BACKGROUND:Multidose human papillomavirus (HPV) vaccination is efficacious, yet the vaccine has been underused globally. Emerging data suggest that a single dose may provide protection. Whether a single dose of HPV vaccine would provide similar protection to two doses is uncertain. METHODS:In this trial, we assessed whether one dose of an HPV vaccine was noninferior to two doses. Girls 12 to 16 years of age were randomly assigned, in a 1:1:1:1 ratio, to receive one or two doses of a bivalent HPV vaccine or one or two doses of a nonavalent HPV vaccine. The primary end point was new HPV type 16 or 18 infection occurring from month 12 to month 60 and persisting for at least 6 months. The prespecified noninferiority margin was 1.25 infections per 100 participants. We also assessed vaccine effectiveness by comparing HPV16 or HPV18 infection among the trial participants with that among girls and women enrolled in a nonrandomized survey. RESULTS:A total of 20,330 participants were enrolled and underwent randomization, and 3005 unvaccinated participants were enrolled in the survey. The noninferiority analysis showed that one vaccine dose was noninferior to two doses in preventing HPV16 or HPV18 infection. The rate difference between one and two doses of the bivalent vaccine was -0.13 infections per 100 participants (95% confidence interval [CI], -0.45 to 0.15; P<0.001 for noninferiority), and the difference between one and two doses of the nonavalent vaccine was 0.21 infections per 100 participants (95% CI, -0.09 to 0.51; P<0.001 for noninferiority). The vaccine effectiveness was at least 97% in each of the four trial groups. No safety concerns were identified. CONCLUSIONS:One dose of either a bivalent or nonavalent HPV vaccine provided protection against HPV16 or HPV18 infection and was not inferior to two doses. (Funded by the National Cancer Institute and others; ESCUDDO ClinicalTrials.gov number, NCT03180034.).

Cervical cancer is caused by persistent infection with carcinogenic human papillomavirus (HPV) genotypes. Prophylactic HPV vaccines are highly efficacious in preventing the acquisition of HPV infection. HPV vaccine trials and epidemiologic studies based on virologic endpoints rely on valid and reproducible measurements of HPV. We evaluated the second version of TypeSeq (TS2), a next-generation, sequencing-based assay that detects 46 HPV genotypes, in a historical phase 3 clinical trial. We used 1214 stored cervical samples from women enrolled in the Costa Rica HPV Vaccine Trial with available HPV results from Short PCR Fragment 10- Line Probe Assay 25 (SPF10-LiPA25). TS2 was first validated at the National Cancer Institute (NCI) and transferred to the laboratory in Costa Rica, where we conducted a second validation study. We compared TS2 results generated at each laboratory to the SPF10-LiPA25 results. Overall, each laboratory demonstrated high positive agreement for most carcinogenic and noncarcinogenic genotypes between TS2 and SPF10-LiPA25. Intralaboratory comparisons revealed very high agreement in repeated testing. Interlaboratory comparisons showed high agreement for most carcinogenic and noncarcinogenic types. Overall, there were no statistically significant differences in vaccine efficacy in the according-to-protocol cohort using TS2 (either in NCI or Costa Rica) or SPF10-LiPA25 (McNemar P values >.05). Costa Rica produced similar vaccine efficacy estimates as NCI for HPV16/18, HPV31/33/45, and HPV35/39/51/52/56/58/59 as NCI (P values ≥.36). Compared to SPF10-LiPA25, a well-established standard for HPV genotyping, TS2 demonstrated high accuracy. Inter- and intralaboratory comparisons demonstrated that TS2 is valid and reproducible. TS2 can accurately classify the presence of HPV, which is essential in HPV vaccine trials evaluating virological endpoints. NCT00128661.

