region of Sweden were personally invited to concomitant HPV vaccination and HPV screening with 26,125 women (29.2%) enrolled between 2021-05-03 and 2022-12-31. Baseline HPV genotyping of cervical samples from the study participants finds, compared to pre-vaccination prevalences, a strong decline of HPV16 and 18 in birth cohorts previously offered vaccination, some decline for cross-protected HPV types but no decline for HPV types not targeted by vaccines. Our dynamic transmission modelling predicts that the trial could reduce the incidence of high-risk HPV infections among the 1994-1998 cohorts by 62-64% in 3 years. Baseline results are prevalences of HPV infection, validated transmission model projections, and power estimates for evaluating HPV incidence reductions at follow-up (+/-0.1% with 99.9% confidence). In conclusion, concomitant HPV vaccination and HPV screening appears to be a realistic option for faster cervical cancer elimination. Clinicaltrials.gov identifier: NCT04910802; EudraCT number: 2020-001169-34., (© 2024. The Author(s).)

Introduction: Persistent infections with the human papilloma viruses, HPV16 and HPV18, are associated with multiple cancers. Although prophylactic vaccines that induce HPV-neutralizing antibodies are effective against primary infections, they have no effect on HPV-mediated malignancies against which there is no approved immuno-therapy. Active research is ongoing in the immunotherapy of these cancers., Areas Covered: In this review, we compared the preclinical efficacy of vaccine platforms used to treat HPV-induced tumors in the standard model of mice grafted with TC-1 cells, which express the HPV16 E6 and E7 oncoproteins. We searched for the key words, 'HPV,' 'vaccine,' 'therapy,' 'E7,' 'tumor,' 'T cells', and 'mice' for the period from 2005 to 2023 in PubMed and found 330 publications. Among them, we selected the most relevant to extract preclinical antitumor results to enable cross-sectional comparison of their efficacy., Expert Opinion Section: We compared these studies for HPV antigen design, immunization regimen, immunogenicity, and antitumor effect, considering their drawbacks and advantages. Among all strategies used in murine models, certain adjuvanted proteins and viral vectors showed the strongest antitumor effects, with the use of lentiviral vectors being the only approach to result in complete tumor eradication in 100% of experimental individuals while providing the longest-lasting memory.

Background: Young survivors of cancer are at increased risk for cancers that are related to human papillomavirus (HPV), primarily caused by oncogenic HPV types 16 and 18. We aimed to examine the immunogenicity and safety of the three-dose series of HPV vaccine in young survivors of cancer., Methods: We conducted an investigator-initiated, phase 2, single-arm, open-label, non-inferiority trial at five National Cancer Institute-designated comprehensive cancer centres in the USA. Eligible participants were survivors of cancer who were HPV vaccine-naive, were aged 9-26 years, in remission, and had completed cancer therapy between 1 and 5 years previously. Participants received three intramuscular doses of either quadrivalent HPV vaccine (HPV4; enrolments on or before March 1, 2016) or nonavalent HPV vaccine (HPV9; enrolments after March 1, 2016) over 6 months (on day 1, at month 2, and at month 6). We also obtained data from published clinical trials assessing safety and immunogenicity of HPV4 and HPV9 in 9-26-year-olds from the general population, as a comparator group. The primary endpoint was antibody response against HPV types 16 and 18 at month 7 in the per-protocol population. A response was deemed non-inferior if the lower bound of the multiplicity-adjusted 95% CI was greater than 0·5 for the ratio of anti-HPV-16 and anti-HPV-18 geometric mean titres (GMTs) in survivors of cancer versus the general population. Responses were examined separately in male and female participants by age group (ie, 9-15 years and 16-26 years). Safety was assessed in all participants who received at least one vaccine dose and for whom safety data were available. This study is registered with ClinicalTrials.gov, NCT01492582. This trial is now completed., Findings: Between Feb 18, 2013, and June 22, 2018, we enrolled 453 survivors of cancer, of whom 436 received one or more vaccine doses: 203 (47%) participants had survived leukaemia, 185 (42%) were female, and 280 (64%) were non-Hispanic white. Mean age at first dose was 15·6 years (SD 4·6). 378 (83%) of 453 participants had evaluable immunogenicity data; main reasons for exclusion from per-protocol analysis were to loss to follow-up, patient reasons, and medical reasons. Data were also obtained from 26 486 general population controls. The ratio of mean GMT for anti-HPV types 16 and 18 in survivors of cancer versus the general population was more than 1 for all subgroups (ie, aged 9-15 years, aged 16-26 years, male, and female groups) in both vaccine cohorts (ranging from 1·64 [95% CI 1·12-2·18] for anti-HPV type 16 in female participants aged 9-15 years who received HPV9, to 4·77 [2·48-7·18] for anti-HPV type 18 in male participants aged 16-26 years who received HPV4). Non-inferiority criteria were met within each age and sex subgroup, except against HPV type 18 in female participants aged 16-26 years receiving HPV9 (4·30 [0·00-9·05]). Adverse events were reported by 237 (54%) of 435 participants; injection site pain was most common (174 [40%] participants). One serious adverse event (ie, erythema nodosum) was possibly related to vaccine (HPV9; 16-26 year female cohort)., Interpretation: Immunogenicity and safety of HPV vaccine three-dose series in survivors of cancer is similar to that in the general population, providing evidence for use in this clinically vulnerable population., Funding: US National Cancer Institute, Merck, Sharp & Dohme, and American Lebanese Syrian Associated Charities., Competing Interests: Declaration of interests JAC reports payment for a consulting or advisory role for X4 Pharmaceuticals. ARG reports payment for membership of a scientific advisory board and global advisory board for, honoraria from, and funds to their institution to conduct research studies unrelated to this research from Merck Sharp & Dohme. MMH reports payment for a consulting or advisory role for the Oncology Research Information Exchange Network Patient Advisory Committee, Princess Maxima Center Scientific Advisory Board, and SurvivorLink. WL reports non-financial support (provision of vaccine and laboratory analysis) to their institution related to this research from Merck Sharp & Dohme and payment for a consulting or advisory role for SurvivorLink. ML reports payment for consulting for Oncoceutics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 ( P <0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.

