Squalene
Encyclopedia
Squalene is a natural organic compound
originally obtained for commercial purposes primarily from shark liver oil
, though plant sources (primarily vegetable oils) are used as well, including amaranth
seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including human
s. Squalene has been proposed to be an important part of the Mediterranean diet
as it may be a chemopreventative
substance that protects people from cancer.
Squalene is a hydrocarbon
and a triterpene
, and is a natural and vital part of the synthesis of cholesterol, steroid hormones, and vitamin D in the human body. Squalene is used in cosmetics, and more recently as an immunologic adjuvant
in vaccines.
) of one of the terminal double bonds of squalene yields 2,3-squalene oxide, which undergoes enzyme-catalyzed cyclization to afford lanosterol
, which is then elaborated into cholesterol
and other steroids.
such as shark
s, which lack a swim bladder and must therefore reduce their body density with fats and oils. Squalene, which is stored mainly in the shark's liver
, is lighter than water with a specific gravity of 0.855. Recently it has become a trend for sharks to be hunted to process their livers for the purpose of making squalene health capsules. Environmental and other concerns over shark hunting have motivated its extraction from vegetable sources, or biosynthetic processes instead.
.
Squalane
is a saturated
form of squalene in which the double bonds have been eliminated by hydrogenation
. Squalane is less susceptible to oxidation
than squalene. Squalane is thus more commonly used than squalene in personal care products, such as moisturizer
s.
Toxicology studies have determined that in the concentrations used in cosmetics, both squalene and squalane have low acute toxicity, and are not significant human skin irritants or sensitizers.
s 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 surfactant
s in certain adjuvant formulations.
An adjuvant using squalene is Novartis
' proprietary adjuvant 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 commercialized 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. It is present in the form of an emulsion
and is added to make the vaccine more immunogenic. 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. 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 behavior by changing the lipid metabolism, namely by inducing accumulation of neutral lipids within the target cells. An MF59-adjuvanted influenza vaccine (Fluad, developed by Chiron, which contains about 10 mg of squalene per dose) has been approved by health agencies and used in several European countries for seasonal flu shots since 1997. However, the Food and Drug Administration
has not authorized the use of such adjuvants in the United States. Glaxo Smith Kline used the squalene-based AS03
adjuvant in their 2009 influenza pandemic vaccine Pandemrix
and Arepanrix.
A 2009 meta-analysis
by researchers at Novartis Vaccines and Diagnostics that was published in the journal Vaccine brought together 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 adjuvanted 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-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines".
mainly due to the idea that squalene might have been present in an anthrax vaccine given to some military personnel during the 1991 Persian Gulf War. Studies led by Dr. Pam Asa of Tulane University found that deployed Persian Gulf War Syndrome patients are significantly more likely to have antibodies to squalene (95 percent) than asymptomatic Gulf War veterans (0 percent; p<.001);. The first of these published results concludes with the following statement: "It is important to note that our laboratory-based investigations do not establish that squalene was added as adjuvant to any vaccine used in military or other personnel who served in the Persian Gulf War era." The second publication, however, links the incidence of anti-squalene antibodies and Gulf War Syndrome to five specific lots of vaccine. Furthermore, they cite results of 1999 testing by the U.S. Food and Drug Administration which found these specific lots of vaccine to contain squalene. In response to these results, a committee of the US Institute of Medicine
stated that "The committee does not regard this study as providing evidence that the investigators have successfully measured antibodies to squalene", since the authors did not perform the normal scientific control
s needed show that their test was specific to anti-squalene antibodies. It has also been determined that the anthrax vaccines given to those US military personnel did not use squalene as an adjuvant. The vaccines were also tested for squalene, and none was detected with standard methods. A much more sensitive method was then developed, which again found no squalene in 37 of the 38 lots tested. One lot contained traces of squalene, at less than ten parts per billion, which is about 30-fold less than the level found in human blood. The FDA stated that this trace of squalene probably came from a fingerprint, since the oils on human skin contain enough squalene to send these extremely sensitive tests "off the chart".
