Human papillomavirus (HPV) vaccination effectively reduces the risk of HPV-attributable cancers, including cervical, vulvar, vaginal, anal, oropharyngeal, and other head and neck cancers. Concerns for a lower-than-expected vaccine impact, as defined as an increase in the prevalence of precancer by nonvaccine types, compared to that anticipated based on attribution studies, have been raised in the postvaccination era. Three distinct and nonmutually exclusive processes-HPV type replacement, clinical unmasking, and viral unmasking-could be responsible for this apparent increase of nonvaccine types. HPV type replacement, in which nonvaccine types fill a niche left vacant after the elimination of vaccine types, is unlikely to occur due to the remarkable genetic stability of the virus and the lack of natural competition between individual HPV types. However, clinical unmasking, in which the absence of clinical interventions aimed at eliminating cervical disease caused by vaccine types permits uninterrupted progression of nonvaccine types, may occur since HPV coinfections are common. Alternatively, the observed shift could be completely erroneous due to the false discovery of type replacement via viral unmasking, a diagnostic assay artifact. In this chapter, we describe these processes and the mechanisms underlying them.

BACKGROUND:Oral cavity cancers are generally considered etiologically similar, with a majority (>75%) attributable to smoking/alcohol. Yet, incidence trends for oral cavity cancers have recently diverged in the United States and several European countries (with declines for most oral cavity cancers but increases for oral tongue cancers), suggesting etiologic differences. This study quantified etiologic heterogeneity across oral cavity cancers using data from the NIH-AARP Diet and Health Study. METHODS:Cox regression models were used to quantify associations (hazard ratios [HRs] and population attributable fractions [PAFs]) and etiologic heterogeneity for risk factors across oral cavity anatomic sites. RESULTS:Among 490,969 individuals (6,732,760 person-years), 765 incident oral cavity cancers occurred. There was substantial heterogeneity in the associations of smoking and alcohol within constituent oral cavity cancers (HRs for current smokers, >2 drinks/day vs. never-smokers/nondrinkers: floor of mouth = 14.7; hard palate and other mouth = 8.1; oral tongue = 4.9; gum = 2.6; lip = 1.5). PAFs for smoking/alcohol varied widely, ranging from 12.0% for the lip to 56% for the floor of mouth. We observed unexpected associations of increased oral tongue cancer risk with increased consumption of vegetables: total vegetables without legumes (HR per cup equivalent/day, 1.13; 95% CI, 1.01-1.27); Solanaceae (HR, 1.43; 95% CI, 1.20-1.70); Umbelliferae (HR, 2.31; 95% CI, 1.30-4.12); and dark green leafy vegetables (HR, 1.38; 95% CI, 1.07-1.78). Associations for total vegetables (HR, 1.12), Solanaceae (HR, 1.26), and dark green leafy vegetables (HR, 1.32) were remarkably similar in the PLCO trial, a prospective US cohort of ∼155,000 individuals. CONCLUSIONS:The results highlight the need for disaggregation of oral cavity cancer sites in etiologic studies and reappraisal of widely accepted smoking/alcohol relative risks/attributable fractions.

Introduction:Recurrent respiratory papillomatosis (RRP), primarily caused by human papillomavirus (HPV) types 6 or 11, is a rare but high-morbidity condition. Nationwide estimates of the incidence of RRP are scarce, and we aimed to estimate the incidence of RRP among children and young adults in Denmark (2000-2023) and Sweden (2000-2021). Methods:Using the Danish Pathology Register and the Swedish Patient Register, we identified all individuals with a first-time occurrence of RRP (definition in Denmark: histologically confirmed, topography code T24 plus SNOMED codes for papillomas; Sweden: International Classification of Diseases-10 code D14.1A for papillomas). Incidence rates were calculated as number of RRP cases per 100 000 person-years (py), stratified by country, sex, and age groups at onset (0-14/juvenile 15-29/adult). Trends in incidence were evaluated in the period before and after introduction of HPV vaccination using Poisson regression to estimate the annual percentage change (APC) and 95% confidence intervals (CI). Results:We found juvenile-onset RRP incidences of 0.14 to 0.20/100 000 py as well as adult-onset RRP incidences at 0.19 to 0.40/100 000 py for women and 0.52 to 0.68/100 000 py for men in the postvaccine introduction period. Danish data showed a decreasing trend in RRP during the period following implementation of HPV vaccination, especially among young adults (women: APC = -11.5 [95% CI, -20.9 to -0.9]; men: APC = -11.0 [95% CI, -16.6 to -4.9]), whereas Swedish data did not show any clear decrease in RRP over time. Conclusions:The incidence of RRP is decreasing in Denmark but not in Sweden. This may be the result of more intense HPV vaccination programs, in particular early catchup vaccination of young adults, in Denmark as compared to Sweden.