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., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination., Methods: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702., Findings: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed)., Interpretation: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests PB has received research funding from GlaxoSmithKline through the Chittaranjan National Cancer Institute (Kolkata, India) during his previous position at the institute. NB has received research funding through her institute from GlaxoSmithKline and Merck. SJ has received funds from GlaxoSmithKline through the Jehangir Clinical Development Center (Pune, India) for a human papillomavirus vaccine study. All other authors declare no competing interests., (© 2021 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Human papilloma virus (HPV) is one of the most common causes of sexually transmitted viral diseases worldwide. High-risk HPV types such as HPV16 and 18 are known to cause cervical dysplasia and carcinoma. In human immunodeficiency virus (HIV)-positive individual, chance of HPV coinfection and risk of cervical dysplasia/carcinoma have been found to be significantly more than in HIV-negative individuals., Aim: In this institution-based, cross-sectional, observational study, we aim to find out the relationship of HPV infection of the uterine cervix with cervical dysplasia and neoplasia in HIV-infected/AIDS patients., Materials and Methods: Conventional Pap smears were taken from HIV-infected individuals admitted in the department of gynecology and obstetrics and reported by the Bethesda system. A second sample was sent to the virology unit of ICMR for detection and typing of HPV. Control samples were taken from HIV-negative individuals., Results: Fifty HIV-positive patients were included in this study. On cervical Pap smear examination, 32 cases were cytologically benign and 18 cases showed atypical cytomorphology. Twenty-four cases were HPV positive, among which 16 were cytologically atypical and 8 were benign. HPV 16 was the most common subtype (50%) followed by HPV 18 (37.5%) and others (12.5%) in HIV-positive patients. Chance of cervical dysplasia increased with age independent of HIV infection and with progressive lower CD4 count. Koilocytosis was a significant predictor of HPV infection. Majority of patients were asymptomatic. Peak incidence of HPV infection occurred in reproductive age group (20-40 years). The association between HIV and HPV coinfection (P = 0.002) and between HPV infection and cytology atypia (P < 0.0001) was statistically significant., Conclusion: Present study highlights the necessity of routine cervical Pap smear screening in HIV infected reproductive age-group women. Early detection enables dysplasia to revert or be effectively managed., Competing Interests: None

More than 99% of cervical cancers are associated with human papillomaviruses (HPVs) worldwide. Current HPV vaccines are safe, highly immunogenic, with effective immunity against specific HPV types. However, DNA vaccines are a new appealing platform which can be considered for designing the HPV vaccines. This study aimed to construct a recombinant eukaryotic expression plasmid containing L1 of HPV-18, tissue plasminogen activators (tPA), and pan HLA DR-binding epitope (PADRE) genes into the pVAX1 vector. The L1, tPA, and PADRE genes were amplified in a thermocycler. The polymerase chain reaction (PCR) products were cloned and insertion of the genes was confirmed using colony PCR, restriction enzymes analysis, and sequencing methods. Indirect immunofluorescence, RT-PCR, and western blot assays were applied to identify the target gene in HEK-293 cells. Total IgG and its isotypes in immunized mice were measured by enzyme-linked immunosorbent assay technique. Western blot analysis showed a protein band of about 67.5 kDa in supernatant and cell lysate of transfected cells. The results of mice immunization with different constructs (group 1: the pVAX-L1, group 2: pVAX-tPA-PADRE-L1, group 3: pVAX1, and group 4: PBS as controls) indicated that the pVAX1-tPA-PADRE-L1 construct induced a significantly higher level of total IgG than pVAX1-L1 (p=0.003). In conclusion, pVAX1-tPA-PADRE-L1 recombinant plasmid is a highly immunogenic construct and suggests as a promising candidate for vaccine development against HPV type 18 in low-middle-income countries.

Objectives: Oropharyngeal squamous cell carcinoma is the most common human papillomavirus (HPV)-associated cancer in the UK, but little is known about the prevalence of oropharyngeal HPV in sexually active teenagers. We investigated reported HPV vaccination coverage (in females) and prevalence of oropharyngeal HPV in sexually active students attending six technical colleges in London, UK., Methods: In 2017, we obtained mouthwash samples and questionnaires from male and female students taking part in the 'Test n Treat' chlamydia screening trial. Samples were subjected to HPV genotyping., Results: Of 232 participants approached, 202 (87%) provided a mouthwash sample and questionnaire. Participants' median age was 17 years and 47% were male. Most (73%) were from black and minority ethnic groups, 64% gave a history of oral sex, 52% reported having a new sexual partner in the past 6 months, 33% smoked cigarettes, 5.9% had concurrent genitourinary Chlamydia trachomatis infection and 1.5% Neisseria gonorrhoeae and 5.0% were gay or bisexual. Only 47% (50/107) of females reported being vaccinated against HPV 16/18, of whom 74% had received ≥2 injections. HPV genotyping showed three mouthwash samples (1.5%, 95% CI 0.3% to 4.3%) were positive for possible high-risk human papillomavirus (HR-HPV), one (0.5%, 0.0% to 2.7%) for low-risk HPV 6/11, but none (0.0%, 0.0% to 1.8%) for HR-HPV. Four samples (2.0%, 0.5% to 5.0%) were positive for HPV16 using a HPV16 type-specific quantitative PCR, but these were at a very low copy number and considered essentially negative., Conclusions: Despite the high prevalence of oral sex and genitourinary chlamydia and low prevalence of HPV vaccination, the prevalence of oropharyngeal HR-HPV in these adolescents was negligible., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood. We evaluated co-factors for acquisition, persistence, and progression of non-HPV-16/18 infections among HPV-vaccinated women., Methods: We analyzed 2153 women aged 18-25 years randomized to the HPV-vaccine arm of the Costa Rica HPV Vaccine Trial. Women were HPV DNA negative for all types at baseline and followed for approximately 11 years. Generalized estimating equation methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonally related factors, number of full-term pregnancies (FTPs), smoking behavior, and baseline body mass index., Results: A total of 1777 incident oncogenic non-HPV-16/18 infections were detected in 12 292 visits (average, 0.14 infections/visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV-16/18 acquisition. Twenty-six percent of incident infections persisted for ≥1 year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV-16/18 infections. Risk of progression to Cervical Intraepithelial Neoplasia grade 2 or worst (CIN2+) increased with increasing age (P for trend = .001), injectable contraceptive use (relative risk, 2.61 [95% confidence interval, 1.19-5.73] ever vs never), and increasing FTPs (P for trend = .034)., Conclusions: In a cohort of HPV-16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV-16/18 infections; no notable factors are associated with persistence of acquired infections; and age, parity, and hormonally related exposures are associated with progression to CIN2+., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial., Methods and Findings: In 2007-2010, the 1992-1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005-2010) and post-vaccination era (2011-2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005-2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR16 = 0.64, 95% CI 0.10-0.85; PR18 = 0.72, 95% CI 0.22-0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR16 = 0.64, 95% CI 0.50-0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR31/33/35/45 = 0.88, 95% CI 0.81-0.97) were replicated in Arm C (PR31/33/35/45 = 0.79, 95% CI 0.69-0.90)., Conclusions: In this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels., Trial Registration: ClinicalTrials.gov number NCT00534638, https://clinicaltrials.gov/ct2/show/NCT00534638., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: M.L. has previously received grants from Merck & Co. and GSK Biologicals through his employers the Finnish Institute of Health and Welfare (THL) and the University of Tampere for HPV vaccination studies.

