Recent articles claim that randomized clinical trials (RCTs) have not documented non-specific effects of vaccines (NSE), i.e. broader immunomodulatory effects of vaccines. We reviewed the role of RCTs in the discovery of NSEs. The articles claiming no NSEs misread the literature, disregarded non-RCT data, and did not take interactions with other interventions into consideration. RCTs have played a limited role in the discovery of the NSEs of vaccines. Instead, contradictions in non-RCT data have helped to document NSEs; most important have been abrupt mortality changes, sex-differential effects, differential effects by sequence of vaccinations, maternal priming effects, beneficial boosting, negative boosting, mortality effects after disease eradication/elimination, and interacting interventions changing the mortality ratio (MR) in RCTs. Vaccine efficacy studies assume that true protective effects are independent of context; in contrast, the immunological mechanisms underlying NSEs are context-dependent as other vaccines, micronutrients and immune history may affect the capacity of the immune system to protect against unrelated infections. Thus, NSEs do exist. The way forward will be to intensify studies of the contextual factors affecting the NSEs to optimize their usefulness for vaccine programmes.
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