BACKGROUND:Critical gaps exist in our understanding of the progression from anal human papillomavirus (HPV) infection to same-type HPV-associated anal disease in human immunodeficiency virus (HIV)-negative men who have sex with men (MSM). We conducted a post hoc analysis of a phase 3 randomized 4-valent HPV vaccine trial (NCT00090285) to assess the natural progression of anal HPV infections to associated anal lesions among MSM. PARTICIPANTS:A total of 602 HIV-negative MSM aged 16-27 years. METHODS:HIV-negative MSM aged 16-27 years enrolled in the placebo arm from 18 countries were included. We estimated the distribution of 9-valent HPV (9vHPV) vaccine types in intra-anal lesions (anal condyloma and anal intraepithelial neoplasia [AIN] 1-3), proportions and rates of progression from incident-persistent (no associated anal disease at baseline) intra-anal HPV infections to the same-type HPV-associated anal lesion, and cumulative incidence over 30 months. RESULTS:Predominant 9vHPV types detected were HPV6 (55.7%) and HPV11 (25.3%) in MSM with anal condyloma/AIN1, and HPV6 (30.5%), HPV16 (22.0%), and HPV11 (15.3%) in those with pooled AIN2/3. Progression from incident-persistent intra-anal 9vHPV infection to anal disease was driven primarily by HPV6, HPV11, and HPV16/18 infections for MSM with anal condyloma/AIN1 (63.0%, 85.7%, and 16.3%, respectively) and AIN2/3 (25.9%, 14.3%, and 32.4%, respectively). Cumulative incidence of anal condyloma/AIN1 and AIN2/3 in MSM with incident-persistent infection was 43.1% and 34.4%, respectively. CONCLUSIONS:A high proportion of unvaccinated HIV-negative MSM with a new intra-anal 9vHPV infection developed same-type HPV-associated anal disease. These findings support HPV vaccination of young HIV-negative MSM to prevent anal HPV infection and associated anal disease. REGISTRATION:ClinicalTrials.gov, NCT00090285.

Background Studies evaluating the association between prevalent human papillomavirus (HPV) infection and the risk of future incident-persistent infection in a broad global sample of men are needed.Methods Heterosexual men (HM) and men who have sex with men (MSM) aged 16-27 years in the placebo arm of a multinational 4-valent HPV vaccine trial (NCT00090285) were assessed. Incident-persistent infection was defined as a new 9-valent (9v) HPV (HPV6/11/16/18/31/33/45/52/58) type at follow-up that was not present at the same anatomic site at baseline and that remained detectable at that same site for 2 or more consecutive visits approximately 6 months apart. Association between baseline prevalent 9vHPV infection and incident-persistent infection at anogenital sites was estimated using incidence rate differences (IRDs) and incidence rate ratios (IRRs).Results Included were 1459 HM and 260 MSM. Incidence rates (per 100 person-years) of incident-persistent infection among HM with or without baseline prevalent 9vHPV infection were 10.18 and 5.94, respectively, and among MSM were 11.74 and 9.78, respectively. Baseline prevalent 9vHPV infection status was associated with incident-persistent 9vHPV infection among HM (IRD, 4.24 [95% CI, 1.24-7.23]; adjusted IRR, 1.52 [1.11-2.09]) but not MSM (IRD, 1.96 [-4.01 to 7.93]; adjusted IRR, 1.02 [0.59-1.79]).Conclusions HM with baseline prevalent 9vHPV infection were more likely to develop an incident-persistent anogenital infection than those without baseline prevalent infection. Risk of incident-persistent infection among MSM was high regardless of baseline prevalent 9vHPV infection status. These findings highlight the importance of vaccinating men against HPV infection.

