Innate immunity is the first line of defense against pathogens, which, consequently has critical roles in shaping further specific adaptive immune responses. To induce host resistance against a given pathogen, the immune system must activate mechanisms that aim to overcome potential escape mechanisms induced by the pathogen. Evolution has enabled cells of the innate immune system to develop multiple pattern recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs). Innate immune cell activation through distinct PRRs leads to the induction of responses that are adapted to the features of the invading pathogen. The type of innate immune response executed downstream of PRRs has important implications for not only initial host resistance but also for the induction of long-lasting adaptive immunity.

In recent years it has been demonstrated that the functionalities of innate immune cells activated by different PRRs can be modified in an epigenetic-dependent manner, including changes in histone H3 methylation. These stable epigenetic modifications, thought to be driven by rewiring of intracellular metabolic pathways, enable innate immune cells to maintain a primed functional state over several months in what has been termed as “trained immunity”. Trained immunity is, therefore, a type of memory within innate immune cells that maintain these cells in a superior functional state over extended periods of time. This activation could result in an obvious advantage for these cells to act against different pathogens in a non-specific manner, as well as to drive specific T-cell activation depending on the priming signals.

Conventional vaccines are intended to be selective for the antigens they contain and are aimed at inducing specific T- and B-cell responses. The concept of trained immunity challenges this view of vaccinology, as vaccines containing PRR ligands that target the innate immune system may be used also for preventive purposes against a broad range of pathogens. This implies that under the trained immunity vaccination umbrella, more effective immune responses may be achieved together with broader responses against pathogens including bystander pathogens. This vaccination approach could be particularly relevant for pathogens that cause recurrent infections to which conventional vaccines are not yet available. In this regard, Trained Immunity-based Vaccines (TIbVs) includes preparations that fulfill two main features: (a) they act on the innate immune system through generic pathogen features such as PRRs, thus triggering trained immunity; (b) they act on the adaptive immune system inducing protective antigen-specific T-cell responses (e.g., Th1/Th17) against vaccine-targeted and bystander pathogens.

This Research Topic aims to gather a series of original research articles, clinical trials, mini-reviews, reviews and perspectives covering, but not limited to, the following topics:

1. Tools and methodologies for identifying antigens that can be used for TIbVs.
2. Vaccines showing protection against a broad pathogen spectrum, beyond their nominal antigenic profile, putatively based on trained immunity.
3. Strategies for immunostimulating prophylactic vaccines.
4. Biological mechanisms of how TIbVs provide non-specific protection while inducing specific responses to vaccine-specific and bystander antigens/pathogens.

Dr. Jose Luis Subiza is the founder and CEO of Inmunotek SL. The other Topic Editors declare no competing interests with regard to the Research Topic subject.

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Frontiers in Immunology

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