immunology Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...

, an adjuvant is a substance that increases or modulates the immune response to a

vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...

. The word "adjuvant" comes from the Latin word ''adiuvare'', meaning to help or aid. "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

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

s." In the early days of vaccine manufacture, significant variations in the efficacy of different batches of the same vaccine were correctly assumed to be caused by contamination of the reaction vessels. However, it was soon found that more scrupulous cleaning actually seemed to ''reduce'' the effectiveness of the vaccines, and some contaminants actually enhanced the immune response. There are many known adjuvants in widespread use, including aluminium salts, oils and

virosome A virosome is a drug or vaccine delivery mechanism consisting of unilamellar phospholipid membrane (either a mono- or bi-layer) vesicle incorporating virus derived proteins to allow the virosomes to fuse with target cells. Viruses are infectious ...

Overview

Adjuvants in

are often used to modify or augment the effects of a vaccine by stimulating the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

respond A respond is a half-pier or half-pillar that is bonded into a wall and designed to carry the springer Springer or springers may refer to: Publishers * Springer Science+Business Media, aka Springer International Publishing, a worldwide publishi ...

to the vaccine more vigorously, and thus providing increased immunity to a particular

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

. Adjuvants accomplish this task by mimicking specific sets of

evolutionarily Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation t ...

conserved molecules, so called pathogen-associated molecular patterns, which include

liposomes A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

, molecular cages for

s, components of bacterial

cell walls A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...

, and endocytosed nucleic acids such as

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

, double-stranded RNA, single-stranded DNA, and unmethylated CpG dinucleotide-containing DNA. Because immune systems have

evolved Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation t ...

to recognize these specific

antigenic In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

moieties, the presence of an adjuvant in conjunction with the vaccine can greatly increase the

innate immune response The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

to the antigen by augmenting the activities of dendritic cells,

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...

, and

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

by mimicking a natural

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

Types

*Inorganic compounds: potassium alum,

aluminium hydroxide Aluminium hydroxide, Al(OH)3, is found in nature as the mineral gibbsite (also known as hydrargillite) and its three much rarer polymorphs: bayerite, doyleite, and nordstrandite. Aluminium hydroxide is amphoteric, i.e., it has both basic and ...

, aluminium phosphate, calcium phosphate hydroxide *Oils: paraffin oil, propolis (only in preclinical studies), Adjuvant 65 (based on

peanut oil Peanut oil, also known as groundnut oil or arachis oil, is a vegetable oil derived from peanuts. The oil usually has a mild or neutral flavor but, if made with roasted peanuts, has a stronger peanut flavor and aroma. It is often used in American ...

. Adjuvant 65 was tested in influenza vaccines in the 1970s, but was never released commercially.) *Bacterial products: killed bacteria of the species ''

Bordetella pertussis ''Bordetella pertussis'' is a Gram-negative, aerobic, pathogenic, encapsulated coccobacillus of the genus ''Bordetella'', and the causative agent of pertussis or whooping cough. Like '' B. bronchiseptica'', ''B. pertussis'' is motile and expres ...

'', ''

Mycobacterium bovis ''Mycobacterium bovis'' is a slow-growing (16- to 20-hour generation time) aerobic bacterium and the causative agent of tuberculosis in cattle (known as bovine TB). It is related to ''Mycobacterium tuberculosis'', the bacterium which causes tube ...

'',

toxoid A toxoid is an inactivated toxin (usually an exotoxin) whose toxicity has been suppressed either by chemical (formalin) or heat treatment, while other properties, typically immunogenicity, are maintained. Toxins are secreted by bacteria, wherea ...

s *Plant

saponin Saponins (Latin "sapon", soap + "-in", one of), also selectively referred to as triterpene glycosides, are bitter-tasting usually toxic plant-derived organic chemicals that have a foamy quality when agitated in water. They are widely distributed ...

s from ''

Quillaja ''Quillaja'' is a genus of flowering plants, the only extant genus in the family Quillajaceae with two or three known species. It was once thought to be in the rose family, Rosaceae, but recent research shows it belongs in its own family. The i ...

