"An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens.
Adjuvants accomplish this task by mimicking specific sets of evolutionarily conserved molecules, so called pathogen-associated molecular patterns, which include liposomes, lipopolysaccharide, molecular cages for antigens, components of bacterial cell walls, and endocytosed nucleic acids such as RNA, double-stranded RNA, single-stranded DNA, and unmethylated CpG dinucleotide-containing DNA.
[4] Because immune systems have evolved to recognize these specific antigenic moieties, the presence of an adjuvant in conjunction with the vaccine can greatly increase the innate immune response to the antigen by augmenting the activities of dendritic cells, lymphocytes, and macrophages by mimicking a natural infection.
[21] Freund's complete adjuvant is a solution of inactivated Mycobacterium tuberculosis in mineral oil developed in 1930.
As of 2021, over 22 million doses of one vaccine with squalene, FLUAD, have been administered with no severe adverse effects reported.
[24] In addition, squalene-based O/W emulsions have also been shown to stably incorporate small molecule TLR7/8 adjuvants (e.g. PVP-037) and lead to enhanced adjuvanticity via synergism.
[25][26] Monophosphoryl lipid A (MPL), a detoxified version of the lipopolysaccharide from the bacterium Salmonella Minnesota, interacts with the receptor TLR4 to enhance immune response.
[11] The adjuvant Matrix-M is an immune stimulating complex (ISCOM) consisting of nanospheres made of QS-21, cholesterol and phospholipids.
[33] The binding of ligands – either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection – to TLRs mark the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.
An increased number of narcolepsy (a chronic sleep disorder) cases in children and adolescents was observed in Scandinavian and other European countries after vaccinations to address the H1N1 "swine flu" pandemic in 2009.
After a series of epidemiological investigations, researchers found that the higher incidence correlated with the use of AS03-adjuvanted influenza vaccine (Pandemrix).
In 1993, a causal relationship between VAS and administration of aluminium adjuvated rabies and FeLV vaccines was established through epidemiologic methods, and in 1996 the Vaccine-Associated Feline Sarcoma Task Force was formed to address the problem.
Investigating the mechanisms which underlie TLR signaling has been significant in understanding why adjuvants used during vaccinations are so important in augmenting adaptive immune responses to specific antigens.
However, with the knowledge that TLR activation is not required for the immune-enhancing effects caused by common adjuvants, we can conclude that there are, in all likelihood, other receptors besides TLRs that have not yet been characterized, opening the door to future research.
Discussing the safety of squalene as an adjuvant in 2006, the World Health Organisation stated "follow-up to detect any vaccine-related adverse events will need to be performed.