Surrogates of protection in repeated low-dose challenge experiments

Stat Med. 2015 May 10;34(10):1747-60. doi: 10.1002/sim.6436. Epub 2015 Jan 28.


A critical step toward developing a successful vaccine to control the human immunodeficiency virus pandemic entails evaluation of vaccine candidates in non-human primates (NHPs). Historically, these studies have usually entailed challenges (i.e., exposures) with very high doses of a simian version of human immunodeficiency virus, resulting in infection of all NHPs in the experiment after a single challenge. More recently, researchers have begun to conduct repeated low-dose challenge (RLC) studies in NHPs that are believed to more closely mimic typical exposure in natural human transmission settings. One objective of RLC studies is to assess whether measured immune responses to vaccination can serve as surrogate endpoints for the primary endpoint of interest, namely infection. In this paper, different designs of RLC studies for assessing a binary surrogate of protection are considered.

Keywords: HIV; causal inference; immunogenicity; infectious diseases; transmission probability; vaccine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • AIDS Vaccines / administration & dosage*
  • AIDS Vaccines / immunology
  • Animals
  • Binomial Distribution
  • Computer Simulation
  • Cross-Over Studies
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • HIV Infections / immunology*
  • HIV Infections / prevention & control
  • Humans
  • Likelihood Functions
  • Primates / immunology*
  • Primates / virology
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Acquired Immunodeficiency Syndrome / prevention & control
  • Simian Immunodeficiency Virus / immunology*
  • Simian Immunodeficiency Virus / pathogenicity


  • AIDS Vaccines