'' (see

Quil A Quillaia is the milled inner bark or small stems and branches of the soapbark ( ''Quillaja saponaria'', Molina). Other names include ''Murillo bark extract'', ''Panama bark extract'', ''Quillaia extract'', ''Quillay bark extract'', and ''Soapbark e ...

soybean The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses. Traditional unfermented food uses of soybeans include soy milk, from which tofu an ...

, ''

Polygala senega ''Polygala senega'' is a species of flowering plant in the milkwort family, Polygalaceae. It is native to North America, where it is distributed in southern Canada and the central and eastern United States.IL-1,

IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...

, IL-12 *Combinations: Freund's complete adjuvant, Freund's incomplete adjuvant *Other organic substances: squalene

Inorganic adjuvants

Aluminium salts

There are many adjuvants, some of which are inorganic, that carry the potential to augment

immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

Alum An alum () is a type of chemical compound, usually a hydrated double salt, double sulfate salt (chemistry), salt of aluminium with the general chemical formula, formula , where is a valence (chemistry), monovalent cation such as potassium or a ...

was the first aluminium

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

used for this purpose, but has been almost completely replaced by

and aluminium phosphate for commercial vaccines. Aluminium salts are the most commonly-used adjuvants in human vaccines. Their adjuvant activity was described in 1926. The precise mechanism of aluminium salts remains unclear but some insights have been gained. It was formerly thought that they function as delivery systems by generating depots that trap antigens at the injection site, providing a slow release that continues to stimulate the immune system. However, studies have shown that surgical removal of these depots had no impact on the magnitude of

IgG1 Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...

response. Alum can trigger

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...

s and other immune cells to secrete Interleukin 1 beta (IL1β), an immune signal that promotes antibody production. Alum adheres to the cell's plasma membrane and rearranges certain lipids there. Spurred into action, the dendritic cells pick up the antigen and speed to lymph nodes, where they stick tightly to a

helper T cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

and presumably induce an immune response. A second mechanism depends on alum killing immune cells at the injection site although researchers aren't sure exactly how alum kills these cells. It has been speculated that the dying cells release DNA which serves as an immune alarm. Some studies found that DNA from dying cells causes them to adhere more tightly to helper T cells which ultimately leads to an increased release of antibodies by B cells. No matter what the mechanism is, alum is not a perfect adjuvant because it does not work with all antigens (e.g. malaria and tuberculosis). However, recent research indicates that alum formulated in a nanoparticle form rather than microparticles can broaden the utility of alum adjuvants and promote stronger adjuvant effects.

Organic adjuvants

Freund's complete adjuvant is a solution of inactivated ''

Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...

'' in mineral oil developed in 1930. It is not safe enough for human use. A version without the bacteria, that is only oil in water, is known as Freund's incomplete adjuvant. It helps vaccines release antigens for a longer time. Despite the side effects, its potential benefit has led to a few clinical trials. Squalene is a naturally-occurring organic compound used in human and animal vaccines. Squalene is an oil, made up of carbon and hydrogen atoms, produced by plants and is present in many foods. Squalene is also produced by the human liver as a precursor to

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

and is present in human

sebum A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest nu ...

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 ...

is an oil-in-water emulsion of squalene adjuvant used in some human vaccines. As of 2021, over 22 million doses of one vaccine with squalene, FLUAD, have been administered with no severe adverse effects reported. AS03 is another squalene-containing adjuvant.Pandemrix – Summary of product characteristics
,

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

websi
European Medicines Agency website
/ref> The plant extract

QS-21 QS-21 is a purified plant extract used as a vaccine adjuvant. It is derived from the soap bark tree (''Quillaja saponaria''), which is native to the countries of Chile, Peru, and Bolivia. The crude drug (''Quillajae cortex'') is imported from Per ...

is a liposome made up of plant

s from ''

Quillaja saponaria ''Quillaja saponaria'', the soap bark tree or soapbark, is an evergreen tree in the family Quillajaceae, native to warm temperate central Chile. In Chile it occurs from 32 to 40° South Latitude approximately and at up to 2000 m (6500&nb ...

