Vaccine adjuvants: mechanisms and platforms

Abstract

Adjuvants are indispensable components of vaccines. Despite being widely used in vaccines, their action mechanisms are not yet clear. With a greater understanding of the mechanisms by which the innate immune response controls the antigen-specific response, the adjuvants' action mechanisms are beginning to be elucidated. Adjuvants can be categorized as immunostimulants and delivery systems. Immunostimulants are danger signal molecules that lead to the maturation and activation of antigen-presenting cells (APCs) by targeting Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) to promote the production of antigen signals and co-stimulatory signals, which in turn enhance the adaptive immune responses. On the other hand, delivery systems are carrier materials that facilitate antigen presentation by prolonging the bioavailability of the loaded antigens, as well as targeting antigens to lymph nodes or APCs. The adjuvants' action mechanisms are systematically summarized at the beginning of this review. This is followed by an introduction of the mechanisms, properties, and progress of classical vaccine adjuvants. Furthermore, since some of the adjuvants under investigation exhibit greater immune activation potency than classical adjuvants, which could compensate for the deficiencies of classical adjuvants, a summary of the adjuvant platforms under investigation is subsequently presented. Notably, we highlight the different action mechanisms and immunological properties of these adjuvant platforms, which will provide a wide range of options for the rational design of different vaccines. On this basis, this review points out the development prospects of vaccine adjuvants and the problems that should be paid attention to in the future.

Fig. 1

Adjuvants enhance the immunogenicity of vaccines. a Vaccines without adjuvants induce modest production of T helper-polarizing cytokines, antibodies, and activated T cells. b In contrast, vaccines with adjuvants promote the maturation of more APCs, increase the interaction between APCs and T cells, promote the production of greater numbers and more types of T helper-polarizing cytokines, multifunctional T cells, and antibodies, leading to broad and durable immunity, as well as dose and antigen savings. This figure was created with BioRender (https://biorender.com/)

Fig. 2

Timeline of major events in the research history of vaccine adjuvants. This figure was created with BioRender (https://biorender.com/)

Fig. 3

The core of the action mechanisms of adjuvants. Adjuvants are classified as immunostimulants and delivery systems. Immunostimulants such as PAMPs, DAMPs, and chemically synthesized small molecule agonists, provide danger signals (signal 0) to activate PRRs on APCs, thereby enhancing antigen presentation on MHC molecules (signal 1). In addition, activation of PRRs leads to upregulation of cytokines and co-stimulatory molecules expression, which results in enhanced co-stimulatory signaling (signal 2). Delivery systems such as LNPs, PLGA, and self-loaded protein nanoparticles, act by facilitating the presentation of antigens on MHC molecules (signal 1). This figure was created with BioRender (https://biorender.com/)

Fig. 4

The simplified diagram of immunostimulants regulating adaptive immune responses by activating PRRs. Different types of immunostimulants send signals through different PRRs, leading to different cytokines secretion, thereby inducing different adaptive immune responses. Immunostimulants induce and modulate adaptive immune responses by targeting and activating a TLRs; b cGAS-STING; c CLRs; d Other PRRs. This figure was created with BioRender (https://biorender.com/)

Fig. 5

The diagram of the action mechanisms of the delivery systems. Delivery systems promote enhanced antigen presentation or antigen cross-presentation to enhance adaptive immune responses by a prolonging the bioavailability of antigens; b targeting antigens to APCs; c trafficking antigens directly to lymph nodes; and d promoting endosomal escape. This figure was created with BioRender (https://biorender.com/)

Fig. 6

Simplified diagram of the major signaling pathways of classical adjuvants. This figure was created with BioRender (https://biorender.com/)