Background: Human papillomavirus (HPV)-associated cervical cancer is a leading cause of death among Indian women. Indian women living with HIV (WLWH) may be at especially high risk. The quadrivalent HPV (qHPV) vaccine is effective in prevention of initial infection with HPV-6/11/16/18 in HIV-negative women. Little is known about previous exposure to HPV-6/11/16/18, safety, and immunogenicity of qHPV in Indian WLWH., Methodology: One hundred fifty WLWH with different CD4 levels and HIV viral load (VL) were vaccinated at 0/2/6 months at CART-CRS-IDMC, Chennai, India. Serology was performed at weeks 0, 28, and 52 for HPV-6/11/16/18 using a competitive Luminex immunoassay and for HPV-16/18 using a pseudovirion-based neutralization assay., Results: Mean age was 30.8 years (range, 19-44 years). 71/87/73/81% of women were naive (sero-negative and DNA-negative) to HPV-6/11/16/18 at baseline, respectively. Among per-protocol women naive to HPV-6/11/16/18 at baseline, 100/99/99/90%, respectively, seroconverted at week 28 and 95/96/98/71% were sero-positive at week 52, respectively. Pseudovirion-based neutralization assay identified more seroconversion to HPV-18 than competitive Luminex immunoassay. There were no significant differences in the proportion seroconverting by baseline or nadir CD4 or HIV VL; however, there was a trend for increased proportion seroconverting to HPV-18 among women with higher baseline CD4 level (P = 0.052). There were no qHPV-related serious adverse events and no change in CD4 level or HIV VL among women on ART., Conclusions: qHPV vaccine was safe and immunogenic in Indian WLWH. A high proportion were naive to HPV-6/11/16/18 and may benefit from vaccination although many were married and several years post-initiation of sexual activity., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical trial data and real-world evidence suggest that the AS04-adjuvanted vaccine targeting human papillomavirus types 16 and 18 (AS04-HPV-16/18) vaccine provides nearly 90% protection against cervical intraepithelial neoplasia grade 3 or higher irrespective of type, among women vaccinated before sexual debut. This high efficacy is not fully explained by cross-protection. Although AS04-HPV-16/18 vaccination does not affect clearance of prevalent infections, it may accelerate clearance of newly acquired infections. We pooled data from 2 large-scale randomized controlled trials to evaluate efficacy of the AS04-HPV-16/18 vaccine against clearance of nontargeted incident infections. Results of our analysis do not suggest an effect in expediting clearance of incident infections., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Objectives/hypothesis: The accurate diagnostic assessment of clinically relevant human papillomavirus (HPV) infections in patients with head and neck squamous cell carcinoma represents an urgent unmet medical need. The aim of this study was to determine feasibility, accuracy, and clinical significance of HPV16/18 E6 oncoprotein detection on cytological specimens from oropharyngeal squamous cell carcinoma (OPSCC) and neck lymph node metastasis of SCC from unknown primary tumor (CUP) via a protein immunochromatographic assay., Study Design: Cross-sectional study., Methods: Cytological specimens from primary tumor and neck metastases were collected from 34 patients with OPSCC or CUP and applied to a lateral flow format test that detects HPV16 and HPV18 E6 oncoproteins. E6 oncoprotein positivity or negativity in these specimens was compared to the specimens' "HPV-driven" reference status, defined by presence of HPV-DNA in combination with p16 INK4a overexpression and/or HPV E6 seropositivity., Results: Eighteen of 29 OPSCC (62%) and three of five CUP (60%) were HPV-driven according to our reference method. The E6 oncoprotein lateral flow test had a sensitivity of 94% (95% CI: 70%-100%) and a specificity of 100% (95% CI: 66%-100%) on primary tumor, and a sensitivity of 88% (95% CI: 64%-99%) and a specificity of 100% (95% CI: 74%-100%) on neck metastases. Test agreement between the E6 lateral flow test and the clinical reference method, HPV-DNA plus p16 INK4a was excellent, both for primary lesion and neck metastases., Conclusions: We found the detection of HPV16/18 E6 oncoproteins to be a feasible, highly reliable, and low-invasive method to assess "HPV-driven" status in OPSCC and CUP., Level of Evidence: II Laryngoscope, 131:1042-1048, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Persistent infection with high-risk mucosal human papillomavirus (HPV) types has much association with the development of cervical cancer. The major capsid protein L1 has been confirmed to be a major candidate antigen for the development of vaccines. Here, the HPV18 L1 protein was successfully expressed and purified, then nine anti-HPV18 L1 monoclonal antibodies were prepared. Four neutralizing monoclonal antibodies (NmAbs) were identified by using hemagglutination inhibition assay and pseudovirus based neutralization assay. The results of Dot-ELISA, Western blot and indirect immunofluorescence assay showed that the neutralizing antibodies could cross-react with HPV16/18/45/31/33/58/35/39 L1. The mimotopes on HPV18/45 L1 proteins were identified and analyzed by using both phage display and Bioinformatics tool. The B cell epitopes 43-54 aa and 116-126 aa of HPV18 L1 protein, the B cell epitope 381-389 aa of HPV45 L1 protein, and the mimotopes epitope of HPV45 L1 protein were identified by peptide-ELISA and competitive ELISA. The results of PyMOL and Pepitope server analysis indicated that epitopes recognized by NmAbs 7F4, 5A6, 3G11, and 2F5 are located on the surface of L1 VLPs. The results of this study enriched the library of HPV neutralizing antibodies, revealed the mechanism of antibody neutralization, might open new perspectives on the antibody-antigen reaction and have important implications for the development of novel HPV vaccines., Competing Interests: Declaration of competing interest The authors declare that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2021. Published by Elsevier B.V.)

