Some adjuvants may exert adverse effects upon injection or, on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of the enormous implications for
vaccine development. In the search for new and safer adjuvants, several new adjuvants were developed by
pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special immune receptors called
toll-like receptors (TLRs) that are expressed on leukocyte membranes. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR
ligands. Alongside their supportive role, adjuvants were found to inflict by themselves an illness of autoimmune nature, defined as 'the adjuvant diseases'. The debatable question of
silicone as an adjuvant and
connective tissue diseases, as well as the
Gulf War syndrome and macrophagic myofaciitis which followed multiple
injections of
aluminium-based
vaccines, are presented here. Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants need to be developed and incorporated into future
vaccines. Other needs in light of new
vaccine technologies are adjuvants suitable for use with mucosally delivered
vaccines, DNA vaccines, cancer and autoimmunity
vaccines. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. More adjuvants were approved to date besides
alum for human
vaccines, including
MF59 in some
viral vaccines, MPL, AS04, AS01B and AS02A against viral and
parasitic infections,
virosomes for HBV, HPV and HAV, and
cholera toxin for
cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely in order to circumvent common side effects of adjuvant-activated TLRs such as local
inflammation and the general malaise felt because of the costly whole-body immune response to
antigen.