Background Gender-neutral vaccination (GNV) for human papillomavirus (HPV) has increasingly been implemented worldwide. However, real-world evidence on vaccine effectiveness (VE) in males and the population-level impact of GNV remains heterogeneous. We summarized real-world VE of HPV vaccination in males and the impact of GNV. Methods A comprehensive review was performed using Embase and PubMed from January 2007 to May 2024, for studies evaluating quadrivalent (4vHPV) or nonavalent (9vHPV) vaccines. Eligible studies assessed VE or GNV impact on HPV infections, precancerous lesions, cancer, or anogenital warts (AGW). Risk of bias was assessed using ROBINS-I and the National Institute of Health quality assessment tool. Results Twenty-one geographically diverse studies were included. Most VE and VI studies demonstrated risk of bias. In males, VE reached up to 100% against oral HPV infection and 41% for penile HPV (4vHPV genotypes), with higher VE among adolescents and those vaccinated before age 23. Among men who have sex with men, VE was higher for penile HPV infection (85%), AGW (55%), and anal infection (60%). Conclusions Real-world evidence indicates that HPV vaccination substantially reduces anogenital and oral HPV infections and AGW in males. GNV programs further reduce HPV-related disease burden, reinforcing the public health significance of universal HPV vaccination programs worldwide.

BACKGROUND:The global prevalence of and risk factors associated with same-type HPV infection across multiple anogenital sites among men has not been quantified. METHODS:Men aged 16-27 years participating in a multi-country 4-valent HPV vaccine trial (NCT00090285) were assessed at baseline for prevalent HPV infection at penile/scrotal and perineal/perianal sites (heterosexual men [HM] and men who have sex with men [MSM]) and additionally at intra-anal sites (MSM). Concordant infection with 9-valent HPV (9vHPV) vaccine types (6/11/16/18/31/33/45/52/58) was defined as same-type 9vHPV infection at 2 or 3 sites. RESULTS:3363 HM and 595 MSM were included. Prevalence of concordant 9vHPV infection at 2 anogenital sites was 3.7% among HM and 9.1% among MSM, and 8.2% at 3 sites (including the intra-anal site) among MSM. HPV6 and HPV16 were most likely to occur at multiple anogenital sites in HM and MSM, with strong agreement observed between perineal/perianal and anal sites among MSM for HPV6 (Cohen's kappa, 0.78; 95% CI, .69-.87) and HPV16 (0.61; 95% CI, .50-.73). CONCLUSIONS:Concordant anogenital 9vHPV infection was more common among MSM than HM, which is consistent with evidence that MSM are at increased risk of HPV-related cancer across multiple anogenital sites. Clinical Trial Registration:  ClinicalTrials.gov, NCT00090285.

OBJECTIVES:The US Advisory Committee on Immunization Practices recommends shared clinical decision-making regarding human papillomavirus (HPV) vaccination for individuals aged 27-45 years. The incidence of HPV infection in this age group is not well-understood. This study assessed anogenital HPV infection incidence in a large cohort of unvaccinated US women aged ≥27 years. METHODS:This retrospective cohort study included women aged ≥27 years who had a documented visit, no prior record of HPV vaccination, and a confirmed negative HPV test within the TriNetX Dataworks-USA network (a large, de-identified, federated network of electronic health records [EHRs]) between January 1, 2012 and January 6, 2024. Cumulative incidence of HPV infection over 5 years was calculated, overall and stratified by age and demographic characteristics. Analyses were also conducted in a subset of the population whose EHRs were linked to closed health insurance claims data via tokenization (the Linked sample). RESULTS:The overall 5-year cumulative incidence rate in the Dataworks sample (n = 305,974) was 10.3% (95% confidence interval, 10.2-10.5%). Cumulative incidence estimates were highest in the younger age groups, declined until age 59, and then increased among women aged ≥70 years. Analyses in a subset of 9772 women in the Linked sample showed similar patterns. Higher HPV infection incidence was observed among Black, Hispanic, and Medicaid-enrolled women. CONCLUSION:In a large cohort of US women aged ≥27 years, new HPV infections were acquired throughout the lifespan. These women and their partners can benefit from preventive strategies to reduce risk of HPV-related diseases.