The human papillomavirus (HPV) vaccines may provide some level of cross-protection against high-risk HPV genotypes not directly targeted by the vaccines. We evaluated the long-term health and economic impacts of routine HPV vaccination using either the nonavalent HPV vaccine or the bivalent HPV vaccine in the context of 48 Gavi-eligible countries. We used a multi-modeling approach to compare the bivalent with or without cross-protection and the nonavalent HPV vaccine. The optimal, that is, most cost-effective, vaccine was the vaccine with an incremental cost-effectiveness ratio below the per-capita gross domestic product (GDP) for each country. By 2100 and assuming 70% HPV vaccination coverage, a bivalent vaccine without cross-protection, a bivalent vaccine with favorable cross-protection and the nonavalent vaccine were projected to avert 14.9, 17.2 and 18.5 million cumulative cases of cervical cancer across all 48 Gavi-eligible countries, respectively. The relative value of the bivalent vaccine compared to the nonavalent vaccine increased assuming a bivalent vaccine conferred high cross-protection. For example, assuming a cost-effectiveness threshold of per-capita GDP, the nonavalent vaccine was optimal in 83% (n = 40) of countries if the bivalent vaccine did not confer cross-protection; however, the proportion of countries decreased to 63% (n = 30) if the bivalent vaccine conferred high cross-protection. For lower cost-effectiveness thresholds, the bivalent vaccine was optimal in a greater proportion of countries, under both cross-protection assumptions. Although the nonavalent vaccine is projected to avert more cases of cervical cancer, the bivalent vaccine with favorable cross-protection can prevent a considerable number of cases and would be considered a high-value vaccine for many Gavi-eligible countries., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Immunotherapy for cervical cancer should target high-risk human papillomavirus types 16 and 18, which cause 50% and 20% of cervical cancers, respectively. Here, we describe the construction and characterization of the pBI-11 DNA vaccine via the addition of codon-optimized human papillomavirus 18 (HPV18) E7 and HPV16 and 18 E6 genes to the HPV16 E7-targeted DNA vaccine pNGVL4a-SigE7(detox)HSP70 (DNA vaccine pBI-1). Codon optimization of the HPV16/18 E6/E7 genes in pBI-11 improved fusion protein expression compared to that in DNA vaccine pBI-10.1 that utilized the native viral sequences fused 3' to a signal sequence and 5' to the HSP70 gene of Mycobacterium tuberculosis Intramuscular vaccination of mice with pBI-11 DNA better induced HPV antigen-specific CD8 + T cell immune responses than pBI-10.1 DNA. Furthermore, intramuscular vaccination with pBI-11 DNA generated stronger therapeutic responses for C57BL/6 mice bearing HPV16 E6/E7-expressing TC-1 tumors. The HPV16/18 antigen-specific T cell-mediated immune responses generated by pBI-11 DNA vaccination were further enhanced by boosting with tissue-antigen HPV vaccine (TA-HPV). Combination of the pBI-11 DNA and TA-HPV boost vaccination with PD-1 antibody blockade significantly improved the control of TC-1 tumors and extended the survival of the mice. Finally, repeat vaccination with clinical-grade pBI-11 with or without clinical-grade TA-HPV was well tolerated in vaccinated mice. These preclinical studies suggest that the pBI-11 DNA vaccine may be used with TA-HPV in a heterologous prime-boost strategy to enhance HPV 16/18 E6/E7-specific CD8 + T cell responses, either alone or in combination with immune checkpoint blockade, to control HPV16/18-associated tumors. Our data serve as an important foundation for future clinical translation. IMPORTANCE Persistent expression of high-risk human papillomavirus (HPV) E6 and E7 is an obligate driver for several human malignancies, including cervical cancer, wherein HPV16 and HPV18 are the most common types. PD-1 antibody immunotherapy helps a subset of cervical cancer patients, and its efficacy might be improved by combination with active vaccination against E6 and/or E7. For patients with HPV16 + cervical intraepithelial neoplasia grade 2/3 (CIN2/3), the precursor of cervical cancer, intramuscular vaccination with a DNA vaccine targeting HPV16 E7 and then a recombinant vaccinia virus expressing HPV16/18 E6-E7 fusion proteins (TA-HPV) was safe, and half of the patients cleared their lesions in a small study (NCT00788164). Here, we sought to improve upon this therapeutic approach by developing a new DNA vaccine that targets E6 and E7 of HPV16 and HPV18 for administration prior to a TA-HPV booster vaccination and for application against cervical cancer in combination with a PD-1-blocking antibody., (Copyright © 2021 Peng et al.)

