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

Silvia Sánchez-Ramón, Laura Conejero, Mihai G Netea, David Sancho, Óscar Palomares, José Luis Subiza, Silvia Sánchez-Ramón, Laura Conejero, Mihai G Netea, David Sancho, Óscar Palomares, José Luis Subiza

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.

Keywords: PRR-ligands; adjuvants; immunostimulants; innate immunity; pattern recognition receptors (PRRs); trained immunity; trained immunity-based vaccines (TIbV); vaccines.

Figures

Figure 1
Figure 1
Trained immunity-based vaccine components. TIbV consist of two essential components: (a) Trained immunity (TI) inducers: a range of PAMPs that target a variety of PRRs triggering different signaling pathways that mediate trained immunity. (b) TIbV-related Ags: the antigens associated with the pathogens acting as TI-inducers to which an adaptive immunity is aimed. Thus, TIbV are characterized by conferring Ag-nonspecific resistance directly dependent on trained immunity stimulation plus an Ag-specific resistance dependent on adaptive immunity against the TIbV components and eventual bystander pathogens. PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; Ag, antigen.
Figure 2
Figure 2
Trained immunity-based vaccine mechanisms of action (A) and clinical outcome (B). (A) TIbV act on the cells of the innate immune system, such as macrophages/monocytes and DCs inducing trained immunity which in turn will lead to nonspecific resistance and pathogen clearance. In addition, trained DCs enhance T cell responses and T helper differentiation (e.g., Th1 and Th17) against TIbV-related and unrelated (bystander pathogens) antigens. (B) In the context of recurrent respiratory or urinary tract infections, TIbV have the potential to induce a protective period of time providing the host resistance against TIbV-related and bystander pathogens during this frame time, reducing the infection rate. DC, dendritic cells; Mo, monocyte; PRR, pattern recognition receptor; Th, T helper cell; Th0, naïve T cells; TIbV, trained immunity-based vaccine. MV130, polybacterial vaccine containing whole cell heat-inactivated bacteria that produce frequent infections in the respiratory tract. MV140, polybacterial vaccine containing whole cell heat-inactivated bacteria that produce frequent infections in the urinary tract.
Figure 3
Figure 3
Trained Immunity-based Immunostimulants (A) and Adjuvants (B). (A) Immunostimulants: trained immunity (TI) inducers that enhance both nonspecific and adaptive immune responses to eventual bystander pathogens. (B) Adjuvants: trained immunity (TI) inducers that are combined with an antigen. This latter can be co-delivered with the TI-inducers in the same vaccine (AgX), or later on (AgY) in a two-step process, once trained immunity has been achieved.

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Source: PubMed

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