Risk factors for human papillomavirus infection and disease: A targeted literature summary.

Adolescents are the primary cohort for routine human papillomavirus (HPV) vaccination, but unvaccinated adults may also benefit. A lack of consensus on which adults to target and the presence of reimbursement barriers likely contribute to the lag in adult vaccinations, highlighting missed prevention opportunities. Understanding factors contributing to risk of HPV infection and disease could help in decision making on vaccination. This review summarizes existing literature on risk factors for HPV infection and disease and includes 153 studies reporting relative risks or odds ratios for factors associated with HPV infection or disease in adults, published between 2009 and 2020. Despite inconsistent design and reporting of risk factors across studies, this review confirmed several risk factors associated with adult infection, including human immunodeficiency virus positivity, number of sex partners, and smoking. These findings can support policymaking, guideline development, and clinical decision making for HPV vaccination and screening of high-risk adult groups.

High Risk of New HPV Infection Acquisition Among Unvaccinated Young Men.

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.

High coverage and adherence to dose intervals of the national school-based HPV vaccination program in Sweden during 2012-2019.

Background: Close monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden's childhood immunization program and provide an estimate on dose timing compliance. Methods: Vaccination records between 2012 and March 2019 were obtained for girls born in 2000-2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen. Results: Vaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001-2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004-2005, and 56.3% in birth cohorts 2000-2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6-12 months after dose one. Discussion: In conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination.

Incident autoimmune conditions among males receiving quadrivalent human papillomavirus vaccine in the United States.

BACKGROUND: The potential for vaccines to induce autoimmunity has been the subject of considerable investigation and autoimmune induction remains a common focus for vaccine safety research. This study assessed the risk of new onset autoimmune conditions among males receiving the 4-valent human papillomavirus (HPV) vaccine (4vHPV). METHODS: Within a US health insurance claims database, we formed a cohort of male 4vHPV vaccine recipients between 2009 and 2016, along with a propensity score matched cohort of males who did not receive the 4vHPV vaccine. The study outcome was new onset autoimmune conditions (20 separate conditions) within four categories (rheumatologic/hematologic, gastroenterologic, endocrinologic and neurologic/ophthalmalogic). Outcomes identified using diagnosis codes were adjudicated through medical record review. Incidence rates (per 1,000 person-years) were estimated for the vaccinated and unvaccinated groups along with rate ratios (RRs). RESULTS: There were 65,606 males receiving at least one dose of 4vHPV vaccine, and 55,670 were matched to a comparator. The matched 4vHPV vaccine cohort provided 35 confirmed cases among 39,735 person-years, for an incidence rate of 0.88 (95% CI: 0.61-1.23), while the comparator cohort provided 47 confirmed cases among 58,215 person-years, an incidence rate of 0.81 (0.59-1.07), a RR of 1.09 (0.70-1.69). The RR within categories was 0.49 (0.10-2.42) for rheumatologic/hematologic, 1.26 (0.58-2.71) for gastroenterologic, 1.11 (0.61-2.02) for endocrinologic and 1.46 (0.21-10.40) for neurologic. CONCLUSIONS: The incidence of autoimmune conditions among males receiving the 4vHPV vaccine was similar to that among unvaccinated males. These results are consistent with other studies that have assessed autoimmunity with the 4vHPV vaccine.

Safety of 9-valent human papillomavirus vaccine administered to males and females in routine use.

