Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations

Abstract

Challenge with specific microbial stimuli induces long lasting epigenetic changes in innate immune cells that result in their enhanced response to a second challenge by the same or unrelated microbial insult, a process referred to as trained immunity. This opens a new avenue in vaccinology to develop Trained Immunity-based Vaccines (TIbV), defined as vaccine formulations that induce training in innate immune cells. Unlike conventional vaccines, which are aimed to elicit only specific responses to vaccine-related antigens, TIbV aim to stimulate broader responses. As trained immunity is generally triggered by pattern recognition receptors (PRRs), TIbV should be formulated with microbial structures containing suitable PRR-ligands. The TIbV concept we describe here may be used for the development of vaccines focused to promote host resistance against a wide spectrum of pathogens. Under the umbrella of trained immunity, a broad protection can be achieved by: (i) increasing the nonspecific effector response of innate immune cells (e.g., monocyte/macrophages) to pathogens, (ii) harnessing the activation state of dendritic cells to enhance adaptive T cell responses to both specific and nonrelated (bystander) antigens. This capacity of TIbV to promote responses beyond their nominal antigens may be particularly useful when conventional vaccines are not available or when multiple coinfections and/or recurrent infections arise in susceptible individuals. As the set of PRR-ligands chosen is essential not only for stimulating trained immunity but also to drive adaptive immunity, the precise design of TIbV will improve with the knowledge on the functional relationship among the different PRRs. While the TIbV concept is emerging, a number of the current anti-infectious vaccines, immunostimulants, and even vaccine adjuvants may already fall in the TIbV category. This may apply to increase immunogenicity of novel vaccine design approaches based on small molecules, like those achieved by reverse vaccinology.

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

“…28 This might be also relevance for those vaccines based on triggering trained immunity, in which the Akt/mTOR activation is essential. 29,30 This is a paradigmatic study revealing the importance of the better understanding of the molecular mechanisms driving alum adjuvanticity in the context of allergy, especially in humans, to continue improving allergen vaccine formulations for AIT. Allergoid-mannan conjugates represent a major development in the search of novel vaccine approaches to improve AIT, 6,[9][10][11] and Alum was introduced as a vaccine adjuvant in 1926 by Glenny et al, 31 and since 1937, it is used in AIT.…”

Immunology of COVID‐19: Mechanisms, clinical outcome, diagnostics, and perspectives—A report of the European Academy of Allergy and Clinical Immunology (EAACI)

“…104,105 As a consequence, trained immunity-based vaccines (TIbV) able to induce potent responses against both specific and nonspecific antigens contained in the formulation has emerged as a novel concept in vaccinology. 105 TIbV might be especially relevant when conventional vaccines are not available, as it is the case for SARS-CoV-2. One of the best examples about trained immunity is the influence of BCG vaccination on unrelated pathogens.…”

Innate immune memory of tissue-resident macrophages and trained innate immunity: Re-vamping vaccine concept and strategies

“…Inducing both TII and adaptive immunity with a given vaccine strategy is expected to offer the best possible immune protection against the intended target pathogen while TII extends protection to a broad range of unrelated pathogens 84,85 . In this regard, keeping the current human vaccines and introducing new vaccines in human immunization programs with the known capability to induce TII will be of particular relevance to control pathogens of great health impact for which there has been a lack of effective human vaccines.…”