Background: Survival outcomes for patients with recurrent or advanced cervical cancer are poor. Pembrolizumab has been approved for the treatment of recurrent or metastatic cervical cancer, with an overall response rate of 14·3%. GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6-specific and E7-specific T-cell responses and cervical lesion regression in patients with cervical precancer. We aimed to investigate whether a combination of GX-188E therapeutic DNA vaccine plus pembrolizumab showed antitumour activity against recurrent or advanced cervical cancer., Methods: In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced, inoperable cervical cancer, who were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically confirmed recurrent or advanced HPV-positive (HPV-16 or HPV-18) cervical cancer, and who had progressed after available standard-of-care therapy were recruited from seven hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, and 19, with one optional dose at week 46 that was at the investigator's discretion, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the overall response rate within 24 weeks assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 in patients who received at least 45 days of treatment 45 days of treatment with at least one post-baseline tumour assessment, and this is the report of a planned interim analysis. This trial is registered with ClinicalTrials.gov, NCT03444376., Findings: Between June 19, 2018, and March 20, 2020, 36 patients were enrolled and received at least one dose of the study treatment. 26 patients were evaluable for interim activity assessment, with at least one post-baseline tumour assessment at week 10. At the data cutoff date on March 30, 2020, median follow-up duration was 6·2 months (IQR 3·5-8·1). At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a partial response. 16 (44%) of 36 patients had treatment-related adverse events of any grade and four (11%) had grade 3-4 treatment-related adverse events. Grade 3 increased aspartate aminotransferase, syncope, pericardial effusion, and hyperkalaemia, and grade 4 increased alanine aminotransferase were reported in one patient each. No treatment-related deaths were reported., Interpretation: Treatment with GX-188E therapeutic vaccine plus pembrolizumab for patients with recurrent or advanced cervical cancer was safe and treatment-related adverse events were manageable. This combination therapy showed preliminary antitumour activity in this interim analysis, which could represent a new potential treatment option for this patient population. This trial is ongoing., Funding: National OncoVenture., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+)., Methods: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464., Findings: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine., Interpretation: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable., Funding: US National Cancer Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: In 9-17-year-old Chinese girls, the AS04-adjuvanted HPV-16/18 vaccine (AS04-HPV-16/18) given as three-dose schedule induced high antibody levels, which were noninferior 1 month after the third dose to those observed in 18-25-year-old Chinese women in a large efficacy study. We assessed the persistence of antibodies 8-9 years after vaccination in the same subjects., Methods: This follow-up phase III, open-label study (NCT03355820) included subjects who had received three doses of AS04-HPV-16/18 in the initial trial (NCT00996125). Serum antibody concentrations were assessed by ELISA and compared to antibody persistence observed in 18-25-year-old Chinese women 6 years after first vaccination in the efficacy study (NCT00779766)., Results: Out of the 227 enrolled subjects, 223 were included in the per-protocol immunogenicity analysis. Mean interval from first AS04-HPV-16/18 dose to blood sampling was 101.4 months (8.5 years). For antibodies against HPV-16 and -18, 8.5 years after first vaccine dose all subjects remained seropositive and antibody. Geometric mean concentrations (GMCs) were 1236.3 (95% confidence interval [CI]: 1121.8; 1362.4) and 535.6 (95% CI: 478.6; 599.4) ELISA Units/mL, respectively. These seropositivity rates and antibody GMCs were higher than those observed 6 years after first vaccination of 18-25-year-old women., Conclusion: Sustained anti-HPV-16 and -18 immune responses were observed 8-9 years after AS04-HPV-16/18 vaccination of 9-17 year-old Chinese girls that were higher than the ones observed 6 years after first vaccination in Chinese adult women in whom AS04-HPV-16/18 efficacy against cervical intraepithelial neoplasia of grade ≥2 was demonstrated., (© 2020 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Human papillomavirus (HPV) causes not only most cervical cancers but also cancers of the vagina, vulva, penis, anus, rectum, and oropharynx. Every year, 200,000 women die of cervical cancer in the world, and China accounts for about 10%. HPV vaccines are effective in preventing HPV infections thus HPV-related cancers worldwide. Studies on the clinical trials of the 2v Cervarix™ and the 4v Gardasil® have suggested that immunization with either of these vaccines provided some level of protection against other HPV types that are closely related to the types contained in the vaccines. Here we conducted a preliminary evaluation on the ability to induce cross-neutralizing antibodies in rhesus monkeys by a 3v HPV vaccine that targets HPV16, 18, and 58 and it is specifically designed for Chinese women. We found that this vaccine is no less than Gardasil® in terms of the ability to induce NAbs against non-vaccine types of HPV in rhesus macaques. These results provided evidence from the immunogenicity point of view that the KLWS 3v HPV vaccine is a strong competitor to the imported 2v and 4v HPV vaccines currently available on the market., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: It is widely acknowledged that HPV prophylactic vaccine could prevent new infections and their associated lesions among women who are predominantly HPV-naive at vaccination. Yet there still remains uncertainty about whether HPV vaccination could benefit to individuals who have undergone surgery for cervical disease., Methods: This post-hoc analysis intends to focus on intent-to-treat participants who underwent excision treatment at baseline and the follow-up period in a phase II/III, double-blind, randomized trial ( ClinicalTrials.gov , number NCT00779766 ) conducted in Jiangsu province, China. We evaluate the impact of HPV vaccination on preventing women from subsequent infection and cervical lesions (LSIL+ and CIN2+) after excision treatment., Results: One hundred sixty-eight (vaccine, n = 87; placebo, n = 81) performed excisional treatment in this clinical trial. We observed a significant effect of vaccination on acquiring 14 high-risk HPV (HR-HPV) infection after treatment (vaccine efficacy: 27.0%; 95% CI 4.9, 44.0%). The vaccine efficacy against new infections after treatment for 14 HR-HPV infection was estimated as 32.0% (95%CI 1.8, 52.8%), and was 41.2% (95%CI -162.7, 86.8%) for HPV16/18 infection. The accumulative clearance rates of the vaccine group and placebo group were 88.9 and 81.6% for HPV16/18 infection (P = 0.345), 63.4, 48.7% for 14 HR-HPV infection (P = 0.062), respectively. No significant difference was observed on the persistent rate of HPV16/18, 14 HR-HPV infection and occurrence rate of LSIL+ between the two groups., Conclusions: No significant evidence from this study showed that HPV-16/18 AS04-adjuvanted vaccine could lead to viral faster clearance or have any effect on the rates of persistent infection among women who had excision treatment. However, the vaccine may still benefit post-treatment women with "primary prophylactic" effect. Further research is required in clarifying the effect of using the prophylactic HPV vaccine as therapeutic agents., Trial Registration: ClinicalTrials.gov identifier: NCT00779766 . Date and status of trial registration: October 24, 2008. Completed; Has Results.