BACKGROUND: The nine-valent human papillomavirus vaccine (HPV9, Gardasil®9) was licensed in the USA in December 2014. This study was a multiyear post-licensure study to assess HPV9 safety following routine administration. METHODS: This retrospective cohort study compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a later interval. Kaiser Permanente Northern California (KPNC) members aged ≥ 9 years who received ≥ 1 HPV9 dose between 10/1/2015-9/30/2017 were included. Outcomes were grouped into predefined diagnostic categories. We compared the odds of events in postvaccination risk intervals (days 0-14, days 1-60) with odds of events during control intervals (days 61-75, days 61-120) using conditional logistic regression. We characterized prespecified events on the day of vaccination (allergic reaction and syncope) and all deaths in the study period. RESULTS: The study included 215,965 individuals receiving ≥ 1 dose of HPV9, of whom 140,628 had no prior HPV vaccination. We observed similar numbers of males and females and racial/ethnic diversity consistent with the underlying population. At first dose median age was 12-13 years and 77% received ≥ 1 concomitant vaccine. Eighteen event categories were significantly elevated, including skin disorders (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.00, 3.53) and ill-defined conditions (OR 1.36, 95% CI 1.13, 1.64; category includes abdominal pain, allergic reactions, syncope, etc.). On review, most findings were previously known, preceded vaccination, or had other causes. Allergic reactions and syncope at vaccination were infrequent but many were potentially related. No deaths (n = 37) were considered related to HPV9 and were consistent with the background rate. CONCLUSIONS: We did not identify new safety concerns related to HPV9. The results are consistent with the HPV9 safety profile as established from previous studies/surveillance. REGISTRATION: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS13151, protocol V503-028).

Safety of 4-valent human papillomavirus vaccine in males: a large observational post-marketing study.

The 4-valent human papillomavirus (HPV) vaccine (4vHPV vaccine), Gardasil®, is indicated for the prevention of several HPV-related diseases. The objective was to assess the safety of 4vHPV vaccine administered to males as part of routine care. The study used a US health insurance claims database, and included males, age 9 to 26 years, who initiated 4vHPV between October 2009 and December 2016. General safety outcomes were identified using ICD diagnosis codes associated with emergency room visits and hospitalizations in the claims database in risk periods (Days 1-60 and Days 1-14 following vaccine administration) and self-comparison periods (Days 91-150 and 91-104 for the Days 1-60 and Days 1-14 analysis, respectively). Incidence rates (IRs) and relative rates (RRs) with 95% confidence intervals (CIs) were calculated comparing the risk and self-comparison periods. In this study, 114,035 males initiated 4vHPV vaccine and received 202,737 doses. Using the 60-day time window, 5 outcomes had significantly elevated RRs after accounting for multiple comparisons: ear conditions (RR 1.28, 95% CI 1.03-1.59); otitis media and related conditions (RR 1.65, 95% CI 1.09-2.54); cellulitis and abscess of arm (RR 2.17, 95% CI 1.06-4.72); intracranial injury (RR 1.23, 95% CI 1.01-1.50); and concussion (RR 1.29, 95% CI 1.05-1.59). A higher rate of allergic reactions was noted on the day of 4vHPV vaccine receipt compared to other vaccines (21.07 events per 10,000 doses, 95% CI 18.89-23.44 versus 11.44 per 10,000 doses, 95% CI 9.84-13.22). A higher incidence rate of VTE was observed following vaccination but this association was not significant (RR 2.17, 95% CI 0.35-22.74). The 4vHPV vaccine was associated with same-day allergic reactions as well as ear infections, intracranial injury, cellulitis, and concussion within 2 months after vaccination. While allergic reaction and cellulitis are consistent with the known safety profile of 4vHPV vaccine, the association of the other outcomes were determined by an independent Safety Review Committee to be most likely a result of activities common in adolescent males that coincide with the timing of vaccination and not directly related to vaccination itself.Implications and Contributions: The study results support the general safety of routine immunization with 4vHPV vaccine among males to prevent HPV-related diseases and cancers.

Human papillomavirus seroprevalence and seroconversion following baseline detection of nine human papillomavirus types in young women.

BACKGROUND: Estimates of the humoral immune response to incident human papillomavirus (HPV) infections are limited. METHODS: In this post hoc analysis of 3875 women aged 16-23 years from a 4-valent HPV vaccine trial (NCT00092482), HPV seroprevalence on day 1 was measured with a 9-valent HPV (HPV 6/11/16/18/31/33/45/52/58) competitive Luminex immunoassay and compared with cervical/external genital HPV detection by polymerase chain reaction. In the control group, among women who were HPV DNA‒negative on day 1, seroconversion following initial HPV detection was estimated using Kaplan-Meier methods. RESULTS: Type-specific HPV seropositivity among women with no day 1 cervical/external genital HPV detection was 0.6%-3.6%. Women with any 9-valent HPV (9vHPV) cervical/external genital detection (796/3875; 20.5%) had concordant seropositivity ranging from 13.4% (HPV 45) to 38.5% (HPV 6). Among women in the control group who were negative for all HPV types on day 1, seroconversion by month 30 after initial detection ranged from 29% (HPV 45) to 75% (HPV 16). CONCLUSIONS: Humoral immune response to HPV is variable and dynamic, depending on type-specific exposure. This longitudinal analysis provides insight into the relationship between incident infection and seropositivity. CLINICALTRIALS: gov; NCT00092482 https://clinicaltrials.gov/ct2/show/NCT00092482.