Antibodies to SARS-CoV-2 are essential for protection or reduction in severity of subsequent disease. We studied antibody responses to spike protein receptor-binding domain (S1-RBD) and nucleocapsid (N) in a population-based sample of COVID-19 cases in Costa Rica. As part of the RESPIRA study, we selected an age-stratified random sample of PCR-confirmed COVID-19 cases diagnosed from March 2020 to July 2021. Antibodies were determined with multiplex serology in 794 unvaccinated subjects diagnosed 3 days to 17 months before recruitment to investigate immune response to natural infection. In addition, neutralizing antibodies were determined in 136 randomly selected participants. We estimated antibody positivity and GMTs by time since diagnosis and explored determinants using multivariate regression. Most participants tested 15–29 days after PCR diagnosis were seropositive for N (90

Global measures and restrictions implemented to control the COVID-19 pandemic had a significant impact and created challenges in regular business, commerce, and scientific activities, including biobank operations. The challenges were exacerbated by a dependence on imported supplies and reagents from countries such as the United States, China, and within Europe, as well as restrictions on exporting biological samples. The pandemic has highlighted the pressing need for regional autonomy in biobanking activities. This article aims to enhance the capacity of biobanks to respond effectively to future crises. Recognizing the importance of adaptability and resilience, our study highlights the specific strategies employed by a large biobank in Costa Rica to ensure the continuity of operations during unprecedented times. During the COVID-19 pandemic, biobanking operations encountered a number of critical challenges, which led to the identification, implementation, and integration of targeted mitigation strategies into our contingency framework. Five challenges were identified and subsequently addressed: disruptions and shortfalls in the supply of essential material, continuity of daily biobank operations, storage capacity constraints coupled with export limitations, difficulties associated with consent procedures, and complications surrounding personnel testing. These lessons underscore the critical importance of contingency planning, digitization of biobanking workflows, and increased regional collaboration to strengthen the autonomy and resilience of biobanks in the face of future crises.

BACKGROUND:In 2022, WHO recommended single-dose human papillomavirus (HPV) vaccination as an alternative schedule to multidose regimens. To provide evidence to support approval of a single-dose indication for the AS04-adjuvanted bivalent HPV vaccine (Cervarix, GlaxoSmithKline), we investigated whether the immune response to a single dose of the bivalent vaccine in girls aged 9-14 years was non-inferior to the immune response to three doses of the quadrivalent HPV vaccine (Gardasil-4, Merck) in women aged 18-25 years, a dose and population combination with demonstrated efficacy. METHODS:This non-randomised, open-label, immunobridging trial enrolled girls aged 9-14 years and women aged 18-25 years in Guanacaste Province, Costa Rica. Healthy girls aged 9-14 years received one dose of bivalent HPV vaccine, whereas healthy women aged 18-25 years received three doses of quadrivalent HPV vaccine at 0, 2, and 6 months. The primary endpoint was geometric mean concentrations (GMCs) of HPV-specific serum antibodies measured by a validated virus-like-particle-based ELISA assay at 36 months. The per-protocol cohort included participants who received the correct number of doses within the predefined vaccination windows, had blood collected at the 36-month study visit for the final analysis, were seronegative at baseline for the specified HPV type, and did not receive additional HPV vaccine doses outside the study. Non-inferiority was declared when the lower bound of the 96% CI for the GMC ratio was greater than or equal to 0·67 for HPV-16 and HPV-18. Seropositivity was a secondary objective. Safety was analysed in the total vaccinated population. This trial is registered with ClinicalTrials.gov, NCT03728881, and is complete. FINDINGS:Between April 1 and Aug 16, 2019, 620 girls and 620 women were enrolled and received their first HPV vaccination. After exclusions, 539 girls and 366 women were HPV-16 seronegative at enrolment and were included in the HPV-16 per-protocol cohort; 523 girls and 373 women were HPV-18 seronegative at enrolment and were included in the HPV-18 per-protocol cohort. At 36 months, the HPV-16 GMC was 21·4 international units (IU)/mL (95% CI 19·7-23·3) in girls in the single-dose bivalent vaccine group and 42·9 IU/mL (95% CI 38·9-47·3) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 0·50 (96% CI 0·44-0·57); the HPV-18 GMC was 8·0 IU/mL (95% CI 7·4-8·8) in girls in the single-dose bivalent vaccine group and 7·2 IU/mL (95% CI 6·4-8·1) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 1·11 (96% CI 0·95-1·29). At 36 months, 538 (99·8%, 95% CI 99·1-100) of 539 girls in the single-dose bivalent vaccine group were seropositive for HPV-16 compared with 366 (100%, 99·2-100) of 366 women in the three-dose quadrivalent vaccine group (p=1·00). The proportion of participants who were seropositive for HPV-18 was higher in the single-dose bivalent vaccine group (517 [98·9%, 95% CI 97·6-99·5] of 523 girls) than in the three-dose quadrivalent vaccine group (358 [96·0%, 93·6-97·6] of 373 women; p=0·0065). Two serious adverse events were reported in 620 girls and 13 serious adverse events were reported in 620 women; all serious adverse events were deemed to be unrelated to HPV vaccination. INTERPRETATION:Non-inferior antibody responses for the single-dose bivalent HPV vaccine were seen for HPV-18 but not HPV-16, which would be insufficient evidence to motivate regulatory change, even though seropositivity approached 100% in the follow-up phase and the observed antibody concentrations were similar to protective levels seen in previous trials. Trials that directly evaluate protection afforded by single-dose HPV vaccination against persistent HPV infection will definitively address the level of protection afforded by single-dose HPV vaccination. FUNDING:National Cancer Institute, Cancer Research UK, and the Gates Foundation. TRANSLATION:For the Spanish translation of the abstract see Supplementary Materials section.