HPV vaccination reduces the risk of developing HPV-attributable cancers, including cervical cancer. However, an attenuation of HPV vaccine impact after the implementation of HPV vaccination may occur through clinical unmasking. Clinical unmasking is a distinct and complex phenomenon that arises in the absence of clinical interventions necessary to treat disease caused by high-risk vaccine-preventable HPV types (mainly HPV16) allowing uninterrupted progression of non-vaccine preventable types that are frequently present as co-infections. Clinical unmasking is distinct from viral unmasking, which is a diagnostic assay artifact, and from HPV type replacement, a theorized biological phenomenon requiring competition between HPV types, which has not yet been documented. All three processes could manifest as an apparent increase in cervical precancer/cancer by non-HPV vaccine types, resulting in a lower-than-anticipated vaccine impact based on projections derived from type attribution studies. Here, we describe these concepts and epidemiological approaches to evaluate clinical unmasking in the post-vaccination era. We propose a historical and a contemporaneous approach, highlighting key considerations and illustrating the potential outcomes with hypothetical data. Both approaches would have a similar outcome and interpretation: an increased incidence of precancerous lesions (CIN2+) due to non-vaccine preventable types among vaccinated versus unvaccinated women (historically in the pre-vaccination era, or contemporaneously) in the long term being indicative of clinical unmasking. Protection afforded by HPV vaccines against high-grade cervical precancers, irrespective of type, remains considerable. However, carefully designed studies are needed to investigate the potential impact of clinical unmasking and its implications on vaccine effectiveness in the post-vaccination era.

OBJECTIVES:Anogenital warts (AGW) are a common manifestation of human papillomavirus (HPV) infection. As HPV vaccination programs expand, updated data are needed to assess the ongoing global AGW burden. This systematic review examined AGW epidemiology, clinical impact, and economic burden, analyzing 187 studies from 49 jurisdictions by income level, sex, and age. METHODS:Publications were retrieved from Embase, MEDLINE, and Evidence-Based Medicine Reviews (January 2013 to October 2023) and conference proceedings (January 2021 to December 2023) (PROSPERO ID: CRD42023489504). RESULTS AND CONCLUSIONS:AGW prevalence ranged from 0.5% to 33.1%, and incidence rates ranged from 24 to 2940 cases/100,000 person-years in mixed-sex populations not stratified by age. Incidence generally declined from the mid-30s but remained substantial across all ages. The clinical and economic burden varied by sex, age, time, and geography. Notably, most epidemiologic data come from high-income jurisdictions, underscoring the need for more comprehensive global surveillance to fully understand AGW trends and impacts.

