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Juvenile- and adult-onset recurrent respiratory papillomatosis (JORRP and AORRP) are rare but serious conditions that are caused by oral human papillomavirus (HPV) infections. The proliferation of wart-like growths throughout the respiratory tract can result in medical problems, including death. The current treatment scheme is surgery, though prevention of HPV infection through vaccination is available. A previously developed model for JORRP and AORRP was adapted to the United States using data on disease burden and HPV infection. The model was validated against post-vaccination reductions in disease and used to forecast the future burden of JORRP and AORRP, estimating the impact that HPV vaccination will have on these diseases. Between 2007 (the beginning of HPV vaccination in the US) and 2021, this model estimates that approximately 1393 lives, 22,867 Quality-Adjusted-Life-Years, and over USD 672 million in treatment costs have been saved by HPV vaccination. There is also a substantial reduction in JORRP and AORRP burden, with a 95% reduction in incidence by 2040. Moreover, between 2040 and 2121, the model predicts 3–11 total cases of HPV6/11-related JORRP in the US, and 36–267 total cases of HPV6/11-related AORRP. HPV vaccination in the United States has driven, and will continue to drive, substantial reductions in the public health and economic burden of HPV6/11-related JORRP and AORRP. [ABSTRACT FROM AUTHOR]

In Denmark, vaccination against human papillomavirus (HPV) has been implemented in the children's vaccination program (January 2009) and in multiple catch‐up cohorts (October 2008 in girls 13‐15 years and in August 2012 in women up to 27 years). In the present study we estimate incidence of cervical intraepithelial neoplasia grade 3 (CIN3), adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma (AC) during 2000‐2019. All cases of CIN3 and AIS were identified from the nationwide Pathology Data Bank, while SCC and AC were identified from the Danish Cancer Registry. We calculated age‐standardized incidence rates and estimated annual percentage change (EAPC) with corresponding 95% confidence interval (CI) for the periods before vaccination implementation (2000‐2005), early after implementation of childhood HPV vaccination and the first catch‐up vaccination program (2006‐2012), and after implementation of the second catch‐up program (2013‐2019). For CIN3 and AIS, age‐specific incidence rates and EAPCs were calculated. An increasing age‐standardized incidence was observed before introduction of HPV vaccination (2000‐2005) for CIN3 [EAPCCIN3: 3.0 (95% CI 1.7 to 4.3)] and AIS [EAPCAIS: 3.5 (95% CI 0.7 to 6.4)]. In the most recent period (2013‐2019), following implementation of the second catch‐up program, a decrease was observed for both CIN3 [EAPCCIN3: ‐6.5 (95% CI ‐8.3 to −4.8)], AIS [EAPCAIS: ‐8.7 (95% CI ‐12.3 to −5.1)] and for SCC [EAPCSCC: ‐3.9 (95% CI ‐7.5 to −0.2)]. In this study we document a decrease in the incidence of CIN3, AIS and SCC in the period after implementation of multi‐cohort HPV vaccination in Denmark. [ABSTRACT FROM AUTHOR]

Background In men, the incidence of human papillomavirus (HPV)–related cancer is rising, but data regarding male HPV infection and seroprevalence are available from only a few countries. Methods This analysis of a global HPV vaccine trial evaluated baseline data from 1399 human immunodeficiency virus–negative heterosexual men (HM) and men who have sex with men (MSM). Key objectives included assessment of HPV prevalence and risk factors for seropositivity to 9-valent HPV (9vHPV) vaccine types (6, 11, 16, 18, 31, 33, 45, 52, and 58), and concordance between seropositivity and prevalent HPV type. Results Overall, 455 of 3463 HM (13.1%) and 228 of 602 MSM (37.9%) were HPV DNA positive for any 9vHPV vaccine type at baseline. Infection prevalence and seroprevalence (≥1 9vHPV vaccine type) were 13.2% and 8.1%, respectively, among 333 HM from Europe, and 37.9% and 29.9%, respectively, among 335 MSM from Europe or North America. Among men with baseline infection, MSM had higher seroprevalence for concordant HPV types (39.5% vs 10.8% in HM). The seropositivity risk (irrespective of baseline infection status) was higher among MSM versus HM (age-adjusted odds ratio, 3.0 [95% confidence interval, 2.4–6.4]). Among MSM, statistically significant seropositivity risk factors included younger age at sexual debut, higher number of receptive anal sex partners, and less frequent condom use. No factors assessed were associated with seropositivity in HM. Conclusions Higher proportions of MSM than HM were HPV DNA positive and seropositive, and concordance between HPV DNA positivity and seropositivity, a potential marker of true infection versus carriage, was higher in MSM. Most MSM and HM were seronegative for all 9vHPV vaccine types, suggesting the potential benefit of catch-up vaccination after sexual debut. Clinical Trials Registration. NCT00090285. [ABSTRACT FROM AUTHOR]

