Primary End-points for Prophylactic HPV Vaccine Trials

Excerpt

The potential of the current licensed preventive virus-like particle (VLP) human papillomavirus (HPV) vaccines to have a major public health impact is leading to additional clinical trials. The goals of such trials may include reducing the number of doses of a current vaccine, evaluating a vaccine similar to a licensed vaccine, increasing the valency of a licensed vaccine by including VLPs for additional HPV types, or evaluating alternative prophylactic vaccines that also use a viral capsid protein or polypeptide to induce neutralizing antibodies.

The Working Group at the IARC/United States National Cancer Institute (NCI) Expert Meeting of September 2013 primarily reviewed the evidence as to whether it might be appropriate to use a virological end-point, rather than a disease end-point such as cervical intraepithelial neoplasia of grade 2 or worse (CIN2+), as the primary end-point for some future clinical efficacy trials, and the circumstances under which immunobridging trials might be sufficient for licensure. Virological end-points could accelerate vaccine evaluation and licensure. Several factors make virological end-points attractive when they represent valid surrogates for clinical premalignant disease end-points. They are more reproducible as end-points than disease end-points, they are the most definitive end-points when there is co-infection by more than one HPV type, and there are substantially more cases of infection by a given HPV type than cases of such disease. In the clinical trials that have been completed, efficacy against persistent infection has been found to be as stringent an outcome as CIN2+. Immunobridging trials have been used to extend the use of currently licensed vaccines to adolescents, an age group not evaluated in the efficacy trials. In these trials, the induction of non-inferior serum antibody titres after the same vaccine dosage schedule as in the efficacy trials has been used as the measure.

Based on a review of the scientific evidence, for most situations, such as infection of the cervix or anus of young adults (e.g. individuals aged 16–26 years), the Working Group recommended that persistent HPV infection of 6 months or longer be used as an appropriate end-point when protection is being evaluated, with reduction in disease being verified by post-licensure monitoring. If vulvar/vaginal protection is to be evaluated in a trial, it is recommended to use HPV 16/18-positive high-grade vulvar intraepithelial neoplasia/vaginal intraepithelial neoplasia (VIN/VAIN) as a disease end-point, as there is relatively little experience in using persistent HPV infection as a surrogate end-point for vulvar and vaginal disease. A persistent infection end-point could be considered at these two sites if subsequent studies validated the ability to detect persistent infection at these sites. A persistent HPV 16/18 infection end-point is recommended for evaluating oral/oropharyngeal infection because an oral/oropharyngeal disease end-point comparable to those associated with anogenital infection is not feasible with current technology. After a vaccine has been shown to be effective in one population group (e.g. individuals aged 16–26 years), immunobridging is sufficient for extending licensure to other population groups (e.g. individuals aged < 16 years). The Working Group recommended that immunological non-inferiority is an appropriate end-point in such situations, independent of the number of vaccine doses used to demonstrate such non-inferiority, with reduction in disease being verified by post-licensure monitoring. The need for standardization of virological and immunological assays was emphasized.