Background: Gay, bisexual, and other men who have sex with men (gbMSM) have a higher risk of human papillomavirus (HPV) infection and related diseases and would benefit from preventive measures such as HPV vaccination. We assessed the association between HPV vaccination and anal HPV infection in HIV-negative gbMSM and gbMSM living with HIV from the Lubricant Investigation in Men to Inhibit Transmission of HPV Infection study. Methods: Participants attended 7 visits over 12 months where they provided a nurse-collected anal sample and self-completed a questionnaire on risk factors and HPV vaccination. Samples were tested for HPV using polymerase chain reaction assays. We assessed the association with HPV vaccination and anal HPV prevalence and incidence using logistic and Cox regression, respectively. Analyses at the individual- (unit of analysis = participant) and HPV-level (unit of analysis = HPV type) considered vaccine-targeted types (any of HPVs 6/11/16/18) as the outcome. To assess construct validity, we repeated analyses considering incidence of non-vaccine-targeted (within- and cross-species) HPV types at the HPV-level. Estimates were adjusted for a propensity score to predict cumulative HPV positivity based on selected study and participant characteristics. Results: Of 258 enrolled participants (18.2-71.7 years; 69 being HIV-positive), 23.3 % were vaccinated at baseline. At the individual-level, there was no association between vaccination and HPVs 6/11/16/18 prevalence (n = 250, aOR = 1.12,95% CI = 0.56-2.22) or incidence (n = 152, aHR = 0.34, 95% CI = 2.19 x 10- 18-1.38). At the HPV-level, while there was no association with HPVs 6/11/16/18 prevalence (n = 1000, aOR = 0.99, 95 % CI = 0.57-1.71), vaccination was associated with a reduction in HPVs 6/11/16/18 incidence (n = 754, aHR = 0.22, 95% CI = 6.01 x 10-18-0.79). Vaccination was not associated with incidence of within-species (n = 2299, aHR = 0.76, CI = 0.42-1.24) or cross-species (n = 3774, aHR = 1.28, CI = 0.89-1.85) HPV types. Results were similar by HIV status. Conclusion: Our findings support that HPV vaccination protects against incident anal infection of vaccine-targeted HPV types, thus, gbMSM should be encouraged to get vaccinated against HPV.

BACKGROUND:Human papillomavirus (HPV) vaccination protects against new HPV infections, but seemingly no impact on the clearance of existing infections. We assessed the association between HPV vaccination and incidence and clearance of HPV infections among sexually active women in the Carrageenan-gel Against Transmission of Cervical HPV trial, conducted in Montreal, Canada (2013-2020). METHODS:Participants attended seven visits over 12 months, where they provided self-collected vaginal samples and completed questionnaires on risk factors. Participants self-reported their HPV vaccination status at screening, enrollment, and follow-up visits. Samples were genotyped for HPV using the Linear Array assay. We used Cox regression to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for incidence and clearance of HPV infections, with the unit of analysis being the HPV type. Analyses considered stringent (reported in ≥2 sources) and non-stringent (reported in ≥1 source) definitions of vaccination status. HPV types were classified as vaccine-targeted (HPVs 6/11/16/18) and non-vaccine-targeted (within-species: HPVs 31/33/35/39/44/45/52/58/59/67/68/70; cross-species: HPVs 26/34/40/42/51/53/54/56/61/62/66/69/71/72/73/81/82/83/84/89). To control for confounding, we applied inverse probability of treatment weights, based on study and participant characteristics. RESULTS:Of 461 participants, 45.8 % and 55.5 % were vaccinated according to the stringent and non-stringent definitions, respectively. Vaccination was associated with a lower risk of new HPVs 6/11/16/18 detection in the most stringent (HR = 0.41, CI:0.23-0.72) and least stringent (HR = 0.41, CI:0.23-0.72) definitions. Vaccination was not associated with incident within-species (most stringent: HR = 1.21, CI:0.90-1.64; least stringent: HR = 1.10, CI:0.82-1.48) or cross-species (most stringent: HR = 1.21, CI:0.94-1.55; least stringent: HR = 1.11, CI:0.87-1.41) HPV types. Vaccination did not impact clearance of baseline HPVs 6/11/16/18 (most stringent: HR = 1.23, CI:0.47-3.24; least stringent: HR = 1.40, CI:0.57-3.47), within-species (most stringent: HR = 1.50, CI:0.88-2.56; least stringent: HR = 1.58, CI:0.98-2.55) or cross-species HPV infections (most stringent: HR = 0.71, CI:0.49-1.03; least stringent: HR = 0.80, CI:0.56-1.16). CONCLUSION:We found that HPV vaccination is effective as a prophylactic measure but has no therapeutic effects on existing infections.