Previous SARS-CoV-2 research indicates that antibody levels and corresponding neutralization potential increase with additional exposures (comprising vaccination or infection), and that hybrid immunity resulting from combined vaccination and natural infection is more robust than either alone. However, it is unclear whether or how antibody levels increase or eventually plateau with repeated exposures and how SARS-CoV-2 exposure differs by sex or other demographic factors. Research regarding the association of antibody production with neutralization potential is also limited. We conducted this analysis within the RESPIRA population-based cohort in Costa Rica to investigate relationships between antibody levels and neutralization potential at increasing exposure levels. We examined immunological profiles from systematically defined single-exposure groups (one vaccine dose or one natural infection), double-exposure groups (two vaccine doses or one vaccine dose following a natural infection), and a triple-exposure group (two vaccine doses following a natural infection). We used a S1-RBD-based serological assay for antibody level detection and a pseudovirion assay for neutralization potential quantification. Using linear regression, we compared antibody levels and pseudoneutralization geometric mean titers between exposure groups. For single exposure groups, one vaccine dose was inferior to natural infection, but a second vaccine dose was superior to natural infection. For double exposure groups, those who were vaccinated once after infection developed higher levels of antibodies and higher neutralization potential compared with those who had only two vaccine doses. We note that peak antibody levels following an exposure may plateau after two exposures while neutralization potential continues to increase with a third exposure dose. Response patterns were comparable in males and females and in sensitivity analyses stratified by age, vaccine type, and pandemic wave. These results provide evidence that SARS-CoV-2 vaccination after COVID infection provides immunological benefit and suggest neutralization potential continues to increase after a second vaccine dose despite plateauing of antibody levels.

Objective. To estimate the prevalence and identify the determinants of human papillomavirus (HPV) infection in young women (18-25 years). Materials and methods. We analyzed data from 5 871 sexually active women who underwent an interview and cervical swab collection for HPV screening and cytology during the enrollment visit of the HPV16/18 Vaccination Trial in Costa Rica. We calculated the total prevalence for any type of HPV, and oncogenic, nononcogenic and specific types, with 95% confidence intervals (95%CI). We used stepwise multiple logistic regression to identify determinants associated with infection. Results. The total prevalence of HPV was 50.0% (95%CI 48.8,51.3) and the prevalence by oncogenic types was 33.8% (95%CI 32.6,35.0).HPV-16 was the most prevalent type (8.3%, 95%CI 7.6,9.0). Determinants associated with a high risk of prevalent oncogenic HPV infection were: not being married/commonlaw marriage, >1 sexual partner, concomitant Chlamydia trachomatis infection, and among those with only one sexual partner in their lifetime, a partner with history of multiple sexual partners. Conclusion. The association of oncogenic HPV infections with the sexual behavior of women is confirmed and the behavior of the sexual partner is highlighted.