Modeling the health and economic implications of adopting a 1-dose 9-valent human papillomavirus vaccination regimen in a high-income country setting: An analysis in the United Kingdom.

Although no human papillomavirus (HPV) vaccine is indicated for single-dose administration, some observational evidence suggests that a 1-dose regimen might reduce HPV infection risk to that achieved with 2 doses. This study estimated the potential health and economic outcomes associated with switching from a 2-dose HPV vaccination program for girls and boys aged 13-14 years to an off-label 9-valent (9vHPV), 1-dose regimen, accounting for the uncertainty of the effectiveness and durability of a single dose. A dynamic HPV transmission infection and disease model was adapted to the United Kingdom and included a probabilistic sensitivity analysis using estimated distributions for duration of protection of 1-dose and degree of protection of 1 relative to 2 doses. One-way sensitivity analyses of key inputs were performed. Outcomes included additional cancer and disease cases and the difference in net monetary benefit (NMB). The 1-dose program was predicted to result in 81,738 additional HPV-related cancer cases in males and females over 100 years compared to the 2-dose program, ranging from 36,673 to 134,347 additional cases (2.5% and 97.5% quantiles, respectively), and had a 7.8% probability of being cost-effective at the £20,000/quality-adjusted life years willingness-to-pay (WTP) threshold. In one-way sensitivity analyses, the number of additional cancer cases was sensitive to the median of the duration of protection distribution and coverage rates. The differences in NMBs were sensitive to the median of the duration of protection distribution, dose price and discount rate, but not coverage variations. Across sensitivity analyses, the probability of 1 dose being cost-effective vs 2 doses was < 50% at the standard WTP threshold. Adoption of a 1-dose 9vHPV vaccination program resulted in more vaccine-preventable HPV-related cancer and disease cases in males and females, introduced substantial uncertainty in health and economic outcomes, and had a low probability of being cost-effective compared to the 2-dose program.

Design of a phase III efficacy, immunogenicity, and safety study of 9-valent human papillomavirus vaccine in prevention of oral persistent infection in men.

BACKGROUND: Seven high-risk human papillomavirus (HPV) types (16/18/31/33/45/52/58) covered by the 9-valent HPV (9vHPV) vaccine cause >90% of HPV-related head and neck cancers (HNCs). An ongoing clinical trial (NCT04199689) was designed to evaluate 9vHPV vaccine efficacy against HPV oral persistent infection, a surrogate endpoint for HPV-related HNCs. METHODS: In this double-blind, placebo-controlled, international trial, men aged 20-45 years (N = 6000) are randomized 1:1 to receive 9vHPV vaccine or placebo on day 1, month 2, and month 6. The primary objective is to demonstrate whether 9vHPV vaccination reduces incidence of HPV16/18/31/33/45/52/58-related 6-month oral persistent infection. Incidence of HPV6/11-related 6-month oral persistent infection will be evaluated as a secondary endpoint. Oral rinse and gargle samples will be collected on day 1, month 7, month 12, and every 6 months thereafter for HPV detection by PCR. Primary analyses will be performed in per-protocol populations. Efficacy in this case-driven study will be analyzed upon accrual of ≥20 primary efficacy endpoint cases. Serum will be collected at day 1 and months 7, 12, 24, 36, and 42; anti-HPV antibody titers will be measured by competitive Luminex immunoassay. Data will be summarized as geometric mean titers and seropositivity rates. Injection-site and systemic adverse events (AEs) will be collected for 15 days post-any vaccination and serious AEs through 6 months after the last vaccination; deaths and vaccine-related serious AEs will be collected throughout the study. DISCUSSION: This trial is expected to generate important data regarding the potential for 9vHPV vaccine to prevent HPV-related head and neck disease.