Adjuvants are a crucial component of recombinant vaccines such as the human papillomavirus (HPV) vaccine. Monophosphoryl lipid A (MPL) extracted from Salmonella Minnesota lipopolysaccharide is used as an adjuvant for the HPV vaccine. Due to the limitations in accessibility and reproducibility of MPL, investigating synthetic analogues of MPL (synMPL) is urgently needed to overcome these limitations. In this study, female BALB/c mice were vaccinated by HPV vaccine formulated with synMPL and aluminum hydroxide gel in which the concentration of synMPL ranged from 0 to 100 μg/dose. Anti-HPV L1 VLP antibody was measured for each group through Indirect ELISA and compared with Cervarix and Gardasil vaccines as approved anti-HPV vaccines. SynMPL showed a concentration-dependent increase up to 50 μg/dose in the immunogenicity of the vaccine. Therefore, synMPL at concentration of 50 μg/dose was selected as optimum concentration. The GMT profiling of synMPL-formulated vaccine (named Papilloguard) and Cervarix was not statistically different (Mann-Whitney test). The Gardasil vaccine showed 10-fold lower GMT for anti-HPV 18 L1 VLP antibody but anti-HPV 16 L1 VLP antibody was similar to Cervarix and Papilloguard. The current findings suggest that the synMPL in combination with aluminum hydroxide could be used as a potential adjuvant candidate for human vaccine., (Copyright © 2020 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

Background: The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women., Methods: HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448)., Results: Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9-11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers., Conclusion: More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses., (Published by Oxford University Press 2020. This work is written by US Government employees and is in the public domain in the US.)

Background: Human papillomavirus (HPV) vaccination of girls with very high (>90%) coverage has the potential to eradicate oncogenic HPVs, but such high coverage is hard to achieve. However, the herd effect (HE) depends both on the HPV type and the vaccination strategy., Methods: We randomized 33 Finnish communities into gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and hepatitis B virus vaccination arms. In 2007-2010, 11 662 of 20 513 of 40 852 of 39 420 resident boys/girls from 1992 to 1995 birth cohorts consented. In 2010-2014, cervicovaginal samples from vaccinated and unvaccinated girls at age 18.5 years were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Vaccine efficacy for vaccinated girls, HE for unvaccinated girls, and the protective effectiveness (PE) for all girls were estimated. We extended the community-randomized trial results about vaccination strategy with mathematical modeling to assess HPV eradication., Results: The HE and PE estimates in the 1995 birth cohort for HPV18/31/33 were significant in the gender-neutral arm and 150% and 40% stronger than in the girls-only arm. Concordantly, HPV18/31/33 eradication was already predicted in adolescents/young adults in 20 years with 75% coverage of gender-neutral vaccination. With the 75% coverage, eventual HPV16 eradication was also predicted, but only with the gender-neutral strategy., Conclusions: Gender-neutral vaccination is superior for eradication of oncogenic HPVs., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities ., Methods: Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline., Results: A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval [CI] = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = -28.6% and 20.7%, respectively; two-sided P = .03)., Conclusions: The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+., (Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the US.)

Objectives: Data from clinical trials of human papillomavirus (HPV) vaccines showed that women naïve (negative for both type-specific antibodies and DNA) to vaccine types would derive benefit from vaccination; therefore, an understanding of the proportion of naïve women in different age groups is important for developing HPV vaccination strategies., Methods: From November 2012 to April 2013, a total of 7372 healthy women aged 18-45 years were recruited in five provinces in China. Cervical specimens and serum samples were collected for each woman at entry. Cervical specimens were first tested by the HPV DNA enzyme immunoassay method; if positive, the specimens were then tested by reverse hybridization line probe assay and HPV-16 and HPV-18 specific polymerase chain reactions. Neutralizing antibodies against HPV-16 or HPV-18 were tested with a pseudovirion-based neutralization assay., Results: The overall prevalence of high-risk HPV DNA was 14.8% (1088/7367, 95% CI 14.0-15.6), and the seroprevalence of neutralizing antibodies against HPV-16 and HPV-18 was 12.6% (925/7367) and 4.9% (364/7367), respectively. In younger women (18-26 years) and middle-aged women (27-45 years), 83.8% (3116/3719) and 81.4% (2968/3648) were naïve to both HPV-16 and HPV-18 (both neutralizing antibodies and DNA were negative), respectively. In addition, 98.5% (3664/3719) and 98.0% (3575/3648) of the younger or middle-aged women were naïve to at least one HPV type (HPV-16 or HPV-18)., Discussion: This study revealed that the majority of Chinese women aged 18-26 years and 27-45 years were naïve to both HPV-16 and HPV-18 and would thus derive full benefit from bivalent HPV vaccination., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Persistent high-risk human papillomavirus (HPV) infection is endorsed by the World Health Organization as an intermediate endpoint for evaluating HPV vaccine effectiveness/efficacy. There are different approaches to estimate the vaccine effectiveness/efficacy against persistent HPV infections., Methods: We performed a systematic literature search in Pubmed to identify statistical approaches that have been used to estimate the vaccine effectiveness/efficacy against persistent HPV infections. We applied these methods to data of a longitudinal observational study to assess their performance and compare the obtained vaccine effectiveness (VE) estimates., Results: Our literature search identified four approaches: the conditional exact test for comparing two independent Poisson rates using a binomial distribution, Generalized Estimating Equations for Poisson regression, Prentice Williams and Peterson total time (PWP-TT) and Cox proportional hazards regression. These approaches differ regarding underlying assumptions and provide different effect measures. However, they provided similar effectiveness estimates against HPV16/18 and HPV31/33/45 persistent infections in a cohort of young women eligible for routine HPV vaccination (range VE 93.7-95.1% and 60.4-67.7%, respectively) and seemed robust to violations of underlying assumptions., Conclusions: As the rate of subsequent infections increased in our observational cohort, we recommend PWP-TT as the optimal approach to estimate the vaccine effectiveness against persistent HPV infections in young women. Confirmation of our findings should be undertaken by applying these methods after longer follow-up in our study, as well as in different populations.