Vaccine effectiveness and impact studies are typically observational, generating evidence after vaccine launch in a real-world setting. For human papillomavirus (HPV) vaccination studies, the variety of data sources and methods used is pronounced. Careful selection of study design, data capture and analytical methods can mitigate potential bias in such studies. We systematically reviewed the different study designs, methods, and data sources in published evidence (1/2007–3/2020), which assessed the quadrivalent HPV vaccine effectiveness and impact on cervical/cervicovaginal, anal, and oral HPV infections, anogenital warts, lesions in anus, cervix, oropharynx, penis, vagina or vulva, and recurrent respiratory papillomatosis. The rapid growth in access to real-world data allows global monitoring of effects of different public health interventions, including HPV vaccination programs. But the use of data which are not collected or organized to support research also underscore a need to develop robust methodology that provides insight of vaccine effects and consequences of different health policy decisions. To achieve the WHO elimination goal, we foresee a growing need to evaluate HPV vaccination programs globally. A critical appraisal summary of methodology used will provide timely guidance to researchers who want to initiate research activities in various settings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The performance of cervical cancer screening will decline as a function of lower disease prevalence—a consequence of successful human papillomavirus (HPV) vaccination. Replacement of cytology with molecular HPV testing as the primary screening test and adoption of risk‐based screening, with less intense screening of vaccinated individuals and initiated at older ages is expected to improve efficiency. However, policy officials may decide to further reduce or eliminate screening as the ratio of benefits to harms continues to decline. To evaluate the level of risk currently tolerated for different cancers in the United States (ie, for which clinical guidelines do not recommend secondary prevention though effective screening methods exist), we used US cancer registry data to compare incidence (2008‐2012) and survival (1988‐2011) associated with different cancers for which organized screening is recommended and not recommended. The most common cancer at ages 70 to 74 years (ie, age group with highest cancer incidence and reasonable life expectancy to consider screening in the US) satisfying Wilson and Jungner's classic screening criteria was vulvar cancer (incidence = 9/100 000 females). In comparison, the incidence of cervical cancer among females 65 years of age (the upper recommended age limit for screening) was 13 cases per 100 000 females (low as a reflection of effective screening), whereas 10‐year survival was 66% (similar to vulvar cancer at 67%). Our approach of defining tolerable risk in cancer screening could help guide future decisions to modify cervical screening programs. [ABSTRACT FROM AUTHOR]

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+. [ABSTRACT FROM AUTHOR]

Background: Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs).Methods: Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)-two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine-to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided.Results: After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70.Conclusion: HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations. [ABSTRACT FROM AUTHOR]

Background: Recent birth cohorts vaccinated against human papillomavirus (HPV) may be protected against up to 4 genotypes (HPV-6, -11, -16, and -18). If natural competition exists between these and other HPV types, then the prevalence of other types may increase after vaccination.Methods: Cohort information from 3 studies was used to compare acquisition and clearance of 30 different HPV types (individually and grouped by species), according to infection status with vaccine-targeted types at baseline and the time of the index infection, respectively. Hazard ratios (HRs) were adjusted for predictors of multiple-type infection.Results: Among 3200 females across all studies, 857 were infected with HPV at baseline, and 994 acquired new infections during follow-up. Females infected with HPV-16 were at higher risk of acquiring other α-9 HPV types (HR, 1.9; 95% confidence interval [CI], 1.2-3.0) but at similar risk of clearing existing α-9 HPV infections (HR, 0.9; 95% CI, .7-1.3). Females infected with vaccine-targeted types were generally at higher risk of acquiring additional types (HRs, > 1.0) and at equal risk of clearing existing infections. Accounting for multiple comparisons, none of the HRs of < 1.0 or >1.0 were statistically significant in our analyses of acquisition or clearance.Conclusions: Vaccine-targeted HPV types do not appear to compete with other types, suggesting that HPV type replacement is unlikely to occur. [ABSTRACT FROM AUTHOR]

