Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica

Abstract

The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.

Trial registration: ClinicalTrials.gov NCT00128661.

Keywords: Human papillomavirus; Long term follow-up; Methods; Vaccines.

Conflict of interest statement

Conflict of Interest and Role of the Funding Source.

The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the NCI. The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women’s Health. GlaxoSmithKline Biologicals (GSK) provided vaccine and support for aspects of the trial associated with regulatory submission needs of the company under a Clinical Trials Agreement (FDA BB-IND 7920) during the four-year, randomized blinded phase of our study. The NCI and Costa Rica investigators are responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. On efficacy-related manuscripts, GSK has the right to review and comment. Registered with Clinicaltrials.gov NCT00128661

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. CONSORT diagram indicating participation in the Costa Rica Vaccine Trial Long-term follow up study

* 65 women from CVT control-arm receive the HPV vaccine at crossover before LTFU baseline visit ** 57 women from CVT and 3 from UCG did not have enrollment cervical sample or HPV result available CVT: Costa Rica Vaccine Trial LTFU: Long Term Follow Up study UCG: Unvaccinated Control Group IC: Informed Consent

Figure 2

Overlay of the distribution of future predicted risk of HPV infection (in year two) by deciles of the population in the original control-arm and the new unvaccinated control group, based on reported risk factors at enrolment into the long-term follow-up study.