Human papillomavirus (HPV) is associated with a significant global burden of precancerous lesions and cancer. People with HIV (PWH) are at higher risk of HPV infection and HPV-related diseases. This systematic review was conducted to synthesize data on the burden of HPV infection and HPV-related diseases among PWH. Studies published between January 2018-June 2023 were sourced from databases and conferences. Included were 221 publications containing epidemiological data on HPV infections and the clinical burden of HPV-related diseases among PWH. The burden varied by geographical region, age, sex, and sexual orientation. Compared to people without HIV (PWoH), PWH had higher prevalence and incidence of HPV infection and HPV-related diseases. Among PWH, the prevalence of anal HPV infection ranged between 44% and 83%; men had a higher prevalence and incidence of anogenital warts than women. The incidence of anal HPV infection was over two-fold greater among transgender women with HIV and men who have sex with men with HIV than among their respective counterparts without HIV. Incident HPV-related anal cancer was up to two-fold higher among PWH than PWoH, and incident cervical cancer was up to six times higher among women with HIV than those without. The most prevalent high-risk (hr) HPV genotypes with HPV-related disease were vaccine genotype HPV16/18/52/58. HPV35 was one of the most prevalent genotypes with anal or cervical HPV infection among PWH of African descent. PWH also have a higher burden of concurrent HPV infections and HPV-related diseases. This study calls for strengthening appropriate HPV vaccine delivery and increasing vaccine uptake among this high-risk group, potentially by integrating HPV vaccination with routine HIV care.

The 9-valent human papillomavirus (9vHPV) vaccine targets human papillomavirus (HPV) types 6/11/16/18/31/33/45/52/58. Although its use in pregnant women is not recommended, inadvertent exposures during early pregnancy could occur as the indicated age range includes the ages of child-bearing potential. A pregnancy registry was created as a post-marketing regulatory commitment using spontaneous reports of 9vHPV vaccine exposure during pregnancy that were received from the United States (from December 2014 through March 2021) and followed through the completion of pregnancy. Primary pregnancy outcomes included congenital anomalies, live births, fetal deaths, elective terminations, and miscarriages. Enrolled prospective reports were used for rate calculations. Of the 180 prospectively enrolled pregnancies, 70 had known outcomes. There were 66 live births that resulted in 67 live born infants (95.7%; one twin pregnancy), one elective termination, and three miscarriages (estimated rate, 4.3% [3/69] of known outcomes excluding elective terminations). All three miscarriages occurred in the first trimester in women who had been vaccinated prior to detection of pregnancy. There were three major birth defects among the prospective reports, with an estimated rate of 4.5% (3/67). Findings from this analysis of the US 9vHPV vaccine pregnancy registry do not suggest an increased risk of major birth defects and miscarriage in women who received the vaccine. There is no apparent pattern of congenital anomalies to suggest potential adverse effects of exposure to the 9vHPV vaccine during pregnancy. This analysis is consistent with prior clinical trial experience and post-licensure observational data with the quadrivalent HPV and 9vHPV vaccines.

In Norway, single-cohort vaccination with quadrivalent human papillomavirus (qHPV) vaccine targeting 12-year-old girls took place in 2009-2016. In 2020, the oldest vaccinated cohort was 23 years old and had approached the age where risk of being diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increases rapidly. The aim of this cohort study was to assess direct qHPV vaccine effectiveness (VE) against CIN2+ among Norwegian women aged 16-30 years in 2007-2020. By using population-based health registries and individual-level data on vaccination status and potential subsequent CIN2+ incidence, we found 82% qHPV VE among women vaccinated before age 17 years. Using individual-level data from Norwegian population-based health registries, this study found 82% vaccine effectiveness against CIN2+ among women vaccinated before 17 years of age.