We studied effectiveness of the AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) vaccine against human papillomavirus (HPV) oropharyngeal infections associated with the increase of head/neck cancers in western countries. All 38,631 resident adolescents from 1994 to 1995 birth cohorts of 33 Finnish communities were invited in this community-randomized trial (NCT00534638). During 2008-2009, 11,275 girls and 6,129 boys were enrolled in three arms of 11 communities each. In Arm A, 90% of vaccinated girls/boys, and in Arm B, 90% of vaccinated girls received AS04-HPV-16/18 vaccine. Other Arm A/B and all Arm C vaccinated participants received control vaccine. All Arm A participants and Arm B female participants were blinded to vaccine allocation. Oropharyngeal samples were analyzed from 4,871 18.5-year-old females who attended follow-up visit 3-6 years postvaccination. HPV DNA prevalence was determined by SPF-10 LiPA and Multiplex type-specific PCR. Total vaccine effectiveness (VE) was defined as relative reduction of oropharyngeal HPV prevalence in pooled Arms A/B HPV-vaccinated females vs. all Arm C females. VE against oropharyngeal HPV-16/18, HPV-31/45 and HPV-31/33/45 infections were 82.4% (95% confidence intervals [CI]: 47.3-94.1), 75.3% (95%CI: 12.7-93.0) and 69.9% (95% CI: 29.6-87.1), respectively. In conclusion, the AS04-HPV-16/18 vaccine showed effectiveness against vaccine and nonvaccine HPV-types oropharyngeal infections in adolescent females up to 6 years postvaccination., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: This study assessed the safety and tolerability of therapeutic immunization against the human papillomavirus (HPV) viral oncoproteins E6 and E7 in patients with cervical cancer after chemoradiation., Methods and Materials: MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks. The primary endpoints were incidence of adverse events and injection site reactions. Immune responses against HPV antigens were measured by ELISpot for interferon-γ (IFNγ), enzyme-linked immunosorbent assay for antibody responses and multiplexed immunofluorescence for immune cells in cervical biopsy specimens., Results: Ten patients (cohort 1, n = 7; cohort 2, n = 3) with HPV16 (n = 7) or HPV18 (n = 3) cervical cancers received MEDI0457 after chemoradiation. Treatment-related adverse events were all grade 1, primarily related to the injection site. Eight of 10 patients had detectable cellular or humoral immune responses against HPV antigens after chemoradiation and vaccination: 6 of 10 patients generated anti-HPV antibody responses and 6 of 10 patients generated IFNγ-producing T cell responses. At the completion of chemoradiation and vaccination, cervical biopsy specimens had detectable CD8 + T cells and decreased PD-1 + CD8 + , PD-L1 + CD8 + , and PD-L1 + CD68 + subpopulations. All patients cleared detectable HPV DNA in cervical biopsies by completion of chemoradiation and vaccination., Conclusions: Adjuvant MEDI0457 is safe and well tolerated after chemoradiation for locally advanced or recurrent cervical cancers, supporting further investigation into combining tumor-specific vaccines with radiation therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer., Materials and Methods: Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic-polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors., Results: hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors., Conclusion: Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies., Competing Interests: Competing interests: Formune holds a patent for the use of peptides described in this work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cervical cancer associated with high risk-human papillomavirus (HR-HPV) infection is becoming the one of the most common female cancer in many sub-Saharan African countries. First-generation immigrant African women living in Europe are at-risk for cervical cancer, in a context of social vulnerability, with frequent lack of cervical cancer screening and HPV vaccination., Objective: Our objective was to address immunologically the issue of catch-up prophylactic HPV vaccination in first-generation African immigrant women living in France., Methods: IgG immune responses and cross-reactivities to α7 (HPV-18, -45 and -68) and α9 (HPV-16, -31, -33, -35, -52 and -58) HPV types, including 7 HR-HPV targeted by the Gardasil-9® prophylactic vaccine, were evaluated in paired serum and cervicovaginal secretions (CVS) by HPV L1-virus-like particles-based ELISA. Genital HPV were detected by multiplex real time PCR (Seegene, Seoul, South Korea)., Results: Fifty-one immigrant women (mean age, 41.7 years; 72.5% HIV-infected) were prospectively included. More than two-third (68.6%) of them carried genital HPV (group I) while 31.4% were negative (group II). The majority (90.2%) exhibited serum IgG to at least one α7/α9 HR-HPV. Serum HPV-specific IgG were more frequently detected in group I than group II (100% versus 68.7%; P = 0.002). The distribution of serum and genital HPV-specific IgG was similar, but mean number of IgG reactivities to α7/α9 HR-HPV was higher in serum than CVS (5.6 IgG per woman in serum versus 3.2 in CVS; P<0.001). Rates of IgG cross-reactivities against HPV different from detected cervicovaginal HPV were higher in serum and CVS in group I than group II. Finally, the majority of groups I and II women (68.6% and 68.7%, respectively) exhibited serum or cervicovaginal IgG to Gardasil-9® HR-HPV, with higher mean rates in group I than group II (6.1 Gardasil-9® HR-HPV per woman versus 1.4; P<0.01). One-third (31.2%) of group II women did not show any serum and genital HPV-specific IgG., Conclusions: Around two-third of first-generation African immigrant women living in France showed frequent ongoing genital HPV infection and high rates of circulating and genital IgG to α7/α9 HPV, generally cross-reacting, avoiding the possibility of catch-up vaccination. Nevertheless, about one-third of women had no evidence of previous HPV infection, or showed only low levels of genital and circulating HR-HPV-specific IgG and could therefore be eligible for catch-up vaccination., Competing Interests: The authors have declared that no competing interests exist.

A new HPV-16/18 bivalent vaccine expressed by the Escherichia coli has been proven to be efficacious in adult women. A randomized, immunogenicity noninferiority study of this candidate vaccine was conducted in December 2015 in China. Girls aged 9-14 years were randomized to receive 2 doses at months 0 and 6 (n=301) or 3 doses at months 0, 1 and 6 (n=304). Girls aged 15-17 years (n=149) and women aged 18-26 years (n=225) received 3 doses. The objectives included noninferiority analysis of the IgG geometric mean concentration (GMC) ratio (95% CI, lower bound>0.5) to HPV-16 and HPV-18 at month 7 in girls compared with women. In the per-protocol set, the GMC ratio of IgG was noninferior for girls aged 9-17 years receiving 3 doses compared with women (1.76 (95% CI, 1.56, 1.99) for HPV-16 and 1.93 (95% CI, 1.69, 2.21) for HPV-18) and noninferior for girls aged 9-14 years receiving 2 doses compared with women (1.45 (95% CI, 1.25, 1.62) for HPV-16 and 1.17 (95% CI, 1.02, 1.33) for HPV-18). Noninferiority was also demonstrated for neutralizing antibodies. The immunogenicity of the HPV vaccine in girls receiving 3 or 2 doses was noninferior compared with that in young adult women.