Currently, 2 vaccines exist that prevent infection by the genotypes of human papillomavirus (HPV) responsible for approximately 70% of cervical cancer cases worldwide. Although vaccination is expected to reduce the prevalence of these HPV types, there is concern about the effect this could have on the distribution of other oncogenic types. According to basic ecological principles, if competition exists between ≥2 different HPV types for niche occupation during natural infection, elimination of 1 type may lead to an increase in other type(s). Here, we discuss this issue of “type replacement” and present different epidemiologic approaches for evaluation of HPV type competition. Briefly, these approaches involve: 1) calculation of the expected frequency of coinfection under independence between HPV types for comparison with observed frequency; 2) construction of hierarchical logistic regression models for each vaccine-targeted type; and 3) construction of Kaplan-Meier curves and Cox models to evaluate sequential acquisition and clearance of HPV types according to baseline HPV status. We also discuss a related issue concerning diagnostic artifacts arising when multiple HPV types are present in specific samples (due to the inability of broad-spectrum assays to detect certain types present in lower concentrations). This may result in an apparent increase in previously undetected types postvaccination. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We assessed the accuracy of human papillomavirus (HPV) vaccination status based on adult proxy recall and household immunization records for adolescent females in the United States. Methods: We used data from the 2010 National Immunization Survey—Teen for females aged 13 to 17 years. The accuracy of HPV vaccination status (≥1 dose) based on adult proxy recall (unweighted n = 6868) and household immunization records (unweighted n = 2216) was assessed by estimating the sensitivity, specificity, and corresponding 95% confidence limits (CL) of these measures with provider-reported HPV vaccination status as the reference standard. Our analyses accounted for the complex survey design and population weights. Results: The sensitivity and specificity of adult proxy recall were 83.9% (95% CL: 81.2%, 86.6%) and 90.4% (95% CL: 88.9%, 92.0%), respectively. Conversely, the sensitivity and specificity of household immunization records were 74.2% (95% CL: 69.1%, 79.2%) and 98.0% (95% CL: 96.8%, 99.1%), respectively. The accuracy of both measures varied by race/ethnicity, proxy respondent, and maternal education. Conclusions: Our results suggest that adult proxy recall and household immunization records have reasonable accuracy for classifying HPV vaccination status for females aged 13 to 17 years in the United States, but these measures present a trade-off between sensitivity and specificity. [Copyright &y& Elsevier]

The article presents information on a study which examined the expected effect of human papillomavirus (HPV) vaccination on cervical cancer screening and a possible new strategy that integrates novel molecular-based screening technologies. It discusses the immediate and long-term effects of HPV vaccination. References to other research studies on alternatives to primary screening with traditional Pap cytology are discussed. Other topics discussed include advantages to adopting the HPV Pap triage strategy for cervical cancer screening, and the need to redesign screening programs.

