Efficacy and safety of immunological adjuvants. Where is the cut-off?

Abstract

Research over the past several decades has provided insight into the mode of action of adjuvants. However, the main focus of attention has been the efficacy in the induction of protective immunogenicity, while less effort has been devoted to the study of toxicity mechanisms. Evidences suggest that several mechanisms that are responsible for the immunostimulating effects are, at the same time, responsible of the adverse effects. In this context, it is often very difficult to establish the boundaries between immunostimulation and immunotoxicity to reach the ideal balance of efficacy/safety. During decades, hundreds of adjuvants and adjuvant formulations have been proposed as immunostimulants for vaccines but very few have been used in human vaccines due to toxicity concerns. In this review, relevant aspects about immunotoxicology of adjuvants, based on clinical and experimental studies are discussed. Some effects are only observed under hyperstimulating regimens using non-approved adjuvants for human use, but these are nonetheless useful to understanding basic principles of adjuvant toxicity. The acute local and systemic reactions, during the first hours and those that can be observed after the third day of vaccination in the inoculation site and systemically are discussed.

Comparison of immunological adjuvants

“…Of the inorganic solids, Al(OH) 3 induced MCP1 release but no IL1b, TNF, IFNc release, which was also observed for silica and HILIC to some extent, and for a single patient sample when stimulated with AlPO 4 . Thus, none of the selected inorganic solids were able to stimulate release of proinflammatory cytokines.…”

“…The modes of action of most vaccine adjuvants remain uncertain, as described in the introduction, despite several theories and decades of research (1)(2)(3)(4)18). As also mentioned in the introduction, adjuvants approved for human vaccine use are relatively few, e.g.…”

“…To 300 µL of NHS various reagents were added either directly to a final suspension of 1.5 mg/mL (insoluble, solid compounds) or 0.35% (w:v) (Al(OH) 3 ), dissolved in the indicated solvent (PBS, EtOH, DMSO, DMF) to a final concentration of 30 mM (low molecular weight compounds), 1.5 mg/mL (nucleic acids) or 1 µg/mL (proteins). Control solvents were added in the same volume as used for diluted reagents.…”

“…Testing of inorganic compounds showed that Al (OH) 3 reduced the activity of all pathways, an effect we mainly ascribe to its influence on the AP (12). AlPO 4 mimicked the effect of Al(OH) 3 to some extent, but most significant on the LP.…”

“…Immunological adjuvants are a diverse group of compounds and their modes of action have remained ill-defined for decades (1)(2)(3). Early studies led to development of well-known adjuvants like aluminum hydroxide and Freund's adjuvant, the first one being used in multiple vaccines for human and animal use, the latter being restricted to animal use due to severe side effects (1,2,(4)(5)(6).…”