Introduction Human papillomavirus (HPV) vaccines protect against incident HPV infections, which cause cervical cancer. Objectives We estimated the prevalence and incidence of HPV infections in young adult women to understand the impact of an HPV vaccination programme in this population. Methods We collected cervical specimens from 6322 unvaccinated women, aged 18–37 years, who participated in the Costa Rica Vaccine Trial and its long-term follow-up. Women were followed for (median) 4.8 years and had (median) 4.0 study visits. Cervical specimens were tested for the presence/absence of 25 HPV genotypes. For each age band, we estimated the percentage of women with 1+ prevalent or 1+ incident HPV infections using generalised estimating equations. We also estimated the prevalence and incidence of HPV as a function of time since first sexual intercourse (FSI). Results The model estimated HPV incident infections peaked at 28.0% (95% CI 25.3% to 30.9%) at age 20 years then steadily declined to 11.8% (95% CI 7.6% to 17.8%) at age 37 years. Incident oncogenic HPV infections (HPV16/18/31/33/35/39/45/51/52/56/58/59) peaked and then declined from 20.3% (95% CI 17.9% to 22.9%) to 7.7% (95% CI 4.4% to 13.1%); HPV16/18 declined from 6.4% (95% CI 5.1% to 8.1%) to 1.1% (95% CI 0.33% to 3.6%) and HPV31/33/45/52/58 declined from 11.0% (95% CI 9.3% to 13.1%) to 4.5% (95% CI 2.2% to 8.9%) over the same ages. The percentage of women with 1+ incident HPV of any, oncogenic, non-oncogenic and vaccine-preventable (HPV16/18, HPV31/33/45, HPV31/33/45/52/58, and HPV6/11) types peaked <1 year after FSI and steadily declined with increasing time since FSI (p for trends <0.001). We observed similar patterns for model estimated HPV prevalences. Conclusion Young adult women may benefit from HPV vaccination if newly acquired vaccine-preventable oncogenic infections lead to cervical precancer and cancer. HPV vaccination targeting this population may provide additional opportunities for primary prevention. Trial registration number NCT00128661.

Purpose The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19.Participants From November 2020, we selected age-stratified random samples of COVID-19 cases from Costa Rica confirmed by PCR. For each case, two population-based controls, matched on age, sex and census tract were recruited, supplemented with hospitalised cases and household contacts. Participants were interviewed and blood and saliva collected for antibodies and PCR tests. Participants will be followed for 2 years to assess antibody response and infection incidence.Findings to date Recruitment included 3860 individuals: 1150 COVID-19 cases, 1999 population controls and 719 household contacts from 304 index cases. The age and regional distribution of cases was as planned, including four age strata, 30% rural and 70% urban. The control cohort had similar sex, age and regional distribution as the cases according to the study design. Among the 1999 controls recruited, 6.8% reported at enrolment having had COVID-19 and an additional 12.5% had antibodies against SARS-CoV-2. Compliance with visits and specimens has been close to 70% during the first 18 months of follow-up. During the study, national vaccination was implemented and nearly 90% of our cohort participants were vaccinated during follow-up.Future plans RESPIRA will enable multiple analyses, including population prevalence of infection, clinical, behavioural, immunological and genetic risk factors for SARS-CoV-2 acquisition and severity, and determinants of household transmission. We are conducting retrospective and prospective assessment of antibody levels, their determinants and their protective efficacy after infection and vaccination, the impact of long-COVID and a series of ancillary studies. Follow-up continues with bimonthly saliva collection for PCR testing and biannual blood collection for immune response analyses. Follow-up will be completed in early 2024.Trial registration number NCT04537338.

