**4.1 Available vaccines with heterologous protection against viral infections**

During the last decades, robust epidemiological data has demonstrated the role of certain vaccines leading to protection against heterologous infection with a high impact on overall mortality in children [111–113]. This protection could not only be explained by protection achieved by the target disease. Studies on MMR vaccination in high-income settings have also evidenced a reduction in non-target infections, particularly in respiratory infections [114]. A limitation for most of these epidemiological studies is that they do not identify the agent (viral, bacterium or parasite) responsible for the infection. These heterologous effects of certain vaccines conferring non-specific protection for a quite long time are believed to be largely due to non-specific stimulation of the innate immune system. It is not yet clear whether this is a direct reflection of trained immunity induction (*i.e.,* acting as TIbVs) in every case. The fact that most of these vaccines use live-attenuated microorganisms, *i.e.,* self-replicating agents, may suggest that a continuous stimulation of innate immune cells is necessary to obtain protection and/or to achieve a proper trained immunity for this purpose.
