Meeting report: Considerations for trial design and endpoints in licensing therapeutic HPV16/18 vaccines to prevent cervical cancer.

Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.

A proteome-wide analysis unveils a core Epstein-Barr virus antibody signature of classic Hodgkin lymphoma across ethnically diverse populations.

Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.

COVID-19 and long-term impact on symptoms and Health-Related Quality of Life in Costa Rica: the RESPIRA cohort study.

BACKGROUND: Evidence continues to accumulate regarding the potential long-term health consequences of COVID-19 in the population. To distinguish between COVID-19-related symptoms and health limitations from those caused by other conditions, it is essential to compare cases with community controls using prospective data ensuring case-control status. The RESPIRA study addresses this need by investigating the lasting impact of COVID-19 on Health-related Quality of Life (HRQoL) and symptomatology in a population-based cohort in Costa Rica, thereby providing a robust framework for controlling HRQoL and symptoms. METHODS: The study comprised 641 PCR-confirmed, unvaccinated cases of COVID-19 and 947 matched population-based controls. Infection was confirmed using antibody tests on enrollment serum samples and symptoms were monitored monthly for 6 months post-enrolment. Administered at the 6-month visit (occurring between 6- and 2-months post-diagnosis for cases and 6 months after enrollment for controls), HRQoL and Self-Perceived Health Change were assessed using the SF-36, while brain fog, using three items from the Mental Health Inventory (MHI). Regression models were utilized to analyze SF-36, MHI scores, and Self-Perceived Health Change, adjusted for case/control status, severity (mild case, moderate case, hospitalized) and additional independent variables. Sensitivity analyses confirmed the robustness of the findings. RESULTS: Cases showed significantly higher prevalences of joint pain, chest tightness, and skin manifestations, that stabilized at higher frequencies from the fourth month post-diagnosis onwards (2.0%, 1.2%, and 0.8% respectively) compared to controls (0.9%, 0.4%, 0.2% respectively). Cases also exhibited significantly lower HRQoL than controls across all dimensions in the fully adjusted model, with a 12.4 percentage-point difference [95%CI: 9.4-14.6], in self-reported health compared to one year prior. Cases reported 8.0% [95%CI: 4.2, 11.5] more physical limitations, 7.3% [95%CI: 3.5, 10.5] increased lack of vitality, and 6.0% [95%CI: 2.4, 9.0] more brain fog compared to controls with similar characteristics. Undiagnosed cases detected with antibody tests among controls had HRQoL comparable to antibody negative controls. Differences were more pronounced in individuals with moderate or severe disease and among women. CONCLUSIONS: PCR-confirmed unvaccinated cases experienced prolonged HRQoL reductions 6 months to 2 years after diagnosis, this was particularly the case in severe cases and among women. Mildly symptomatic cases showed no significant long-term sequelae.

Differential long-term bivalent HPV vaccine cross-protection by variants in the Costa Rica HPV vaccine trial.

The AS04-adjuvanted human papillomavirus (HPV)16/18 vaccine, an L1-based vaccine, provides strong vaccine efficacy (VE) against vaccine-targeted type infections, and partial cross-protection to phylogenetically-related types, which may be affected by variant-level heterogeneity. We compared VE against incident HPV31, 33, 35, and 45 detections between lineages and SNPs in the L1 region among 2846 HPV-vaccinated and 5465 HPV-unvaccinated women through 11-years of follow-up in the Costa Rica HPV Vaccine Trial. VE was lower against HPV31-lineage-B (VE=60.7%;95%CI = 23.4%,82.8%) compared to HPV31-lineage-A (VE=94.3%;95%CI = 83.7%,100.0%) (VE-ratio = 0.64;95%CI = 0.25,0.90). Differential VE was observed at several lineage-associated HPV31-L1-SNPs, including a nonsynonymous substitution at position 6372 on the FG-loop, an important neutralization domain. For HPV35, the only SNP-level difference was at position 5939 on the DE-loop, with significant VE against nucleotide-G (VE=65.0%;95%CI = 28.0,87.8) but not for more the common nucleotide-A (VE=7.4%;95%CI = -34.1,36.7). Because of the known heterogeneity in precancer/cancer risk across cross-protected HPV genotype variants by race and region, our results of differential variant-level AS04-adjuvanted HPV16/18 vaccine efficacy has global health implications.