Objetivo. Estimar la prevalencia e identificar determinantes de la infección por el virus del papiloma humano (VPH) en mujeres jóvenes (18-25 años). Material y métodos. Se analizaron datos de 5 871 mujeres sexualmente activas a quienes se les realizó una entrevista y toma de muestras cervicouterinas para detección de VPH y citología durante la visita de reclutamiento del Ensayo de Vacunación contra VPH16/18 en Costa Rica. Se calculó la prevalencia total para cualquier tipo de VPH y tipos oncogénicos, no oncogénicos y específicos, con intervalos de confianza al 95% (IC95%). Se utilizó regresión logística múltiple paso-a-paso para identificar determinantes asociados con la infección. Resultados. La prevalencia total de VPH fue 50.0% (IC95% 48.8,51.3) y por tipos oncogénicos fue 33.8% (IC95% 32.6,35.0). El VPH-16 fue el tipo más prevalente (8.3%, IC95% 7.6,9.0). Los determinantes asociados con un alto riesgo de infección prevalente por VPH oncogénicos fueron no estar casada/unión libre, >1 compañero sexual, infección concomitante por Chlamydia trachomatis, y entre aquéllas con un único compañero sexual en su vida, un compañero con antecedente de múltiples compañeras sexuales. Conclusión. Se confirma la asociación de las infecciones por VPH oncogénicos con el comportamiento sexual de la mujer y se destacan los comportamientos del compañero sexual.

The HPV vaccine has shown sustained efficacy and consistent stabilization of antibody levels, even after a single dose. We defined the HPV16-VLP antibody avidity patterns over 11 years among women who received one- or three doses of the bivalent HPV vaccine in the Costa Rica HPV Vaccine Trial. Absolute HPV16 avidity was lower in women who received one compared to three doses, although the patterns were similar (increased in years 2 and 3 and remained stable over the remaining 8 years). HPV16 avidity among women who were HPV16-seropositive women at HPV vaccination, a marker of natural immune response to HPV16 infection, was significantly lower than those of HPV16-seronegative women, a difference that was more pronounced among one-dose recipients. No differences in HPV16 avidity were observed by HPV18 serostatus at vaccination, confirming the specificity of the findings. Importantly, point estimates for vaccine efficacy against incident, six-month persistent HPV16 infections was similar between women who were HPV16 seronegative and seropositive at the time of initial HPV vaccination for both one-dose and three-dose participants. It is therefore likely that this lower avidity level is still sufficient to enable antibody-mediated protection. It is encouraging for long-term HPV-vaccine protection that HPV16 antibody avidity was maintained for over a decade, even after a single dose.

Background: Bile acid (BA) and short chain fatty acid (SCFA) production is affected by diet and microbial metabolism. These metabolites may play important roles in human carcinogenesis. Methods: We used a fully quantitative targeted LC-MS/MS system to measure serum and fecal BA and SCFA concentrations in 136 Costa Rican adults at study baseline and 6-months. We randomly selected 50 participants and measured their baseline samples in duplicate. Our objective was to evaluate: Technical reproducibility; 6-month temporal variability; and concordance between sample type collected from the same individual at approximately the same time. Results: Technical reproducibility was excellent, with intraclass correlation coefficients (ICC) ≥0.83 for all BAs except serum tauroursodeoxycholic acid (ICC = 0.72) and fecal glycolithocholic acid (ICC = 0.66) and ICCs ≥0.81 for all SCFAs except serum 2-methylbutyric acid (ICC = 0.56) and serum isobutyric acid (ICC = 0.64). Temporal variability ICCs were generally low, but several BAs (i.e., deoxycholic, glycoursodeoxycholic, lithocholic, taurocholic, and tauroursodeoxycholic acid) and SCFAs (i.e., 2-methylbutyric, butyric, propionic, and valeric acid) had 6-month ICCs ≥0.44. The highest degree of concordance was observed for secondary and tertiary BAs. Conclusions: Serum and fecal BAs and SCFAs were reproducibly measured. However, 6-month ICCs were generally low, indicating that serial biospecimen collections would increase statistical power in etiologic studies. The low concordance for most serum and fecal metabolites suggests that consideration should be paid to treating these as proxies. Impact: Our findings will inform the design and interpretation of future human studies on associations of BAs, SCFAs, and potentially other microbial metabolites, with disease risk.

