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Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: The Costa Rica ESCUDDO trial.

ABSTRACT: 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.

SUBMITTER: Porras C

PROVIDER: S-EPMC8759448 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: The Costa Rica ESCUDDO trial.

Porras Carolina C Sampson Joshua N JN Herrero Rolando R Gail Mitchell H MH Cortés Bernal B Hildesheim Allan A Cyr Jean J Romero Byron B Schiller John T JT Montero Christian C Pinto Ligia A LA Schussler John J Coronado Karla K Sierra Mónica S MS Kim Jane J JJ Torres Catherine M CM Carvajal Loretto L Wagner Sarah S Campos Nicole G NG Ocampo Rebecca R Kemp Troy J TJ Zuniga Michael M Lowy Douglas R DR Avila Carlos C Chanock Stephen S Castrillo Ariane A Estrada Yenory Y Barrientos Gloriana G Monge Cindy C Oconitrillo María Y MY Kreimer Aimée R AR

Vaccine 20211129 1

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 d ...[more]

PMID: 34857420

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Project description:ObjectiveTo examine the effect of the bivalent human papillomavirus (HPV) vaccine on miscarriage.DesignObservational long term follow-up of a randomized, double blinded trial combined with an independent unvaccinated population based cohort.SettingSingle center study in Costa Rica.Participants7466 women in the trial and 2836 women in the unvaccinated cohort enrolled at the end of the randomized trial and in parallel with the observational trial component.InterventionWomen in the trial were assigned to receive three doses of bivalent HPV vaccine (n=3727) or the control hepatitis A vaccine (n=3739). Crossover bivalent HPV vaccination occurred in the hepatitis A vaccine arm at the end of the trial. Women in the unvaccinated cohort received (n=2836) no vaccination.Main outcome measureRisk of miscarriage, defined by the US Centers for Disease Control and Prevention as fetal loss within 20 weeks of gestation, in pregnancies exposed to bivalent HPV vaccination in less than 90 days and any time from vaccination compared with pregnancies exposed to hepatitis A vaccine and pregnancies in the unvaccinated cohort.ResultsOf 3394 pregnancies conceived at any time since bivalent HPV vaccination, 381 pregnancies were conceived less than 90 days from vaccination. Unexposed pregnancies comprised 2507 pregnancies conceived after hepatitis A vaccination and 720 conceived in the unvaccinated cohort. Miscarriages occurred in 451 (13.3%) of all exposed pregnancies, in 50 (13.1%) of the pregnancies conceived less than 90 days from bivalent HPV vaccination, and in 414 (12.8%) of the unexposed pregnancies, of which 316 (12.6%) were in the hepatitis A vaccine group and 98 (13.6%) in the unvaccinated cohort. The relative risk of miscarriage for pregnancies conceived less than 90 days from vaccination compared with all unexposed pregnancies was 1.02 (95% confidence interval 0.78 to 1.34, one sided P=0.436) in unadjusted analyses. Results were similar after adjusting for age at vaccination (relative risk 1.15, one sided P=0.17), age at conception (1.03, P=0.422), and calendar year (1.06, P=0.358), and in stratified analyses. Among pregnancies conceived at any time from bivalent HPV vaccination, exposure was not associated with an increased risk of miscarriage overall or in subgroups, except for miscarriages at weeks 13-20 of gestation (relative risk 1.35, 95% confidence interval 1.02 to 1.77, one sided P=0.017).ConclusionsThere is no evidence that bivalent HPV vaccination affects the risk of miscarriage for pregnancies conceived less than 90 days from vaccination. The increased risk estimate for miscarriages in a subgroup of pregnancies conceived any time after vaccination may be an artifact of a thorough set of sensitivity analyses, but since a genuine association cannot totally be ruled out, this signal should nevertheless be explored further in existing and future studies.Trial registration Clinicaltrials.gov NCT00128661 and NCT01086709.

Project description:BackgroundThere is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received.MethodsSummary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase.FindingsWe assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group.Interpretation4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine.FundingUS National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA).

Project description:BackgroundNew approaches to control HPV infections and prevent progression to cervical precancer are needed. We investigate the probability of viral clearance and progression to cervical precancer in women infected with HPV16/18 without evidence of precancer at study enrollment to inform research efforts targeted at reducing cervical cancer.MethodsWe included 530 women aged 18-25 who tested HPV16/18 DNA-positive and did not have cytological evidence of high-grade-squamous-intraepithelial-lesion (HSIL) at enrollment in CVT. At each visit, clinicians collected cervical cells for cytology and HPV-DNA testing. Those with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. We estimated the probability of HPV clearance (loss of detection) and progression to intraepithelial neoplasia grades 2 or 3 or worse (CIN2+, CIN3+) based on histological findings by expert pathologists over 4-years of follow-up.ResultsAt enrollment, there were 550 prevalently detected HPV16 and/or HPV18 infections among 530 women without cytologic HSIL. Corresponding probabilities of HPV16 and HPV18 clearance were 68.5 % (95 %CI 63.6 %-73.0 %) and 85.0 % (78.6 %-90.1 %) by 24-months and 82.1 % (78.0 %-85.7 %) and 90.2 % (84.7 %-94.2 %) by 48-months after initial detection. Risk of clearance of prevalently detected HPV16 and HPV18 infections decreased with increasing age by 12-, 24-, 36-, and 48-months after initial detection (ptrend-values≥0.31). Among the same 530 women, by 24-months and 48-months of follow-up, the corresponding probabilities of progression to CIN2+ were 5.5 % (3.8 %-7.7 %) and 13.0 % (10.4 %-16.1 %), and to CIN3+ were 2.6 % (1.5 %-4.3 %) 7.5 % (5.5 %-10.0 %). Probability of progression was 2-5 times higher in women with HPV16 infections than with HPV18. Risk of progression to CIN2+ and CIN3+ increased with increasing age during the follow-up period (ptrend-values≥0.11).ConclusionsAmong young adult women without evidence of HSIL by cytology, clearance of prevalently detected HPV16/18 infection is a common event, and progression to precancer occurs infrequently but in a sizeable proportion of those with prevalent infection.

Dataset Information

Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: The Costa Rica ESCUDDO trial.

Publications

Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: The Costa Rica ESCUDDO trial.

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