Anogenital Human Papillomavirus (HPV) Infection, Seroprevalence, and Risk Factors for HPV Seropositivity Among Sexually Active Men Enrolled in a Global HPV Vaccine Trial.

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.

Real-world impact and effectiveness assessment of the quadrivalent HPV vaccine: a systematic review of study designs and data sources.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Vaccine initiation and 3-dose series completion of 4vHPV vaccine among US insured males 2012-2016.

OBJECTIVE: The quadrivalent human papillomavirus vaccine (4vHPV, GARDASIL®), was approved in the US in 2009 for use in males aged 9 to 26 for the prevention of HPV-related genital warts, and in 2010 for the prevention of certain HPV-related anogenital diseases. A regimen was approved in 2016 for those who initiate the vaccine series between the ages of 9 to 14 years. We describe patterns of 4vHPV administration among US males before this modification. METHODS: The study used a US health insurance claims database, and included males, age 9 to 26 years, who initiated 4vHPV between 2012 and 2016. Time from first dose to subsequent doses was estimated. Logistic regression identified factors associated with regimen completion. RESULTS: Among 100,786 males who initiated 4vHPV (corresponding to âˆ¼ 13% of male birth cohorts), 50,573 (50.2%) and 25,763 (25.6%) received a second and third dose, respectively. Annual administration was common, with 47% of males receiving 3 doses over 3 years (1 dose per year) as compared to 12% receiving the 3-dose series in the recommended 6-month timeframe. Receipt of 4vHPV was 2.2 (range 1.5 to 2.9) times as likely to occur in summer months compared to other times of the year. Individuals aged 18 to 21 years and those living in Western states or rural regions were less likely to complete the 3-dose regimen. CONCLUSIONS: The real-world patterns of 4vHPV vaccination observed, particularly the low uptake and regimen completion, suggest that better strategies are needed for males to improve 4vHPV vaccine use in males.

Prevalence, incidence, and natural history of HPV infection in adult women ages 24 to 45 participating in a vaccine trial.

OBJECTIVES: The natural history of human papillomavirus (HPV) infection has been studied extensively in young women; this study investigated HPV infection in adult women. METHODS: Data from 3817 women aged 24-45 years in a global trial of the 4-valent HPV (6/11/16/18) vaccine were used to calculate prevalence of anogenital infections containing 9-valent (9v) HPV vaccine types (6/11/16/18/31/33/45/52/58) and five non-vaccine types (35/39/51/56/59). Incidence of infections and persistent infections was estimated for 989 placebo recipients naive to all 14 HPV types at baseline. Age-adjusted hazard ratios were calculated for various sociodemographic factors. RESULTS: Prevalence of anogenital infection was highest in France at 29.2% (9vHPV types) and 21.7% (non-vaccine types) and lowest in the Philippines at 7.6% (9vHPV types) and 5.1% (non-vaccine types). Overall, HPV incidence (per 100 person-years) was 5.2 (9vHPV types) and 4.7 (non-vaccine types), and incidence of persistent infection was 2.7 (9vHPV types) and 2.1 (non-vaccine types). Factors associated with new HPV infections included younger age, younger age at first intercourse, being single, current use of tobacco, and higher number of past and recent sex partners. CONCLUSIONS: Because mid-adult women acquire new HPV infections, administration of the 9vHPV vaccine could reduce HPV-related morbidity and mortality in this population.

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

Postlicensure safety surveillance of congenital anomaly and miscarriage among pregnancies exposed to quadrivalent human papillomavirus vaccine.

Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.

Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience.

Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.

Human papillomavirus detection in cervical neoplasia attributed to 12 high-risk human papillomavirus genotypes by region.