HPV vaccination of adolescent girls is the most effective measure to prevent cervical cancer. The World Health Organization recommends that adolescent girls receive two doses of vaccine but only a small proportion of girls from regions with the highest disease burden are vaccinated because of cost and logistical considerations. Our Costa Rica HPV Vaccine trial suggested that one dose of the bivalent HPV vaccine provides robust and lasting protection against persistent HPV infections for over a decade. Data from a post-licensure trial of the quadrivalent vaccine in India also suggested that a single dose may be effective in reducing cervical cancer risk. To formally compare one versus two doses of the bivalent and nonavalent HPV vaccines, we implemented a large, randomized, double-blind trial to investigate the non-inferiority of one compared to two vaccine doses in the prevention of new HPV16/18 infections that persist 6 or more months. Bivalent and nonavalent vaccines will be evaluated separately. The trial enrolled and randomized (1:1:1:1 to 1- and 2-dose arms of the bivalent and nonavalent vaccines) 20,330 girls 12 to 16 years old residing in Costa Rica. Trial participants are followed every 6 months for up to 5 years. We also aim to estimate vaccine efficacy by comparing the rates of 6 month persistent infection in unvaccinated women with the rates in the follow-up visits of trial participants. We included one survey of unvaccinated women at the start of the study (N = 4452) and will include another survey concomitant with follow up visits of trial participants at year 4.5 (planned N = 3000). Survey participants attend two visits 6 months appart. Herein, we present the rationale, design, and enrolled study population of the ESCUDDO trial. ClinicalTrials.gov Identifier: NCT03180034.

BACKGROUND:Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood. We evaluated co-factors for acquisition, persistence, and progression of non-HPV-16/18 infections among HPV-vaccinated women. METHODS:We analyzed 2153 women aged 18-25 years randomized to the HPV-vaccine arm of the Costa Rica HPV Vaccine Trial. Women were HPV DNA negative for all types at baseline and followed for approximately 11 years. Generalized estimating equation methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonally related factors, number of full-term pregnancies (FTPs), smoking behavior, and baseline body mass index. RESULTS:A total of 1777 incident oncogenic non-HPV-16/18 infections were detected in 12 292 visits (average, 0.14 infections/visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV-16/18 acquisition. Twenty-six percent of incident infections persisted for ≥1 year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV-16/18 infections. Risk of progression to Cervical Intraepithelial Neoplasia grade 2 or worst (CIN2+) increased with increasing age (P for trend = .001), injectable contraceptive use (relative risk, 2.61 [95% confidence interval, 1.19-5.73] ever vs never), and increasing FTPs (P for trend = .034). CONCLUSIONS:In a cohort of HPV-16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV-16/18 infections; no notable factors are associated with persistence of acquired infections; and age, parity, and hormonally related exposures are associated with progression to CIN2+.

Background: The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types. Methods: We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time. Results: Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval [CI] = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided P-trend > .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure. Conclusions: Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.

BACKGROUND Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood, especially among vaccinated women. We evaluated co-factors for acquisition, persistence and progression of non-HPV16/18 infections in a cohort of HPV-vaccinated women. METHODS We analyzed 2,153 18-25-year-old women randomized to the HPV-vaccine arm of CVT. Women were HPV-DNA-negative for all types at baseline and followed for ~11 years. Acquisition was a type-specific cervical infection not present/detected at the previously scheduled visit. Persistence was a type-specific incident infection that persisted for ≥1-year with no intervening negatives. Progression of persistent incident infections to CIN2+ was based on histological findings by expert pathologists. GEE methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonal-related factors, number of full-term pregnancies (FTP), smoking behavior, and baseline-BMI. RESULTS 1,777 incident oncogenic non-HPV16/18 infections were detected in 12,292 visits (average 0.14 infections per visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV16/18 acquisition. 26% of incident infections persisted for ≥1-year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV16/18 infections. Risk of progression to CIN2+ increased with increasing age (p-trend=0.001), injectable contraceptives use [relative risk 2.61 (95%CI 1.19-5.73) ever vs. never] and increasing FTP (p-trend=0.034). CONCLUSION In a cohort of HPV16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV16/18 infections, no notable factors are associated with persistence of acquired oncogenic non-HPV16/18 infections, and age, parity and hormonally-related exposures are associated with progression to CIN2+.

