Evaluating a surrogate endpoint at three levels, with application to vaccine development

Stat Med. 2008 Oct 15;27(23):4758-78. doi: 10.1002/sim.3122.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Vaccines / immunology
  • AIDS Vaccines / pharmacology
  • Algorithms
  • Biomarkers*
  • Clinical Trials as Topic / statistics & numerical data*
  • Humans
  • Immunotherapy, Active / statistics & numerical data*
  • Influenza Vaccines / immunology
  • Influenza Vaccines / pharmacology
  • Meta-Analysis as Topic
  • Research Design / statistics & numerical data
  • Treatment Outcome

Substances

  • AIDS Vaccines
  • Biomarkers
  • Influenza Vaccines