'', the soap bark tree. It is a part of the

Shingrix A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and ...

vaccine approved in 2017. Monophosphoryl

lipid A Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS), also called endotoxin molecule, and its hydrophobic nature allows it ...

(MPL), a detoxified version of ''

Salmonella minnesota ''Salmonella'' is a genus of rod-shaped (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two species of ''Salmonella'' are ''Salmonella enterica'' and ''Salmonella bongori''. ''S. enterica'' is the type species and is fur ...

, interacts with the receptor TLR4 to enhance immune response. It is also a part of the Shingrix vaccine.

Adaptive immune response

In order to understand the links between the innate immune response and the adaptive immune response to help substantiate an adjuvant function in enhancing adaptive immune responses to the specific antigen of a vaccine, the following points should be considered: *Innate immune response cells such as

s engulf pathogens through a process called phagocytosis. *Dendritic cells then migrate to the

lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

where T cells (adaptive immune cells) wait for signals to trigger their activation. *In the lymph nodes, dendritic cells mince the engulfed pathogen and then express the pathogen clippings as antigen on their cell surface by coupling them to a special receptor known as a

major histocompatibility complex The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...

. *T cells can then recognize these clippings and undergo a

cellular transformation In molecular biology and genetics, transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s). For transformation to ta ...

resulting in their own activation. *

γδ T cells Gamma delta T cells (γδ T cells) are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ (alpha beta) T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, ...

possess characteristics of both the innate and adaptive immune responses. *

Macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

can also activate T cells in a similar approach (but do not do so naturally). This process carried out by both dendritic cells and macrophages is termed

antigen presentation Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now ...

and represents a physical link between the innate and adaptive immune responses. Upon activation,

mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

release

heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...

and

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

to effectively increase trafficking to and seal off the site of

to allow immune cells of both systems to clear the area of pathogens. In addition, mast cells also release chemokines which result in the positive

chemotaxis Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

of other immune cells of both the innate and adaptive immune responses to the infected area. Due to the variety of mechanisms and links between the innate and adaptive immune response, an adjuvant-enhanced innate immune response results in an enhanced adaptive immune response. Specifically, adjuvants may exert their immune-enhancing effects according to five immune-functional activities. *First, adjuvants may help in the translocation of

antigens In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

to the

where they can be recognized by T cells. This will ultimately lead to greater T cell activity resulting in a heightened clearance of

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

throughout the

organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...

. *Second, adjuvants may provide physical protection to antigens which grants the antigen a prolonged delivery. This means the organism will be exposed to the antigen for a longer duration, making the immune system more robust as it makes use of the additional time by upregulating the production of B and T cells needed for greater immunological

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...

in the adaptive immune response. *Third, adjuvants may help to increase the capacity to cause local reactions at the

injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...

site (during vaccination), inducing greater release of danger signals by

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

releasing cells such as

helper T cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

and

. *Fourth, they may induce the release of inflammatory cytokines which helps to not only recruit B and T cells at sites of

but also to increase

transcriptional Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

events leading to a net increase of

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

as a whole. *Finally, adjuvants are believed to increase the innate immune response to antigen by interacting with

pattern recognition receptors Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...

(PRRs) on or within accessory cells.

Toll-like receptors

The ability of the immune system to recognize

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

s that are broadly shared by

s is, in part, due to the presence of

immune receptor An immune receptor (or immunologic receptor) is a receptor, usually on a cell membrane, which binds to a substance (for example, a cytokine) and causes a response in the immune system. Types The main receptors in the immune system are pattern rec ...

s called

toll-like receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize st ...

(TLRs) that are expressed on the membranes of

leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

s including dendritic cells,

, natural killer cells, cells of the adaptive immunity (T and B lymphocytes) and non-immune cells (

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

and endothelial cells, and fibroblasts). The binding of

ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...

either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infectionTLR marks the key

molecular A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...

events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity. As of 2016, several TLR ligands were in clinical development or being tested in animal models as potential adjuvants.