BACKGROUND: We estimated the proportion of cervical intraepithelial neoplasia (CIN) cases attributed to 14 HPV types, including quadrivalent (qHPV) (6/11/16/18) and 9-valent (9vHPV) (6/11/16/18/31/33/45/52/58) vaccine types, by region METHODS: Women ages 15-26 and 24-45 years from 5 regions were enrolled in qHPV vaccine clinical trials. Among 10,706 women (placebo arms), 1539 CIN1, 945 CIN2/3, and 24 adenocarcinoma in situ (AIS) cases were diagnosed by pathology panel consensus. RESULTS: Predominant HPV types were 16/51/52/56 (anogenital infection), 16/39/51/52/56 (CIN1), and 16/31/52/58 (CIN2/3). In regions with largest sample sizes, minimal regional variation was observed in 9vHPV type prevalence in CIN1 (~50%) and CIN2/3 (81-85%). Types 31/33/45/52/58 accounted for 25-30% of CIN1 in Latin America and Europe, but 14-18% in North America and Asia. Types 31/33/45/52/58 accounted for 33-38% of CIN2/3 in Latin America (younger women), Europe, and Asia, but 17-18% of CIN2/3 in Latin America (older women) and North America. Non-vaccine HPV types 35/39/51/56/59 had similar or higher prevalence than qHPV types in CIN1 and were attributed to 2-11% of CIN2/3. CONCLUSIONS: The 9vHPV vaccine could potentially prevent the majority of CIN1-3, irrespective of geographic region. Notwithstanding, non-vaccine types 35/39/51/56/59 may still be responsible for some CIN1, and to a lesser extent CIN2/3.

9-Valent HPV vaccine for cancers, pre-cancers and genital warts related to HPV.

Human papillomavirus (HPV) is the causative agent of nearly all cervical cancer cases as well as a substantial proportion of anal, vulvar, vaginal, penile and oropharyngeal cancers, making it responsible for approximately 5% of the global cancer burden. The first-generation HPV vaccines that is, quadrivalent HPV type 6/11/16/18 vaccine and bivalent HPV type 16/18 vaccine were licensed in 2006 and 2007, respectively. A second-generation 9-valent HPV type 6/11/16/18/31/33/45/52/58 vaccine with broader cancer coverage was initiated even before the first vaccines were approved. By preventing HPV infection and disease due to HPV31/33/45/52/58, the 9vHPV vaccine has the potential to increase prevention of cervical cancer from 70 to 90%. In addition, the 9vHPV vaccine has the potential to prevent 85-95% of HPV-related vulvar, vaginal and anal cancers. Overall, the 9vHPV vaccine addresses a significant unmet medical need, although further health economics and implementation research is needed.

An Overview of Quadrivalent Human Papillomavirus Vaccine Safety: 2006 to 2015.

BACKGROUND: A quadrivalent human papillomavirus (HPV4) type 6/11/16/18 vaccine (GARDASIL/SILGARD®) has been licensed in many countries around the world for the prevention of cervical, vulvar, vaginal, and anal cancers and precancers, as well as external genital warts causally related to HPV types 6/11/16/18. Across 7 phase 3 clinical trials involving more than 29,000 males and females ages 9-45 years, vaccination was generally well tolerated. Because of its expected public health benefit in reducing cervical cancer and other HPV-related diseases, the vaccine has been implemented in the national vaccination programs of several countries, with over 178 million doses distributed worldwide. METHODS: Extensive efforts to assess the safety of the vaccine in routine practice have been conducted over the past 9 years since licensure, including more than 15 studies in more than 1 million preadolescents, adolescents and adults from various countries. Most have been performed in the general population although there have been some in special populations (pregnant women, HIV-infected individuals and those with systemic lupus erythematosus). RESULTS: We present a summary of the published, postlicensure safety data from active and passive surveillance. Only syncope, and possibly skin infections were associated with vaccination in the postlicensure setting. Serious adverse events, such as adverse pregnancy outcomes, autoimmune diseases (including Guillain-Barre Syndrome and multiple sclerosis), anaphylaxis, venous thromboembolism and stroke, were extensively studied, and no increase in the incidence of these events was found compared with background rates. CONCLUSIONS: These results, along with the safety data from the prelicensure clinical trials, confirm that the HPV4 vaccine has a favorable safety profile. Key policy, medical and regulatory organizations around the world have independently reviewed these data and continue to recommend routine HPV vaccination.