A later study reported that about one in ten people have squalene antibodies in their blood, regardless of whether or not they received squalene from a vaccination. A later study confirmed this result, and also showed that vaccination with squalene-containing vaccines do not alter the levels of these naturally-occurring antibodies. A third study showed that these naturally-occurring antibodies were no more common in Gulf war veterans than in the general population.
Oil-water suspensions, including MF59
, were associated with the ability to induce lupus autoantibodies in non-autoimmune mice. In one study, endogenous squalene was linked to autoimmune arthritis in rats. An epidemiologic analysis of safety data on MF59 seasonal and pandemic influenza vaccines showed no evidence of increased risk of vaccine adverse events of potential autoimmune origin.
The World Health Organization
and the US Department of Defense have both published extensive reports that emphasize that squalene is a chemical naturally occurring in the human body, present even in oils of human fingerprints. WHO goes further to explain that squalene has been present in over 22 million flu vaccines given to patients in Europe since 1997 and there have never been significant vaccine-related adverse events.
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
originally obtained for commercial purposes primarily from shark liver oil
Shark liver oil
Shark liver oil is obtained from sharks that are caught for food purposes and are living in cold, deep oceans. The liver oil from sharks has been used by fishermen for centuries as a folk remedy for general health...
, though plant sources (primarily vegetable oils) are used as well, including amaranth
Amaranth
Amaranthus, collectively known as amaranth, is a cosmopolitan genus of herbs. Approximately 60 species are recognized, with inflorescences and foliage ranging from purple and red to gold...
seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including human
Human
Humans are the only living species in the Homo genus...
s. Squalene has been proposed to be an important part of the Mediterranean diet
Mediterranean diet
The Mediterranean diet is a modern nutritional recommendation inspired by the traditional dietary patterns of southern Italy, Crete and much of the rest of Greece in the 1960s....
as it may be a chemopreventative
Chemoprophylaxis
Chemoprophylaxis refers to the administration of a medication for the purpose of preventing disease or infection. Antibiotics, for example, may be administered to patients with disorders of immune system function to prevent bacterial infections...
substance that protects people from cancer.
Squalene is a hydrocarbon
Hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls....
and a triterpene
Triterpene
Triterpenes are terpenes consisting of six isoprene units and have the molecular formula C30H48.The pentacyclic triterpenes can be classified into lupane, oleanane or ursane groups.Animal- and plant-derived triterpenes exist, such as:*squalene...
, and is a natural and vital part of the synthesis of cholesterol, steroid hormones, and vitamin D in the human body. Squalene is used in cosmetics, and more recently as an immunologic adjuvant
Immunologic adjuvant
In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid...
in vaccines.
Role in steroid synthesis
Squalene is the biochemical precursor to the whole family of steroids. Oxidation (via squalene monooxygenaseSqualene monooxygenase
Squalene monooxygenase is an enzyme that uses NADPH and molecular oxygen to oxidize squalene to 2,3-oxidosqualene . Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway...
) of one of the terminal double bonds of squalene yields 2,3-squalene oxide, which undergoes enzyme-catalyzed cyclization to afford lanosterol
Lanosterol
Lanosterol is a tetracyclic triterpenoid, which is the compound from which all steroids are derived.-Role in creation of steroids:Elaboration of lanosterol under enzyme catalysis leads to the core structure of steroids. 14-Demethylation of lanosterol by CYP51 eventually yields...
, which is then elaborated into cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and other steroids.
Biosynthesis
- Two molecules of farnesyl pyrophosphateFarnesyl pyrophosphateFarnesyl pyrophosphate is an intermediate in the HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes, terpenoids, and sterols...
condense with reduction by NADPH to form squalene - by squalene synthase.
