Toward precision adjuvants: optimizing science and safety

Abstract

Purpose of review: The gradual replacement of inactivated whole cell and live attenuated vaccines with subunit vaccines has generally reduced reactogenicity but in many cases also immunogenicity. Although only used when necessary, adjuvants can be key to vaccine dose/antigen-sparing, broadening immune responses to variable antigens, and enhancing immunogenicity in vulnerable populations with distinct immunity. Licensed vaccines contain an increasing variety of adjuvants, with a growing pipeline of adjuvanted vaccines under development.

Recent findings: Most adjuvants, including Alum, Toll-like receptor agonists and oil-in-water emulsions, activate innate immunity thereby altering the quantity and quality of an adaptive immune response. Adjuvants activate leukocytes, and induce mediators (e.g., cytokines, chemokines, and prostaglandin-E2) some of which are biomarkers for reactogenicity, that is, induction of local/systemic side effects. Although there have been safety concerns regarding a hypothetical risk of adjuvants inducing auto-immunity, such associations have not been established. As immune responses vary by population (e.g., age and sex), adjuvant research now incorporates principles of precision medicine. Innovations in adjuvant research include use of human in vitro models, immuno-engineering, novel delivery systems, and systems biology to identify biomarkers of safety and adjuvanticity.

Summary: Adjuvants enhance vaccine immunogenicity and can be associated with reactogenicity. Novel multidisciplinary approaches hold promise to accelerate and de-risk targeted adjuvant discovery and development. VIDEO ABSTRACT: http://links.lww.com/MOP/A53.

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FIGURE 1

Adjuvants enhance vaccine immunogenicity. (a) Nonadjuvanted subunit vaccines that contain only purified recombinant antigens induce modest T helper-polarizing cytokines, T-cell activation, and antibody production typically require multiple booster doses and often result in narrow and/or waning immunity. (b) Adjuvanted vaccines, in turn, enhance the quality and quantity of antigen presenting cell maturation and costimulation, T helper-polarizing cytokine production, polyfunctional T cells, and antibody production, resulting in broad and durable immunity, as well as dose and antigen sparing. Multiple cell colors indicate broader protective immunity. APC, antigen presenting cell; DC, dendritic cell. This figure was created using BioRender (https://biorender.com/).

FIGURE 2

Medicinal chemistry and formulation can limit adjuvant-related systemic reactogenicity. (a) Free small molecule adjuvants are rapidly released and dissipated from the injection site. Entry of such adjuvants into the systemic circulation induces production of cytokines and prostaglandin-E₂ thereby increasing systemic reactogenicity, including fever and malaise. (b) Lipidation of small molecules adjuvants, is one approach to reduce the systemic reactogenicity without reducing immunogenicity through the slow release of the adjuvant with low systemic distribution. PGE₂, prostaglandin-E₂. This figure was created using BioRender (https://biorender.com/).