Human papillomavirus (HPV) vaccines are indicated for anal cancer prevention, but evidence for vaccine effectiveness (VE) against anal HPV infections among women is limited. We estimated the VE (≥1 dose) against anal HPV positivity of the bivalent vaccine, whose target types HPV-16/18 are associated with approximately 90% of HPV-related anal cancers. Among 548 female STI clinic visitors 16-24 years old who provided an anal swab sample as part of a repeated cross-sectional survey, VE against HPV-16/18 was 89.9% (95% confidence interval, 63.0%-97.2%). Type-specific VE correlated well with VE against cervicovaginal HPV (Spearman ρ = 0.76), suggesting comparable effectiveness of HPV-16/18 vaccination against genital and anal infections., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

More than 170 types of human papilloma viruses (HPV) exist with many causing proliferative diseases linked to malignancy in indications such as cervical cancer and head and neck squamous cell carcinoma. Characterization of antibody levels toward HPV serology is challenging due to complex biology of oncoproteins, pre-existing titers to multiple HPV types, cross-reactivity, and low affinity, polyclonal responses. Using multiplex technology from MSD, we have developed an assay that simultaneously characterizes antibodies against E6 and E7 oncoproteins of HPV16 and 18, the primary drivers of HPV-associated oncogenesis. We fusion tagged our E6 and E7 proteins with MBP via two-step purification, spot-printed an optimized concentration of protein into wells of MSD 96-well plates, and assayed various cynomolgus monkey, human and HPV+ cervical cancer patient serum to validate the assay. The dynamic range of the assay covered 4-orders of magnitude and antibodies were detected in serum at a dilution up to 100,000-fold. The assay was very precise (n = 5 assay runs) with median CV of human serum samples ~ 5.3% and inter-run variability of 11.4%. The multiplex serology method has strong cross-reactivity between E6 oncoproteins from human serum samples as HPV18 E6 antigens neutralized 5 of 6 serum samples as strongly as HPV16 E6. Moderate concordance (Spearman's Rank = 0.775) was found between antibody responses against HPV16 E7 in the multiplex assay compared to standard ELISA serology methods. These results demonstrate the development of a high-throughput, multi-plex assay that requires lower sample quantity input with greater dynamic range to detect type-specific anti-HPV concentrations to E6 and E7 oncoproteins of HPV16 and 18., Competing Interests: HL, KAR, SW, NS, CJD are current or former employees of AstraZeneca. They received compensation in the form of salary and stock as employees. AAA, JMD, and DN are current or former employees of Meso Scale Diagnostics LLC and receive compensation in the form of salary and stock. The commercial affiliations of AstraZeneca and Meso Scale Diagnostics LLC does not alter any adherence to PLOS ONE policies on sharing data and materials.

Objectives: This study aimed to systematically review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants., Methods: Medline, EMBASE, Global Health Database and Cochrane Central Register of Controlled Trials were searched for publications and conference abstracts (dated January 1999-August 2018) using MeSH and non-MeSH terms for human papillomavirus AND vaccines AND (immunogenicity OR efficacy/effectiveness) AND dosage. Search results were screened against pre-specified eligibility criteria. Data were extracted from included articles, and a narrative synthesis conducted on efficacy against HPV16/18 infection and humoral immunogenicity., Results: Seven of 6,523 unique records identified were included in the review. Six were nested observational studies of participants randomised to receive two or three doses in three large HPV vaccine trials, in which some participants did not complete their allocated schedules. One small pilot study prospectively allocated participants to receive one or no vaccine dose. Frequency of HPV16/18 infection was low (e.g. <1% for 12-month-persistent infection) in all vaccinated participants up to seven years post vaccination and did not significantly differ by number of doses (p > 0.05 in all cases). Frequency of infection was significantly lower in one-dose recipients compared to unvaccinated controls (p < 0.01 for all infection endpoints in each study). HPV16/18 seropositivity rates were high in all HPV vaccine recipients (100% in three of four studies reporting this endpoint), though antibody levels were lower with one compared to two or three doses., Conclusions: This review supports the premise that one HPV vaccine dose may be as effective in preventing HPV infection as multi-dose schedules in healthy young women. However, it also highlights the paucity of available evidence from purpose-designed, prospectively-randomised trials. Results from ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination compared to currently-recommended schedules are awaited., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)

Background: The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine., Methods: A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission., Results: In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months., Conclusions: The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18-associated high-grade genital lesions and persistent infection in women., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Data to inform evidence-based policy of human papillomavirus (HPV) vaccine delivery strategies in low- and middle-income countries are limited. We examined the cost-effectiveness of campaign compared with routine delivery strategies of adolescent female HPV vaccination in Uganda., Methods: We used a multiple modeling approach that captured HPV transmission, cervical carcinogenesis, and population demographics to project health and economic outcomes associated with HPV vaccination. Costs included vaccination and operational costs and cervical cancer costs over the lifetimes of the current female population in Uganda. Health outcomes included number of cervical cancer cases and disability-adjusted life years (DALY). Incremental cost-effectiveness ratios (i.e., cost per DALY averted) were calculated and compared against gross domestic product (GDP) per capita., Results: Compared with routine HPV vaccination of 9-year-old girls at 70% coverage, campaign vaccination yielded greater health benefits if campaigns occurred frequently and targeted a wide age range. Campaign delivery strategies were both less costly and more effective than routine HPV vaccination. Campaign vaccination of 9- to 30-year-old girls/women at a 3-year frequency (40% coverage) was considered cost-effective compared with the GDP per capita threshold for Uganda ($674 in U.S. 2015 dollars)., Conclusions: We projected that campaign HPV vaccination would provide substantial population health benefits compared with routine vaccination. Expanding the target age range of campaign vaccination up to age 30 years may be an efficient strategy, depending on the achievable coverage level and campaign frequency., Impact: In settings where routine health systems infrastructure may be limited, reaching adolescent populations with a campaign delivery strategy may be an efficient use of resources., (©2019 American Association for Cancer Research.)