Squalene

Biosynthesis

Squalene is biosynthesised by coupling two molecules of farnesyl pyrophosphate. The condensation requires NADPH and the enzyme squalene synthase.

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

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Statin pathway edit

1. The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Shark

Among natural sources of squalene, the liver oil of certain deep-water (500 m and below) sharks is the most concentrated, up to 50% to 80%.

In 2020, conservationists raised concerns about the potential slaughter of sharks to obtain squalene for a COVID-19 vaccine.^[21] Environmental and other concerns over shark hunting have motivated its extraction from other sources.^[22]

Plants

Plant oils are generally squalene-poor. In terms of concentration by oil-weight, amaranth oil has the highest weight concentration of squalene (1-7%), followed by olive oil (0.2-0.5%). Distillation can increase squalene concentration. Deodorized and distilled olive oil is 28% squalene by weight.^[16]

Because squalene is thermolabile, direct distillation of vegetable oils would not concentrate squalene. Liquid–liquid extraction by organic solvents, such as hexane, chloroform, or methanol, is not suitable for producing squalene for cosmetics, food, and other products due to their toxicity. Supercritical extraction with carbon dioxide does not have such a problem, as squalene is extracted from oil, rather than from seeds.^[16]

Microbes

Genetically engineered microbes have been used to produce squalene.^[23][24]

Synthesis

Synthetic squalene is prepared commercially from geranylacetone.^[25]

As an adjuvant in vaccines

Immunologic adjuvants are substances, administered in conjunction with a vaccine, that stimulate the immune system and increase the response to the vaccine. Squalene is not itself an adjuvant, but it has been used in conjunction with surfactants in certain adjuvant formulations.^[11]

An adjuvant using squalene is Seqirus' proprietary MF59, which is added to influenza vaccines to help stimulate the human body's immune response through production of CD4 memory cells. It is the first oil-in-water influenza vaccine adjuvant to be commercialised in combination with a seasonal influenza virus vaccine. It was developed in the 1990s by researchers at Ciba-Geigy and Chiron; both companies were subsequently acquired by Novartis.^[11] The Influenza vaccine business of Novartis was later acquired by CSL Bering and created the company Seqirus.^[26] It is present in the form of an emulsion and is added to make the vaccine more immunogenic.^[11] However, the mechanism of action remains unknown. MF59 is capable of switching on a number of genes that partially overlap with those activated by other adjuvants.^[27] How these changes are triggered is unclear; to date, no receptors responding to MF59 have been identified. One possibility is that MF59 affects the cell behaviour by changing the lipid metabolism, namely by inducing accumulation of neutral lipids within the target cells.^[28] An influenza vaccine called FLUAD which used MF59 as an adjuvant was approved for use in the US in people 65 years of age and older, beginning with the 2016–2017 flu season.^[29]

A 2009 meta-analysis assessed data from 64 clinical trials of influenza vaccines with the squalene-containing adjuvant MF59 and compared them to the effects of vaccines with no adjuvant. The analysis reported that the adjuvated vaccines were associated with slightly lower risks of chronic diseases, but that neither type of vaccines altered the rate of autoimmune diseases; the authors concluded that their data "supports the good safety profile associated with MF59-adjuvated influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines".^[30]

Controversies

There have been attempts to link squalene to Gulf War syndrome, but these have been debunked, and it was later revealed that squalene was not an ingredient of the vaccines in question.^{[34][35][36][37]}