Association of plasma aflatoxin with persistent detection of oncogenic human papillomaviruses in cervical samples from Kenyan women enrolled in a longitudinal study.

BACKGROUND: Cervical cancer is caused by oncogenic human papillomaviruses (HR-HPV) and is common among Kenyan women. Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of HR-HPV detection in cervical specimens. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. METHODS: Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. RESULTS: Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). CONCLUSIONS: Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies, including mechanistic studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.

Non-Vaccine-Type Human Papillomavirus Prevalence After Vaccine Introduction: No Evidence for Type Replacement but Evidence for Cross-Protection.

BACKGROUND: We examined non-vaccine-type human papillomavirus (HPV) prevalence in a community before and during the first 8 years after vaccine introduction, to assess for (1) type replacement with any non-vaccine-type HPV and (2) cross-protection with non-vaccine types genetically related to vaccine-type HPV. METHODS: Sexually experienced 13- to- 26-year-old women were recruited for 3 cross-sectional studies from 2006 to 2014 (N = 1180). Outcome variables were as follows: (1) prevalence of at least 1 of 32 anogenital non-vaccine-type HPVs and (2) prevalence of at least 1 HPV type genetically related to HPV-16 and HPV-18. We determined changes in proportions of non-vaccine-type HPV prevalence across the study waves using logistic regression with propensity score inverse probability weighting. RESULTS: Vaccine initiation rates increased from 0% to 71.3%. Logistic regression demonstrated that from 2006 to 2014, there was no increase in non-vaccine-type HPV among vaccinated women (adjusted odds ratio [AOR], 1.02; 95% confidence interval [CI], 0.73-1.42), but an increase among unvaccinated women (AOR, 1.88; 95% CI, 1.16-3.04). Conversely, there was a decrease in types genetically related to HPV-16 among vaccinated (AOR, 0.57; 95% CI, 0.38-0.88) but not unvaccinated women (AOR, 1.33; 95% CI, 0.81-2.17). CONCLUSIONS: We did not find evidence of type replacement, but did find evidence of cross-protection against types genetically related to HPV-16. These findings have implications for cost-effectiveness analyses, which may impact vaccine-related policies, and provide information to assess the differential risk for cervical cancer in unvaccinated and vaccinated women, which may influence clinical screening recommendations. The findings also have implications for public health programs, such as health messaging for adolescents, parents, and clinicians about HPV vaccination.

Impaired immune function in children and adults with Fanconi anemia.

BACKGROUND: Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, bone marrow failure, and cancer predisposition. Previously, small studies have reported heterogeneous immune dysfunction in FA. PROCEDURE: We performed a detailed immunologic assessment in a large FA cohort who have not undergone bone marrow transplantation or developed malignancies. Comprehensive quantitative and functional immunologic assessment of 29 FA individuals was compared to healthy age-matched controls. RESULTS: Compared to non-FA persons of similar ages, FA individuals showed lower absolute total B cells (P < 0.001), lower memory B cells (P < 0.001), and decreased IgM (P < 0.001) but normal IgG. NK cells (P < 0.001) and NK cytotoxicity (P < 0.001) were decreased. CD4+ T cells were decreased (P = 0.022), while CD8+ T cell and absolute T-cell numbers were comparable. Cytotoxic T cells (P < 0.003), and antigen proliferation response to tetanus (P = 0.019) and candida (P = 0.019), were diminished in FA. Phytohemagglutinin responses and plasma cytokines were normal. Within FA subjects, adults and older children (≥10 years) exhibited higher CD8+ T cells than younger children (P = 0.004). Documented atypical infections were infrequent, although oral human papilloma virus (HPV) prevalence was higher (31% positive) in FA. CONCLUSIONS: Overall, these results demonstrate a high rate of significant humoral and cellular immune dysfunction. Continued longitudinal study of immune function is critical to understand evolution with age, bone marrow failure, and cancer development.

Substantial Decline in Vaccine-Type Human Papillomavirus (HPV) Among Vaccinated Young Women During the First 8 Years After HPV Vaccine Introduction in a Community.

BACKGROUND: Human papillomavirus (HPV) vaccine effectiveness and herd protection are not well established in community settings. Our objective was to determine trends in vaccine-type HPV in young women during the 8 years after vaccine introduction, to assess changes in HPV prevalence and characterize herd protection in a community. METHODS: We recruited 3 samples of sexually experienced, 13-26-year-old adolescent girls and young women (hereafter women; N = 1180) from 2006-2014: before widespread vaccine introduction (wave 1) and 3 (wave 2) and 7 (wave 3) years after vaccine introduction. We determined the prevalence of vaccine-type HPV (HPV-6, -11, -16, and -18) among all, vaccinated, and unvaccinated women at waves 1, 2, and 3, adjusted for differences in participant characteristics, then examined whether changes in HPV prevalence were significant using inverse propensity score-weighted logistic regression. RESULTS: Vaccination rates increased from 0% to 71.3% across the 3 waves. Adjusted vaccine-type HPV prevalence changed from 34.8% to 8.7% (75.0% decline) in all women, from 34.9% to 3.2% (90.8% decline) in vaccinated women, and from 32.5% to 22.0% (32.3% decline) in unvaccinated women. Among vaccinated participants, vaccine-type HPV prevalence decreased significantly from wave 1 to wave 2 (adjusted odds ratio, 0.21; 95% confidence interval, .13-.34) and from wave 1 to wave 3 (0.06; .03-.13). The same decreases were also significant among unvaccinated participants (adjusted odds ratios, 0.44; [95% confidence interval, .27-.71] and 0.59; [.35-.98], respectively). CONCLUSIONS: The prevalence of vaccine-type HPV decreased >90% in vaccinated women, demonstrating high effectiveness in a community setting, and >30% in unvaccinated women, providing evidence of herd protection.

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.

Episodic detection of human papillomavirus within a longitudinal cohort of young women.

Redetection of a type-specific human papillomavirus (HPV) infection may represent reinfection. However, a growing body of literature suggests that reactivation of HPV is common and that episodic detection of a HPV infection may represent reactivation of a persistent virus. A cohort of prospectively followed adolescent women (N = 150), ages 14-17, was observed on average 6.4 years. The authors describe the redetection of 37 HPV types and associated factors of redetection of high-risk (HR) and low-risk (LR) types using Cox proportional hazard models. Of 1,248 HPV type-specific infections, 286 (22.9%) were associated with redetection after apparent clearance. Chlamydia infections (HR = 1.99 [95%CI, 1.15-3.49]) and non-condom use (HR = 1.1 [95%CI, 1.04-1.99]) were associated with increased redetection of HR-HPV infections. Oral contraceptive pills (HR = 2.73 [95%CI, 1.52-4.90]) and number of sexual partners (HR = 1.44 [95%CI, 1.04-1.99]) were associated with increased redetection of LR-HPV infections. Episodic detection of HPV is common for HR- and LR-HPV types. This finding and identified factors or redetection have clinical implications and enhances the understanding of HPV natural history.

DNA detection and seroprevalence of human papillomavirus in a cohort of adolescent women.

OBJECTIVES: Human papillomavirus (HPV) infections are common in adolescent women, while the rare cancerous sequelae of HPV infections do not generally occur until the 4th or 5th decades of life. This prospective study of a cohort of adolescent women was performed to further our knowledge of the natural history of incident and prevalent HPV infections. METHODS: Self-vaginal swabs collected from high-risk, unvaccinated adolescent women in a longitudinal study were analysed for HPV DNA. Sera were collected at enrolment and later tested for HPV antibodies. Statistical analysis was performed to determine the HPV genotype distribution and duration of detection, and to determine rates of seropositivity and seroconversion for HPV types represented in the assays. RESULTS: 146 subjects (mean enrolment age=15.4 years; mean duration of follow-up=5.8 years) had samples adequate for analysis of HPV detection, and 95 of these subjects had paired sera available. The cumulative prevalence for high-risk and low-risk HPV types was 95.9% and 91.1%, respectively. HPV types 6, 11, 16 and 18 (HPV types represented in the quadrivalent vaccine) were found at some point in 40.4%, 6.2%, 48% and 24% of participants, respectively. Serological data confirmed exposure to these vaccine-covered types, as well as to other high-risk HPV types. CONCLUSIONS: In this cohort of adolescent women, high- and low-risk HPV types were frequently detected, and serological data confirmed exposure in most subjects. The high-prevalence HPV types represented in the quadrivalent HPV vaccine further support vaccination of women at an age well before sexual debut.

High frequency of human papillomavirus detection in the vagina before first vaginal intercourse among females enrolled in a longitudinal cohort study.

BACKGROUND: Genital human papillomavirus (HPV) infection is believed to be primarily sexually transmitted. Few studies have documented the detection of HPV in the vagina before first vaginal intercourse. METHODS: We used a longitudinally followed cohort of adolescent females without prior vaginal intercourse to examine the frequency of detection of vaginal HPV and the association between first reported HPV detection and noncoital sexual behaviors. RESULTS: HPV was detected in 45.5% of subjects (10 of 22) before first vaginal sex. Seven of these 10 subjects reported noncoital behaviors that, in part, might have explained genital transmission. CONCLUSIONS: HPV can be detected in the vagina before first sexual intercourse, highlighting the need for early vaccination.

Association of Chlamydia trachomatis infection with redetection of human papillomavirus after apparent clearance.

BACKGROUND: Persistent infection with oncogenic human papillomavirus (HPV) is associated with an increased risk of cervical malignancy. Redetection of type-specific HPV after a period of nondetection may be caused by reactivation of a low-level persistent infection. Little is known about factors associated with type-specific HPV redetection. METHODS: For a longitudinal cohort of adolescent women with frequent behavioral and sexually transmitted infection (STI) information (every 3 months), Cox proportional hazard models were used to assess the influence of sexual behaviors and STIs on the redetection of oncogenic or high-risk HPV infections. RESULTS: A total of 210 type-specific high-risk HPV detection episode periods were identified in this longitudinal cohort; 71 (33.8%) were characterized by a period of nondetection followed by redetection. Chlamydia trachomatis (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.44-6.86) was associated with redetection; redetection was >2 times more likely with each additional self-reported sex partner in the past 3 months (HR, 2.26; 95% CI, 1.35-3.78). CONCLUSIONS: This study demonstrates the role of C. trachomatis and number of recent sexual partners in type-specific HPV redetection. Given that persistent oncogenic HPV infections are associated with cancer-related outcomes, understanding the potential role of such factors in the pathogenesis of HPV-related outcomes is important.

Real-World Cervical Cancer Screening Uptake and Predictors of Visual Inspection With Acetic Acid Positivity Among Women Living With HIV in Care Programs in Western Kenya.

PURPOSE: To achieve the WHO cervical cancer elimination targets, countries globally must achieve 70% cervical cancer screening (CCS) coverage. We evaluated CCS uptake and predictors of screening positive at two public HIV care programs in western Kenya. METHODS: From October 2007 to February 2019, data from the Family AIDS Care and Education Services (FACES) and Academic Model Providing Access to Healthcare (AMPATH) programs in western Kenya were analyzed. The study population included women age 18-65 years enrolled in HIV care. Screening uptake was calculated annually and overall, determining the proportion of eligible women screened. Multivariate logistic regression assessed predictors of positive screening outcomes. RESULTS: There were 57,298 women living with HIV (WLWHIV) eligible for CCS across both programs during the study period. The mean age was 31.4 years (IQR, 25.9-37.8), and 39% were on antiretroviral therapy (ART) at the first CCS-eligible visit. Of all eligible women, 29.4% (95% CI, 29.1 to 29.8) underwent CCS during the study period, 27.0% (95% CI, 26.5 to 27.4) in the AMPATH program, and 35.6% (95% CI, 34.9 to 36.4) in the FACES program. Annual screening uptake varied greatly in both programs, with coverage as low as 1% of eligible WLWHIV during specific years. Age at first screening, CD4 count within 90 days of screening, current use of ART, and program (AMPATH v FACES) were each statistically significant predictors of positive screening. CONCLUSION: CCS uptake at two large HIV care programs in Kenya fell short of the WHO's 70% screening target. Screening rates varied significantly on the basis of the availability of funding specific to CCS, reflecting the limitations of vertical funding programs.

The fanconi anemia pathway limits human papillomavirus replication.

High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.

Association of HPV types 6, 11, 16, and 18 DNA detection and serological response in unvaccinated adolescent women.

Antibodies directed against the human papillomavirus (HPV) L1 protein are detected in approximately 70% of individuals with HPV infections. The factors associated with a serological response are not characterized. It is hypothesized that the HPV viral load, duration of detection, or both would be associated with seropositivity in adolescent women. Adolescent women (n = 117), ages 15-17 at enrolment were followed for a mean of 6.2 years. Quarterly vaginal swabs (mean 22 per participant) were used to identify HPV 6, 11, 16, or 18 DNA (Roche PCR/Linear Array). Type-specific HPV infection was defined as ≥2 positive assays. To approximate viral load, Roche PCR/Linear Array test strips were scored visually based on the strength of signal relative to beta-globin controls. Sera collected near the end of study were tested by cLIA. Regression models were fit to assess associations between strength of signal (as represented by mean and cumulative strength of signal), duration of HPV detection, seropositivity, and serotiter. Detection of HPV DNA was associated with seropositivity for four types combined and for types 6, 16, and 18. Overall, 70.1% of DNA positive episodes were associated with type-specific seropositivity. The cumulative HPV DNA signal strength during periods of HPV detection for types 6, 11, 16, and 18 combined was associated with seropositivity (OR = 1.21, 95% CI 1.02-1.44 P = 0.026). No other HPV DNA predictors were found to be associated with seropositivity or serotiter.

Association of Plasma Aflatoxin With Persistent Detection of Oncogenic Human Papillomaviruses in Cervical Samples From Kenyan Women Enrolled in a Longitudinal Study.

Background Cervical cancer is common among Kenyan women and is caused by oncogenic human papillomaviruses (HR-HPV). Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of cervical HR-HPV detection. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. Methods Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. Results Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). Conclusions Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.

A community-based approach to cervical cancer prevention in western Kenya: An AMPATH feasibility project.

Objectives: Centralized programs have been ineffective in reducing the burden of cervical cancer among Kenyan women. A community-based pilot study was initiated to screen Kenyan women for cervical cancer and to vaccinate their children against human papillomavirus (HPV). Methods: Women were educated about cervical cancer prevention at community meetings. Women then provided self-collected vaginal swabs for oncogenic HPV testing using the Roche Cobas Assay. All women were then referred to the local clinic for Visual Inspection with Acetic Acid (VIA). Women were offered the quadrivalent HPV vaccine for their children if and when it became available for the study. Results: Women in western Kenya were invited to participate in community meetings. A total of 200 women were enrolled: 151 (75.5%) were HIV-uninfected and 49 (24.5%) were HIV-infected; the median age for all women was 42 years. High-risk (HR)-HPV types were detected in 49 of swabs from all 200 participants (24.5%) including 20.5% of HIV-uninfected women and 36.7% of HIV-infected women (P = .022). VIA was performed on 198 women: 192 had normal examinations and six had abnormal examinations. Five cervical biopsies revealed two cases of CIN 2 and one CIN 3. Although all mothers were willing to have their children (N = 432) vaccinated, the HPV vaccine could not be delivered to Kenya during the study period. Conclusions: Kenyan women were willing to attend community meetings to learn about prevention of cervical cancer, to provide self-collected vaginal swabs for HPV testing, to travel to the Webuye Clinic for VIA following the collection of swabs, and to have their children vaccinated against HPV. HR-HPV was prevalent, especially in HIV-infected women. As a result of this pilot study, this community-based strategy to prevent cervical cancer will be continued in western Kenya.

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.

Impact of an HPV6/11/16/18 L1 virus-like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection.

The impact of a human papillomavirus (HPV) vaccine on development of cervical intraepithelial neoplasia grade 2-3 or adenocarcinoma in situ (CIN2-3/AIS) in women with ongoing HPV16 or 18 infections prevaccination is reported. Seventeen thousand six-hundred and twenty-two women aged 16-26 were enrolled in 1 of 2 randomized, placebo-controlled, efficacy trials (Protocols 013 and 015). Vaccine or placebo was given at day 1, month 2 and 6. Women were tested for HPV6/11/16/18 DNA and antibodies at day 1. We focus on the subset of women who were seropositive and DNA positive to HPV16 or HPV18 prevaccination. Incidence is expressed as the number of women with an endpoint per 100 person-years-at-risk. In total, 419 vaccine and 446 placebo recipients were both seropositive and DNA positive to HPV16 or HPV18 prevaccination and had at least one follow-up visit. In Protocol 013, the incidence of HPV16/18-related CIN2-3/AIS among these women was 10.9 in the vaccine arm and 7.0 in the placebo arm (vaccine efficacy = -54.9; 95% CI: -181.7, 13.0). In Protocol 015, the incidence of HPV16/18-related CIN2-3/AIS was 5.5 in the vaccine arm and 6.2 in the placebo arm (vaccine efficacy = 12.2%; 95% CI: -29.8, 40.9). These data suggest HPV vaccination neither reduces nor enhances progression to HPV16/18-related high grade cervical lesions, and cervical cytology screening and corresponding management should continue as per local recommendations. Ultimately, population-based surveillance of vaccinated individuals beyond these clinical trials will be required to further address questions regarding the impact of vaccination in women exposed to vaccine HPV types before vaccination.

Adenocarcinoma in situ and associated human papillomavirus type distribution observed in two clinical trials of a quadrivalent human papillomavirus vaccine.

The primary objective of this report is to describe the detection of adenocarcinoma in situ (AIS) and associated human papillomavirus (HPV) type distribution that was observed in the context of two phase 3 clinical trials of a quadrivalent HPV6/11/16/18 vaccine. In this intention-to-treat analysis, we include all women who had at least one follow-up visit postenrollment. Healthy women (17,622) aged 15-26 with no history of HPV disease and a lifetime number of less than five sex partners (average follow-up of 3.6 years) were randomized (1:1) to receive vaccine or placebo at day 1, months 2, and 6. Women underwent colposcopy and biopsy according to a Papanicolaou triage algorithm. All tissue specimens were tested for 14 HPV types and were adjudicated by a pathology panel. During the trials, 22 women were diagnosed with AIS (six vaccine and 16 placebo). There were 25 AIS lesions in total, with HPV16/18 present in 96% (24 of 25 with 15 of 25 as single infections). Only two of 22 women had concomitant cytology results suggesting glandular abnormality. Colposcopic impressions (25 total) were either negative or indicated squamous lesions only. Of women with AIS, all six in the vaccine cohort and seven of 16 in the placebo cohort were infected at baseline with the same HPV type that was detected in the AIS lesion. Concurrent squamous lesions were detected in 20 of these 22 women. In summary, our findings show that AIS evades colposcopic and cervical cytologic detection. As most AIS lesions were HPV16/18-related, prophylactic HPV vaccination should reduce the incidence of invasive adenocarcinoma.

The humoral response to Gardasil over four years as defined by total IgG and competitive Luminex immunoassay.

Safe and effective vaccines against anogenital human papillomaviruses (HPV) are now available. These vaccines, composed of virus-like particles (VLPs) made from the L1 major capsid protein of specific HPV types, induce a polyclonal antibody response directed against specific conformational and linear epitopes displayed on the VLP. Numerous studies indicated the importance of neutralizing antibodies in protection from infection. However, our understanding of the antibody responses to these vaccines is not complete, and there is no established immune correlate of protection nor antibody threshold that correlates with protection against HPV infection or disease. In the current study, antibody responses of young women to Gardasil®, the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (qHPV), were assessed through 48 months (M) in total IgG and competitive Luminex immunoassays (total IgG LIA and cLIA). The total IgG LIA was developed as a research assay to evaluate preclinical multivalent HPV VLP vaccine formulations. The cLIA simultaneously evaluates the antibody response to a unique conformational, neutralizing epitope on each of the four HPV types present in the quadrivalent vaccine; HPV 6, 11, 16 and 18. The same sera from women vaccinated with the qHPV vaccine were tested in both the total IgG LIA and the cLIA assays. The proportion of vaccinated women achieving seropositivity and the anti-HPV VLP total IgG and cLIA geometric mean titers (GMTs) were summarized at M7, M24, M48 based on the serostatus cut-points defined for each immunoassay. Overall, greater than 99% of subjects seroconverted to all four vaccine types in both assays; GMTs peaked at M7. For all four HPV types, regardless of the immunoassay used, the most significant decline in GMTs was observed between M7 and M24. By M24, the antibody titers had reached a plateau and minimal declines in antibody titers were observed between M24 and M48 for all four HPV types in both immunoassays. Testing the same sera, seropositivity for M48 HPV18 remained high (96.7%) in the total IgG LIA, but was 64.8% in the cLIA. The current study illustrates potential important differences in serologic assays utilized in the clinical trials of the two currently available HPV VLP vaccines (quadrivalent and bivalent). Differences in seropositivity status are attributed to the measurement parameters and sensitivity of the individual immunoassays and do not indicate reduced anti-HPV18 protective antibodies.

Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines.

INTRODUCTION: Studies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58). METHODS: PubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58. RESULTS: Eighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time. CONCLUSIONS: The cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence.

BACKGROUND: The extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies. METHODS: PubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts. RESULTS: Data from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3-66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines. CONCLUSIONS: RCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.