Abstract
The mechanism by which vaccine adjuvants enhance immune responses has historically been considered to be the creation of an antigen depot. From here, the antigen is slowly released and provided to immune cells over an extended period of time. This “depot” was formed by associating the antigen with substances able to persist at the injection site, such as aluminum salts or emulsions. The identification of Pathogen-Associated Molecular Patterns (PAMPs) has greatly advanced our understanding of how adjuvants work beyond the simple concept of extended antigen release and has accelerated the development of novel adjuvants. This review focuses on the mode of action of different adjuvant classes in regards to the stimulation of specific immune cell subsets, the biasing of immune responses towards cellular or humoral immune response, the ability to mediate epitope spreading and the induction of persistent immunological memory. A better understanding of how particular adjuvants mediate their biological effects will eventually allow them to be selected for specific vaccines in a targeted and rational manner.
Highlights
The mechanism by which vaccine adjuvants enhance immune responses has historically been considered to be the creation of an antigen depot
An example is the attempt since the 1960s to use malaria parasites as vaccine by immunizing with sporozoites attenuated through irradiation [3], or the repeated in vivo attenuation of the infectious malaria parasite through drug treatment following infection which is designed to convert the pathogen into a vaccine inside the host rather than in vitro
The development of mucosal vaccines faces several technical challenges: (1) The effects and the efficacy of adjuvants depends on the target site and many adjuvants that are suitable for needle/syringe based delivery to e.g., muscle or skin are not suited for mucosal delivery to sites with significantly different immune cells expressing a different array of PRRs; (2) intranasally delivered formulations have to be tested in animals which have a nasal architecture similar to that of humans such as rabbits [176], making these studies more expensive
Summary
Vaccines have gone through a dramatic evolution over the last century and a large number of routinely used vaccines are relatively “old” (i.e., are based on traditional approaches to vaccination), many new approaches and technologies are in the pipeline (reviewed in [1]). “immune potentiators” such as Pathogen Associated Molecular Patterns (PAMPs)—or their synthetic derivatives or the increasing number of small-molecule agonists which mimic their activity—and particulate antigen-delivery systems are capable of initiating and/or enhancing immune responses. By definition, both are classified as adjuvants. These early adjuvants, did trigger inflammation, which subsequently enhanced vaccine-specific lymphocyte responses Adjuvanticity in this scenario is through a bystander effect with a significant amount of “wasted inflammation” (Quote from N.M. Valiante (Novartis Vaccines)), defined as excessive innate immune responses, which result in reactogenicity but only partially contribute to the adaptive immune response. This subset of T cells is able to eliminate cells infected by viruses and other intracellular pathogens, which—once inside cells—are not accessible to antibodies
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