How to evaluate potential non-specific effects of vaccines: the quest for randomized trials or time for triangulation?

Expert Rev Vaccines. 2018 May;17(5):411-420. doi: 10.1080/14760584.2018.1471987. Epub 2018 May 10.


Introduction: Emerging evidence suggests that vaccines, in addition to their disease-specific effects, have important non-specific effects (NSEs), which contribute to their overall effect on mortality and morbidity. Immunological studies have shown that NSEs are biologically plausible. Many advocate that randomized controlled trials (RCTs) with overall mortality or morbidity as the outcome are the only way forward to confirm or refute NSEs.

Areas covered: We discuss the limitations of using RCTs only as a tool to evaluate NSEs of vaccines. Such RCTs can be ethically problematic, they are time consuming and expensive. Furthermore, they only assess the NSEs in a given context, but it is inherent in the concept of NSEs that the NSEs of a given vaccine are modified by other immunomodulatory conditions. As an alternative, we propose that triangulation of RCTs and observational studies, merging multiple lines of evidence with different underlying bias structures, can build a strong argument for causality. We examine two examples related to measles vaccine and oral polio vaccine.

Expert commentary: Using RCTs alone to evaluate NSEs of vaccines severely limits the possibilities for studying NSEs. Results from both RCTs and non-RCT studies should be triangulated to strengthen causal interpretation.

Keywords: Vaccines; child morbidity; child mortality; evaluation; non-specific effects; observational studies; randomized controlled trials; triangulation; vaccine policy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bias
  • Humans
  • Immunity, Heterologous / immunology*
  • Measles Vaccine / administration & dosage
  • Measles Vaccine / immunology
  • Poliovirus Vaccine, Oral / administration & dosage
  • Poliovirus Vaccine, Oral / immunology
  • Randomized Controlled Trials as Topic / methods
  • Research Design
  • Vaccination / methods*
  • Vaccines / administration & dosage*
  • Vaccines / immunology


  • Measles Vaccine
  • Poliovirus Vaccine, Oral
  • Vaccines