Shark squalene
Squalene is a low density compound often stored in the bodies of cartilaginous fishChondrichthyes
Chondrichthyes or cartilaginous fishes are jawed fish with paired fins, paired nares, scales, two-chambered hearts, and skeletons made of cartilage rather than bone...
such as shark
Shark
Sharks are a type of fish with a full cartilaginous skeleton and a highly streamlined body. The earliest known sharks date from more than 420 million years ago....
s, which lack a swim bladder and must therefore reduce their body density with fats and oils. Squalene, which is stored mainly in the shark's liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, is lighter than water with a specific gravity of 0.855. Recently it has become a trend for sharks to be hunted to process their livers for the purpose of making squalene health capsules. Environmental and other concerns over shark hunting have motivated its extraction from vegetable sources, or biosynthetic processes instead.
Derivative used as a skin moisturizer in cosmetics
Squalene oil is the most common fat and antioxidant produced in and on human skin. It is a natural moisturizerMoisturizer
Moisturizers or emollients are complex mixtures of chemical agents specially designed to make the external layers of the skin softer and more pliable, by increasing its hydration by reducing evaporation. Naturally occurring skin lipids and sterols as well as artificial or natural oils,...
.
Squalane
Squalane
Squalane is a natural hydrocarbon and triterpene derived from a variety of plant and animal sources. It is a component of human sebum. Squalane is a saturated analog of squalene, from which it can also be produced by hydrogenation....
is a saturated
Saturation (chemistry)
In chemistry, saturation has six different meanings, all based on reaching a maximum capacity...
form of squalene in which the double bonds have been eliminated by hydrogenation
Hydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
. Squalane is less susceptible to oxidation
Organic redox reaction
Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions because many reactions carry the name but do not actually involve electron...
than squalene. Squalane is thus more commonly used than squalene in personal care products, such as moisturizer
Moisturizer
Moisturizers or emollients are complex mixtures of chemical agents specially designed to make the external layers of the skin softer and more pliable, by increasing its hydration by reducing evaporation. Naturally occurring skin lipids and sterols as well as artificial or natural oils,...
s.
Toxicology studies have determined that in the concentrations used in cosmetics, both squalene and squalane have low acute toxicity, and are not significant human skin irritants or sensitizers.
Use as an adjuvant in vaccines
Immunologic adjuvantImmunologic adjuvant
In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid...
s are substances, administered in conjunction with a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
, that stimulate the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
and increase the response to the vaccine. Squalene is not itself an adjuvant, but it has been used in conjunction with surfactant
Surfactant
Surfactants are compounds that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid...
s in certain adjuvant formulations.
An adjuvant using squalene is Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
' proprietary adjuvant MF59
MF59
MF59 is an immunologic adjuvant that uses squalene. It is Novartis' proprietary adjuvant that is added to influenza vaccines to help stimulate the human body's immune response through production of CD4 memory cells. MF59 is the first oil-in-water influenza vaccine adjuvant to be commercialized in...
, which is added to influenza vaccines to help stimulate the human body's immune response through production of CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
memory cells. It is the first oil-in-water influenza vaccine adjuvant to be commercialized in combination with a seasonal influenza virus vaccine. It was developed in the 1990s by researchers at Ciba-Geigy and Chiron
Chiron Corporation
Chiron Corporation was a multinational biotechnology firm based in Emeryville, California that was acquired by Novartis International AG on April 20, 2006. It had offices and facilities in eighteen countries on five continents. Chiron's business and research was in three main areas:...
; both companies were subsequently acquired by Novartis. It is present in the form of an emulsion
Emulsion
An emulsion is a mixture of two or more liquids that are normally immiscible . Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion is used when both the dispersed and the...
and is added to make the vaccine more immunogenic. 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. 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 behavior by changing the lipid metabolism, namely by inducing accumulation of neutral lipids within the target cells. An MF59-adjuvanted influenza vaccine (Fluad, developed by Chiron, which contains about 10 mg of squalene per dose) has been approved by health agencies and used in several European countries for seasonal flu shots since 1997. However, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
has not authorized the use of such adjuvants in the United States. Glaxo Smith Kline used the squalene-based AS03
AS03
AS03 is the trade name for a squalene-based immunologic adjuvant used in various vaccine products by GlaxoSmithKline...
adjuvant in their 2009 influenza pandemic vaccine Pandemrix
Pandemrix
Pandemrix is an influenza vaccine for influenza pandemics, such as the H1N1 2009 flu pandemic colloquially called the swine flu. The vaccine was developed by GlaxoSmithKline and patented in September 2006....
and Arepanrix.
