title: Evaluating a surrogate endpoint at three levels, with application to vaccine development.
abstract: Identification of an immune response to vaccination that reliably predicts protection from clinically significant infection, i.e. an immunological surrogate endpoint, is a primary goal of vaccine research. Using this problem of evaluating an immunological surrogate as an illustration, we describe a hierarchy of three criteria for a valid surrogate endpoint and statistical analysis frameworks for evaluating them. Based on a placebo-controlled vaccine efficacy trial, the first level entails assessing the correlation of an immune response with a study endpoint in the study groups, and the second level entails evaluating an immune response as a surrogate for the study endpoint that can be used for predicting vaccine efficacy for a setting similar to that of the vaccine trial. We show that baseline covariates, innovative study design, and a potential outcomes formulation can be helpful for this assessment. The third level entails validation of a surrogate endpoint via meta-analysis, where the goal is to evaluate how well the immune response can be used to predict vaccine efficacy for new settings (building bridges). A simulated vaccine trial and two example vaccine trials are presented, one supporting that certain anti-influenza antibody levels are an excellent surrogate for influenza illness and another supporting that certain anti-HIV antibody levels are not useful as a surrogate for HIV infection.
authors.affiliation: Fred Hutchinson Cancer Research Center and Department of Biostatistics, University of Washington, Seattle, WA 98109, USA. pgilbert@scharp.org
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Steven G
authors.initials: SG
authors.lastname: Self
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology / Q000494:pharmacology; D000465:Algorithms; D015415:Biomarkers; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D006801:Humans; D016233:Immunotherapy, Active / Q000706:statistics & numerical data*; D007252:Influenza Vaccines / Q000276:immunology / Q000494:pharmacology; D015201:Meta-Analysis as Topic; D012107:Research Design / Q000706:statistics & numerical data; D016896:Treatment Outcome
chemical_list: D016915:AIDS Vaccines; D015415:Biomarkers; D007252:Influenza Vaccines