Background: The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women. Methods: HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of threedose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n =448). Results: Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9-11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers. Conclusion: More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.

Background In Latin America (LA), there is a high incidence rate of breast cancer (BC) in premenopausal women, and the genomic features of these BC remain unknown. Here, we aim to characterize the molecular features of BC in young LA women within the framework of the PRECAMA study, a multicenter population-based case-control study of BC in premenopausal women. Methods Pathological tumor tissues were collected from incident cases from four LA countries. Immunohistochemistry (IHC) was performed centrally for ER, PR, HER2, Ki67, EGFR, CK5/6, and p53 protein markers. Targeted deep sequencing was done on genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissues and their paired blood samples to screen for somatic mutations in eight genes frequently mutated in BC. A subset of samples was analyzed by exome sequencing to identify somatic mutational signatures. Results The majority of cases were positive for ER or PR (168/233; 72%), and 21% were triple-negative (TN), mainly of basal type. Most tumors were positive for Ki67 (189/233; 81%). In 126 sequenced cases, TP53 and PIK3CA were the most frequently mutated genes (32.5% and 21.4%, respectively), followed by AKT1 (9.5%). TP53 mutations were more frequent in HER2-enriched and TN IHC subtypes, whereas PIK3CA/AKT1 mutations were more frequent in ER-positive tumors, as expected. Interestingly, a higher proportion of G:C>T:A mutations was observed in TP53 in PRECAMA cases compared with TCGA and METAB-RIC BC series (27% vs 14%). Exome-wide mutational patterns in 10 TN cases revealed alterations in signal transduction pathways and major contributions of mutational signatures caused by altered DNA repair pathways. Conclusions These pilot results on PRECAMA tumors give a preview of the molecular features of premenopausal BC in LA. Although the overall mutation burden was as expected from data in other populations, mutational patterns observed in TP53 and exome-wide suggested possible differences in mutagenic processes giving rise to these tumors compared with other populations. Further-omics analyses of a larger number of cases in the near future will enable the investigation of relationships between these molecular features and risk factors.

BACKGROUND:Human papillomaviruses (HPV) cause over 500 000 cervical cancers each year, most of which occur in low-resource settings. Human papillomavirus genotyping is important to study natural history and vaccine efficacy. We evaluated TypeSeq, a novel, next-generation, sequencing-based assay that detects 51 HPV genotypes, in 2 large international epidemiologic studies.METHODS:TypeSeq was evaluated in 2804 cervical specimens from the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED) and in 2357 specimens from the Costa Rica Vaccine Trial (CVT). Positive agreement and risks of precancer for individual genotypes were calculated for TypeSeq in comparison to Linear Array (SUCCEED). In CVT, positive agreement and vaccine efficacy were calculated for TypeSeq and SPF10-LiPA.RESULTS:We observed high overall and positive agreement for most genotypes between TypeSeq and Linear Array in SUCCEED and SPF10-LiPA in CVT. There was no significant difference in risk of precancer between TypeSeq and Linear Array in SUCCEED or in estimates of vaccine efficacy between TypeSeq and SPF10-LiPA in CVT.CONCLUSIONS:The agreement of TypeSeq with Linear Array and SPF10-LiPA, 2 well established standards for HPV genotyping, demonstrates its high accuracy. TypeSeq provides high-throughput, affordable HPV genotyping for world-wide studies of cervical precancer risk and of HPV vaccine efficacy.

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose.