It took almost 70 years from the discovery of the immunostimulatory potential of alum in 1926 until the next adjuvant was included in a vaccine licensed for human use, when the oil-in-water emulsion MF59 was included in the influenza vaccine Fluad, licensed for use in Europe in 1997. In 2005, the highly efficacious HPV vaccine Cervarix, which included the adjuvant system AS04 as part of its formulation, was rolled out. AS04 is a formulation of the detoxified LPS-derivative MPL adsorbed onto alum. Another oil-in-water emulsion, AS03, was next to be utilized as part of the pandemic influenza vaccine Pandemrix in 2009. The multicomponent AS04, a combination of MPL and the saponin extract QS-21 encapsulated within liposomes, formed part of the highly effective shingles vaccine Shingrix in 2017, the same year the TLR9 agonist CpG-ODN 1018 was included as part of the new and improved HBV vaccine Heplisav-B. The COVID-19 pandemic, brought on by the outbreak of the novel SARS-CoV-2 virus, led to three more adjuvants being used clinically since 2020. LNPs serve as delivery systems and adjuvants for spike-encoding mRNA vaccines; Alhydroxyquim, a combination of alum and the TLR7/8 agonist imidazoquinolinone, is utilized in the whole-killed-virion vaccine Covaxin; and another saponin extract called Matrix-M, formulated as immune-stimulating complex (ISCOM) nanospheres, is the adjuvant component of the R21/Matrix-M malaria vaccine and the subunit COVID-19 vaccine Covovax.