Human papillomavirus (HPV) infection, a common sexually transmitted infection, is causally associated with cervical cancer. Vaccination against HPV provides protection; however, HPV vaccines are exclusively prophylactic. Carrageenan, an extract from red algae, demonstrated potent anti-HPV activity in in vitro and animal studies. We describe the protocol for the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) study, an ongoing randomized controlled trial among sexually active young females, aimed at evaluating the efficacy of a carrageenan-based gel in reducing type-specific incidence (i.e. new detections of HPV) and prevalence (i.e. absence of a previously detected HPV) of genital HPV infections as well as participant adherence to the intervention. The CATCH study is a phase IIB double-blind randomized placebo-controlled trial. Eligible women 18 years and older are randomized 1:1 to the carrageenan-containing gel or placebo gel arm. For the first month, participants use the study gel intra-vaginally every other day, and over the 12-month study period, prior to and after each act of vaginal intercourse. At each study visit (months 0, 0.5, 1, 3, 6, 9, 12), participants provide a self-collected vaginal sample and record information on sexual activities, adherence, and adverse events using a computerized questionnaire. The primary outcomes are incident and prevalent type-specific cervicovaginal HPV infection. The primary analyses are based on intention-to-treat whereas per-protocol analyses are conducted based on measures of adherence. Trial registration: ISRCTN96104919. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nine-valent human papillomavirus (9vHPV) vaccines can be administered in 2 doses 6 to 12 months apart in adolescents. The impact of extended dose intervals is unknown. We report immunogenicity and safety data in adolescents of a second 9vHPV vaccine dose administered ≥1 year after the first. METHODS: This open-label safety and immunogenicity study (NCT04708041) assessed extended-interval 2-dose regimens of 9vHPV vaccine among adolescents (10 to 15 years) who received 2 9vHPV vaccine doses: the first ≥1 year before enrollment, and second, at enrollment (day 1). We measured serologic responses to vaccine-targeted human papillomavirus (HPV) types at enrollment day 1 (pre-dose 2) and 1 month post-dose 2 (month 1) using a competitive LuminexV® immunoassay. We estimated effects of dose interval on geometric mean titers (GMTs) using regression modeling. Participants reported adverse events (AEs) through 15 days after vaccination. RESULTS: We enrolled 146 adolescents (mean age 13.3 years) with median 25 months since first 9vHPV vaccine dose (range: 12-53 months). Across vaccine-targeted HPV types, GMTs increased from day 1 to month 1; seropositivity at month 1 was 100%. Anti-HPV GMTs at month 1 were not affected by differences in dose interval of 12 to 53 months, based on regression modeling. The most common AEs were mild-to-moderate injection site reactions; no serious AEs were reported. CONCLUSIONS: Extending the interval between first and second 9vHPV vaccine doses to 12 to 53 months did not affect antibody responses, with favorable safety profile. These results support feasibility of extended interval regimens for 9vHPV vaccine. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infection is a necessary, although not sufficient cause of cervical cancer. Globally, HPV infection accounts for an estimated 530,000 cervical cancer cases (~270,000 deaths) annually, with the majority (86% of cases, 88% of deaths) occurring in developing countries. Approximately 90% of anal cancers and a smaller subset (<50%) of other cancers (oropharyngeal, penile, vaginal, vulvar) are also attributed to HPV. In total, HPV accounts for 5.2% of the worldwide cancer burden. HPVs 16 and 18 are responsible for 70% of cervical cancer cases and, especially HPV 16, for a large proportion of other cancers. Prophylactic vaccination targeting these genotypes is therefore expected to have a major impact on the burden of cervical cancer as well as that of other HPV-related cancers. Over the past 50years, organized or opportunistic screening with Papanicolaou (Pap) cytology has led to major reductions in cervical cancer in most developed countries. However, due to lack of resources or inadequate infrastructure, many countries have failed to reduce cervical cancer mortality through screening. HPV DNA testing recently emerged as a likely candidate to replace Pap cytology for primary screening. It is less prone to human error and more sensitive than Pap in detecting high-grade cervical lesions. For countries with national vaccination programs, HPV testing may also serve as a low cost strategy to monitor long term vaccine efficacy. Introduction of well organized vaccination and screening programs should be a priority for all countries. Increased support from donors is needed to support this cause. [Copyright &y& Elsevier]

We used modeling approaches to estimate the impact of human papillomavirus (HPV) vaccination on the performance of Pap cytology screening under different assumptions of lesion prevalence and expected changes in sensitivity and specificity likely to prevail post-vaccination. A major driver of the efficiency and costs of screening, the positive predictive value will be severely affected if Pap cytology continues to serve as the primary screening test in the post-vaccination era. Molecular-based screening with an HPV DNA test followed by Pap triage of HPV-positive cases has the potential for circumventing this problem. As a primary screening test, HPV testing can improve the overall quality of screening programs, thus allowing for increased testing intervals that would lower program costs with acceptable safety. Cytology should be reserved for the more labor-efficient task of triaging HPV-positive cases, a situation in which case loads would be “enriched” with smears containing relevant abnormalities. HPV followed by Pap strategy can also serve a secondary role in post-vaccination surveillance. [Copyright &y& Elsevier]