Medical complications

Humans

Aluminium salts used in many human vaccines are regarded as safe by

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

, Although there are studies suggesting the role of aluminium, especially injected highly bioavailable antigen-aluminium complexes when used as adjuvant, in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

development, the majority of researchers do not support a causal connection with aluminium. Adjuvants may make vaccines too reactogenic, which often leads to

fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

. This is often an expected outcome upon vaccination and is usually controlled in infants by

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...

medication if necessary. An increased number of narcolepsy (a chronic sleep disorder) cases in children and adolescents was observed in

Scandinavia Scandinavia; Sámi languages: /. ( ) is a subregion#Europe, subregion in Northern Europe, with strong historical, cultural, and linguistic ties between its constituent peoples. In English usage, ''Scandinavia'' most commonly refers to Denmark, ...

n and other European countries after vaccinations to address the H1N1 “swine flu” pandemic in 2009. Narcolepsy has previously been associated with HLA-subtype DQB1*602, which has led to the prediction that it is an autoimmune process. After a series of epidemiological investigations, researchers found that the higher incidence correlated with the use of AS03-adjuvanted influenza vaccine ( Pandemrix). Those vaccinated with Pandemrix have almost a twelve-times higher risk of developing the disease. The adjuvant of the vaccine contained

vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...

that was no more than a day's normal dietary intake. Vitamin E increases

hypocretin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...

-specific fragments that bind to DQB1*602 in cell culture experiments, leading to the hypothesis that autoimmunity may arise in genetically susceptible individuals, but there is no clinical data to support this hypothesis. The third AS03 ingredient is polysorbate 80. Polysorbate80 is also found in both the Oxford–AstraZeneca and Janssen

COVID-19 vaccine A COVID19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 ( COVID19). Prior to the COVID19 pandemic, an e ...

Animals

Aluminium adjuvants have caused motor neuron death in mice when injected directly onto the spine at the scruff of the neck, and oil–water suspensions have been reported to increase the risk of

autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

in mice. Squalene has caused

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

in rats already prone to arthritis. In cats, vaccine-associated sarcoma (VAS) occurs at a rate of 1–10 per ten thousand injections. In 1993, a causal relationship between VAS and administration of aluminium adjuvated rabies and FeLV vaccines was established through

epidemiologic Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evidenc ...

methods, and in 1996 the Vaccine-Associated Feline Sarcoma Task Force was formed to address the problem. However, evidence conflicts on whether types of vaccines, manufacturers or factors have been associated with sarcomas.

Controversy

TLR signalling

, the premise that TLR signaling acts as the key node in antigen-mediated inflammatory responses has been in question as researchers have observed antigen-mediated inflammatory responses in

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

in the absence of TLR signaling. One researcher found that in the absence of MyD88 and

Trif TIR-domain-containing adapter-inducing interferon-β (TRIF) is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent ...

(essential adapter proteins in TLR signaling), they were still able to induce inflammatory responses, increase T cell activation and generate greater

B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

abundancy using conventional adjuvants (

alum An alum () is a type of chemical compound, usually a hydrated double salt, double sulfate salt (chemistry), salt of aluminium with the general chemical formula, formula , where is a valence (chemistry), monovalent cation such as potassium or a ...

, Freund's complete adjuvant, Freund's incomplete adjuvant, and monophosphoryl-lipid A/trehalose dicorynomycolate ( Ribi's adjuvant)). These observations suggest that although TLR activation can lead to increases in antibody responses, TLR activation is not required to induce enhanced innate and adaptive responses to antigens. 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

. 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.

Safety

Reports after the first Gulf War linked anthrax vaccine adjuvants to Gulf War syndrome in American and British troops. The US Defence Department strongly denied the claims. 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." No such followup has been published by the WHO. Subsequently, the American National Center for Biotechnology Information published an article discussing the comparative safety of vaccine adjuvants which stated that "the biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer's disease."

References

External links

Adjuvant therapyAnimal researchVaxjo database
{{Authority control Adjuvants Immunology