Kinetics of EBV antibody-based NPC risk scores in Taiwan NPC multiplex families.

Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein-Barr virus (EBV)-antibody testing have shown potential for screening of NPC; however, the long-term stability is unclear. Here, we investigated the kinetics of two EBV-antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2-marker enzyme-linked immunosorbent assay score and 13-marker multiplex serology score using the intra-class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20-year follow-up, the 2-marker score showed high stability over time, whereas the 13-marker score was more variable (p < .05). Case-control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2-marker score than the 13-marker score (p < .05). The 2-marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13-marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high-risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high-risk regions.

Optimization and Local Cost-Effectiveness of Nasopharyngeal Carcinoma Screening Strategies in Southern China: Secondary Analysis of the Guangdong Randomized Trial.

BACKGROUND: Screening with anti-Epstein-Barr virus (EBV) serology and endoscopy decreased nasopharyngeal carcinoma (NPC) mortality in Guangdong in a randomized trial. We conducted a secondary analysis of this trial using local incidence and cost data to optimize screening programs, hypothesizing that screening could be cost-effective in southern China. METHODS: Screening costs and life-years after NPC diagnosis were obtained from the Guangdong trial's intent-to-screen population (men and women aged 30-69). Seropositive subjects were rescreened annually for 5 years. Thereafter, we evaluated 12 screening strategies in Guangdong and Guangxi using a validated model. Strategies used combinations of serology, nasopharyngeal swab PCR (NP PCR), endoscopy, and MRI from trial subcohorts. Incidence data and costs were obtained from local cancer registries and the provincial healthcare system. RESULTS: In the intent-to-screen population, screening with serology and endoscopy was cost-effective (¥42,366/life-year, 0.52 GDP per capita). Screening for 5 to 15 years between ages 35 and 59 years met a willingness-to-pay threshold of 1.5 GDP/quality-adjusted life-years in all modeled populations. Despite doubling costs, adding MRI could be cost-effective via improved sensitivity. NP PCR triage reduced endoscopy/MRI referrals by 37%. One-lifetime screen could reduce NPC mortality by approximately 20%. CONCLUSIONS: EBV-based serologic screening for NPC is likely to be cost-effective in southern China. Among seropositive subjects, the preferred strategies use endoscopy alone or selective endoscopy triaged by MRI with or without NP PCR. These data may aid the design of screening programs in this region. IMPACT: These findings support population-based screening in southern China by defining the target population, cost-effectiveness, and optimized screening approach.

Statin use is not associated with inflammation among Chilean women of Mapuche and non-Mapuche ancestry with gallstones.

Aim: Statins are associated with lower risk of gallstones due to anti-inflammatory effects. We assessed whether statins impact circulating inflammation among Chilean women with gallstones. Materials & methods: 200 Mapuche women were matched on statin use and age to 200 non-Mapuche women in the Chile Biliary Longitudinal Study. We analyzed 92 inflammatory biomarkers using multivariable-adjusted regression models, random forests and pathway analyses. Results: Statins were not significantly associated with any inflammation marker when women were analyzed jointly or stratified by ancestry. No significant associations were found through random forest methods and pathway analyses. Discussion: We did not find significant associations between statin use and inflammation markers in women with gallstones, suggesting that statins do not reduce inflammation once gallstones have formed.

Statins are prescribed to lower cholesterol and can also decrease the risk of gallstone formation by reducing inflammation. We assessed whether statin use reduces inflammation among women who have already developed gallstones. We analyzed 92 inflammation markers among 400 women in Chile, including 200 women with Mapuche Amerindian ancestry and 200 women of Latina/European ancestry. We found that statin use was not correlated with inflammation in this group of women overall nor by ancestry. This may mean that statin use does not reduce inflammation in women who already were diagnosed with gallstones.