A 2009 meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
by researchers at Novartis Vaccines and Diagnostics that was published in the journal Vaccine brought together 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 adjuvanted 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-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines".
Health controversy
There have been attempts to link squalene to Gulf War SyndromeGulf War syndrome
Gulf War syndrome or Gulf War illness describes a medical condition that affected veterans and civilians who were near conflicts during or downwind of chemical weapons depot demolition, after the 1991 Gulf War. A wide range of acute and chronic symptoms have included fatigue, musculoskeletal...
mainly due to the idea that squalene might have been present in an anthrax vaccine given to some military personnel during the 1991 Persian Gulf War. Studies led by Dr. Pam Asa of Tulane University found that deployed Persian Gulf War Syndrome patients are significantly more likely to have antibodies to squalene (95 percent) than asymptomatic Gulf War veterans (0 percent; p<.001);. The first of these published results concludes with the following statement: "It is important to note that our laboratory-based investigations do not establish that squalene was added as adjuvant to any vaccine used in military or other personnel who served in the Persian Gulf War era." The second publication, however, links the incidence of anti-squalene antibodies and Gulf War Syndrome to five specific lots of vaccine. Furthermore, they cite results of 1999 testing by the U.S. Food and Drug Administration which found these specific lots of vaccine to contain squalene. In response to these results, a committee of the US Institute of Medicine
Institute of Medicine
The Institute of Medicine is a not-for-profit, non-governmental American organization founded in 1970, under the congressional charter of the National Academy of Sciences...
stated that "The committee does not regard this study as providing evidence that the investigators have successfully measured antibodies to squalene", since the authors did not perform the normal scientific control
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...
s needed show that their test was specific to anti-squalene antibodies. It has also been determined that the anthrax vaccines given to those US military personnel did not use squalene as an adjuvant. The vaccines were also tested for squalene, and none was detected with standard methods. A much more sensitive method was then developed, which again found no squalene in 37 of the 38 lots tested. One lot contained traces of squalene, at less than ten parts per billion, which is about 30-fold less than the level found in human blood. The FDA stated that this trace of squalene probably came from a fingerprint, since the oils on human skin contain enough squalene to send these extremely sensitive tests "off the chart".
A later study reported that about one in ten people have squalene antibodies in their blood, regardless of whether or not they received squalene from a vaccination. A later study confirmed this result, and also showed that vaccination with squalene-containing vaccines do not alter the levels of these naturally-occurring antibodies. A third study showed that these naturally-occurring antibodies were no more common in Gulf war veterans than in the general population.
Oil-water suspensions, including MF59
MF59
MF59 is an immunologic adjuvant that uses squalene. It is Novartis' proprietary adjuvant that is added to influenza vaccines to help stimulate the human body's immune response through production of CD4 memory cells. MF59 is the first oil-in-water influenza vaccine adjuvant to be commercialized in...
, were associated with the ability to induce lupus autoantibodies in non-autoimmune mice. In one study, endogenous squalene was linked to autoimmune arthritis in rats. An epidemiologic analysis of safety data on MF59 seasonal and pandemic influenza vaccines showed no evidence of increased risk of vaccine adverse events of potential autoimmune origin.
The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
and the US Department of Defense have both published extensive reports that emphasize that squalene is a chemical naturally occurring in the human body, present even in oils of human fingerprints. WHO goes further to explain that squalene has been present in over 22 million flu vaccines given to patients in Europe since 1997 and there have never been significant vaccine-related adverse events.