Previous research has shown that women's use of a carrageenan gel reduces the risk of acquiring genital human papillomavirus (HPV) infections but does not help to clear existing ones. Although gel use may not result in complete clearance, it may decrease the viral load of HPV infections. We tested this hypothesis in the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) randomized controlled trial. Participants of the CATCH study were selected for viral load testing if they had completed the first four study visits and tested positive for HPV42 or HPV51 in at least one of these visits. HPV42 and HPV51 were chosen as they were among the most abundant low- and high-risk types, respectively, in the study sample. We measured viral load with a type-specific real-time polymerase chain reaction. Results were displayed using summary statistics. Of 461 enrolled participants, 39 were included in the HPV42 analysis set and 56 in the HPV51 analysis set. The median time between visits 1 and 4 was 3.7 months. The viral load (copies/cell) of HPV42 ranged from <0.001 to 13 434.1, and that of HPV51 from <0.001 to 967.1. The net median change in HPV42 viral load over all four visits was -1.04 copies/cell in the carrageenan and -147 copies/cell in the placebo arm (Wilcoxon rank sum test, p = 0.26). There was no net median change in HPV51 viral load over all four visits in either arm (p = 0.45). The use of a carrageenan-based gel is unlikely to reduce the viral load of HPVs 42 or 51.

BACKGROUND:International data on anogenital HPV infection incidence among men are limited. METHODS:Incidence of incident-persistent (IP) anogenital HPV infections was evaluated among 295 men who have sex with men (MSM) and 1576 heterosexual men (HM) aged 16-27 years in the placebo arm of a global, multicenter 4-valent (4v) HPV vaccine trial. We estimated IP incidence (penile/scrotal, perineal/perianal, anal) for 4vHPV and 9-valent (9v) HPV vaccine types and cumulative IP incidence over 36 months. RESULTS:IP infection incidence per 100 person-years (95% CI) among HM for 4vHPV and 9vHPV types was 4.1 (3.5-4.9) and 6.8 (5.9-7.6) at penile/scrotal, and 1.2 (.8-1.6) and 1.9 (1.5-2.4) at perineal/perianal sites, respectively; and among MSM, IP infection incidence was 2.3 (1.3-3.8) and 3.2 (2.0-4.9) at penile/scrotal, 6.8 (4.9-9.2) and 9.0 (6.9-11.6) at perineal/perianal, and 12.0 (9.4-15.1) and 16.8 (13.7-20.2) at anal sites, respectively. Cumulative IP incidence over 36 months (excluding anal canal; any 9vHPV type) was higher among MSM versus HM (24.1% vs 18.4%). CONCLUSIONS:A substantial proportion of unvaccinated men of catch-up vaccination age developed IP 9vHPV-related infections. Gender-neutral vaccination could decrease male HPV infection, contribute to herd protection, and reduce disease burden. Clinical Trials Registration. NCT00090285.

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.

The Lubricant Investigation in Men to Inhibit Transmission of human papillomavirus (HPV) Infection randomized control trial in gay, bisexual, and other men who have sex with men (gbMSM) found that carrageenan use neither reduced acquisition of anal HPV infections nor influenced infection clearance. To investigate carrageenan's lack of protective effect, we compared the change in anal HPV16 and HPV18 viral loads following carrageenan use against placebo. We restricted our analysis to participants who completedthe first four study visits and had a valid baseline sample (n=161, 54 HIV-positive). Samples were tested for HPV detection using the linear array PCR assay. HPV16- and/or HPV18-positive samples were tested for viral load using real-time PCR. For participants who tested HPV16- (n=29) or HPV18-positive (n=10) at least once across visits 1-4, we compared the change in type-specific viral load between study arms using the Mann-Whitney U test. Although the median net change in HPV16 and HPV18 viral loads across visits 1-4 was higher in the treatment than placebo arm (HPV16: 0.68 vs. 0.18 copies/cell, p=0.60; HPV18: 18.32 vs. 10.12 copies/cell, p=0.52), these differences were not statistically significant. Results were similar by HIV status. Carrageenan use did not impact anal HPV16 or HPV18 viral loads, which may further explain its lack of protective effect in gbMSM.

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.