Description of a seven-year prospective study of human papillomavirus infection and cervical neoplasia among 10 000 women in Guanacaste, Costa Rica / Descripción de un estudio prospectivo de siete años sobre la infección por el virus del papiloma humano y el cáncer cervicouterino en 10 000 mujeres de Guanacaste, Costa Rica

OBJETIVOS: El estudio de cohorte de Guanacaste, o Proyecto Epidemiológico Guanacaste, fue diseñado para investigar el papel que desempeñan la infección por el virus del papiloma humano (VPH) y sus cofactores en el desarrollo de neoplasias cervicouterinas y para evaluar nuevas tecnologías de tamizaje del cáncer del cuello de útero. La fase de seguimiento de este proyecto se diseñó para analizar por qué una pequeña parte de las mujeres infectadas por el VPH desarrollan neoplasias intraepiteliales cervicouterinas (NIC) grados 2 y 3, o cáncer (que en lo adelante se llamarán en conjunto > NIC 2, es decir, NIC 2 o peor). El propósito de este artículo es describir en detalle ese estudio prospectivo y presentar los resultados preliminares relacionados con la incidencia de neoplasias cervicouterinas. MÉTODOS: Se realizó el tamizaje intensivo de una cohorte de 10 049 mujeres de 18 a 97 años de edad seleccionadas aleatoriamente en Guanacaste, provincia del noroeste de Costa Rica, en 1993-1994 con un seguimiento ulterior de siete años. A las participantes se les aplicó un cuestionario para conocer sus características demográficas y sus factores de riesgo, y a las sexualmente activas se les realizó además un examen pélvico en cada una de las visitas de seguimiento, a fin de obtener muestras para las pruebas de tamizaje y la investigación. El diagnóstico obtenido al final de la fase de captación permitió clasificar a las mujeres en varios grupos de acuerdo con el riesgo que presentaban de desarrollar cáncer o alguno de sus precursores de alto grado. Estos grupos tuvieron seguimientos a intervalos diferentes, según su riesgo de desarrollar > NIC 2. El seguimiento más activo (cada 6-12 meses) se concentró en las mujeres con mayores probabilidades de desarrollar > NIC 2, según los resultados citológicos (n = 492). Las mujeres restantes recibieron visitas de seguimiento anualmente (n = 2 574) o después de cinco a siete años de seguimiento pasivo (n = 3 926). A todas las mujeres en quienes se detectaron lesiones que pudieran ser graves, por cualquiera de las técnicas empleadas, se les remitió a una evaluación ulterior mediante colposcopia y a tratamiento médico, y se retiraron del estudio. Las lesiones > NIC 2 se utilizaron como criterio para la salida del estudio y como indicadores indirectos del riesgo de cáncer. RESULTADOS: La participación durante la fase de seguimiento fue alta (cercana al 90%). Cualquier indicio de > NIC 2, según cualquiera de las técnicas...

Objective. The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the role of human papillomavirus (HPV) infection and its cofactors in the development of cervical neoplasia and to evaluate new cervical cancer screening technologies. The follow-up phase of the GP was designed to study why a small proportion of women infected with HPV develop cervical intraepithelial neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally referred to as ≥ CIN 2, that is, CIN 2 or worse). The purpose of this article is to describe this prospective study in detail and to present the preliminary findings regarding the incidence of cervical neoplasia. Methods. A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 1993­1994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing ≥ CIN 2. The most active follow-up (every 6­12 months) was concentrated on the women most likely to develop ≥ CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions ≥ CIN 2 served as both the censoring outcome and our surrogate for cancer risk. Results. Participation during follow-up was high (near 90%). Suspected ≥ CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected ≥ CIN 2 came from the large group perceived at entry as being at low risk of developing ≥ CIN 2, but the greatest rates of progression to ≥ CIN 2 were observed among women perceived at entry to be at highest risk of ≥ CIN 2, based on their cytology, virology, or sexual behavior. Conclusions. The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide

Desing and methods of a population-based natural history study of cervical neoplasia in a rural province of Costa Rica: the Guanacaste Project / Diseño y métodos usados en un estudio poblacional sobre la historia natural de las neoplasias de cuello uterino en una provincia rural de Costa Rica: el Proyecto de Guanacaste

En el presente trabajo se describe la fase de reclutamiento de un estudio poblacional sobre la historia natural de las neoplasias de cuello uterino en Guanacaste, provincia rural costarricense donde las tasas de cáncer cervicouterino invasor son invariablemente altas. Las metas principales del estudio son investigar el papel que desempeñan la infección por el virus del papiloma humano (VPH) y sus cofactores en la etiología de las neoplasias cervicouterinas de alto grado, y evaluar las nuevas tecnologías empleadas en el tamizaje del cáncer cervical. Para empezar se seleccionó una muestra aleatoria de segmentos censuales y, con la ayuda de trabajadores de acción comunitaria del Ministerio de Salud de Costa Rica, se hizo un recuento de todas las habitantes de 18 años de edad o mayores. De las 10 738 mujeres que cumplían con los requisitos para participar, 10 049 (93,6%) fueron entrevistadas después de haber dado su consentimiento informado por escrito. Después de la entrevista sobre los factores de riesgo del cáncer cervicouterino, se hizo un examen pélvico a las mujeres que dijeron haber tenido actividad sexual. El examen pélvico incluyó la determinación del pH vaginal y la obtención de células para análisis citológico mediante tres técnicas distintas. También se obtuvieron células cervicales para determinar la presencia y cantidad de ADN de 16 tipos de VPH diferentes y se tomaron dos fotografías del cérvix que fueron interpretadas en un local distinto por un experto en colposcopia. Por último, se sacaron muestras de sangre para hacer ensayos inmunológicos y determinaciones de micronutrientes. Las mujeres con un diagnóstico citológico anormal o un cervigrama positivo, más una muestra del grupo en general, fueron remitidas para hacerles colposcopia y se tomaron biopsias cuando se observaron lesiones. El tamizaje con fines de reclutamiento servirá de base para un estudio de prevalencia de casos y controles, y las integrantes de la cohorte sin enfermedad avanzada tendrán un seguimiento activo a intervalos mínimos de un año, con el propósito de estudiar la historia natural de la infección por VPH y los orígenes de las lesiones escamosas intraepiteliales de alto grado. Se describe en detalle la operación de campo y se hace especial alusión a la realización de estudios de este tipo en países en desarrollo. También se presentan datos descriptivos sobre la prevalencia de la enfermedad y la exposición a diversos factores de riesgo

This paper reports on the enrollment phase of a population-based natural history study of cervical neoplasia in Guanacaste, a rural province of Costa Rica with consistently high rates of invasive cervical cancer. The main goals of the study are to investigate the role of human papillomavirus (HPV) infection and its co-factors in the etiology of high-grade cervical neoplasia, and to evaluate new cervical cancer screening technologies. To begin, a random sample of censal segments was selected and enumeration of all resident women 18 years of age and over was conducted with the aid of outreach workers of the Costa Rican Ministry of Health. Of the 10 738 women who were eligible to participate, 10 049 (93.6%) were interviewed after giving written informed consent. After the interview on cervical cancer risk factors was administered, a pelvic examination was performed on those women who reported previous sexual activity. The pelvic examination included a vaginal pH determination and collection of cervical cells for cytologic diagnosis using three different techniques. Additional cervical cells were collected for determination of the presence and amount of DNA from 16 different types of HPV, and two photographic images of the cervix were taken and interpreted offsite by an expert colposcopist. Finally, blood samples were collected for immunologic and micronutrient assays. Women with any abnormal cytologic diagnosis or a positive Cervigram, as well as a sample of the whole group, were referred for colposcopy, and biopsies were taken when lesions were observed. The enrollment screening will serve as the basis for a prevalent case-control study, and the members of the cohort free from serious disease will be followed actively, at intervals of no more than a year, to study the natural history of HPV infection and the origins of high-grade squamous intraepithelial lesions (HSIL). Details of the field operation are outlined, with particular reference to the realization of this kind of study in developing countries. Descriptive data on the prevalence of disease and exposure to various risk factors are also presented.