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

ABSTRACT

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
• non-specific effects
• child mortality
• child morbidity
• randomized controlled trials
• observational studies
• evaluation
• triangulation
• vaccine policy

Box 1. Examples of relevant study designs for testing NSEs, and hints that vaccines have NSEs.

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Acknowledgment

George Davey Smith is thanked for constructive comments which greatly improved the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The manuscript was funded by the Danish National Research Foundation [DNRF108].