immunologic adjuvant

Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to respond to the vaccine more vigorously, and thus providing increased immunity to a particular disease. 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.{{cite journal | vauthors = Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D | title = Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling | journal = Science | volume = 314 | issue = 5807 | pages = 1936–1938 | date = December 2006 | pmid = 17185603 | pmc = 1868398 | doi = 10.1126/science.1135299 | bibcode = 2006Sci...314.1936G }} 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.{{cite book | veditors = Majde JA |title=Immunopharmacology of infectious diseases: vaccine adjuvants and modulators of non-specific resistance | series = Progress in leukocyte biology | volume = 6 |publisher=Alan R. Liss |isbn=978-0845141052|year=1987 }}{{cite web |url=http://www.superbabyonline.com/immunization-schedule-in-india/ |title=Immunization schedule in India 2016 |publisher=Superbabyonline |access-date=5 May 2016 |archive-date=28 June 2021 |archive-url=https://web.archive.org/web/20210628151838/https://www.superbabyonline.com/immunization-schedule-in-india/ |url-status=live }}

• Inorganic compounds: potassium alum, aluminium hydroxide, aluminium phosphate,{{cite journal | vauthors = Guimarães LE, Baker B, Perricone C, Shoenfeld Y | title = Vaccines, adjuvants and autoimmunity | journal = Pharmacological Research | volume = 100 | pages = 190–209 | date = October 2015 | pmid = 26275795 | pmc = 7129276 | doi = 10.1016/j.phrs.2015.08.003 }} calcium phosphate hydroxide
• Oils: paraffin oil, propolis (only in preclinical studies).{{cite journal | vauthors = El Ashry ES, Ahmad TA | title = The use of propolis as vaccine's adjuvant | journal = Vaccine | volume = 31 | issue = 1 | pages = 31–39 | date = December 2012 | pmid = 23137844 | doi = 10.1016/j.vaccine.2012.10.095 }} Adjuvant 65 (based on peanut oil){{cite news| vauthors = Jones SV |title=Peanut Oil Used in a New Vaccine|url=https://www.nytimes.com/1964/09/19/peanut-oil-used-in-a-new-vaccine.html|access-date=27 August 2017|work=New York Times|date=19 September 1964|archive-date=9 August 2021|archive-url=https://web.archive.org/web/20210809055828/https://www.nytimes.com/1964/09/19/archives/peanut-oil-used-in-a-new-vaccine-product-patented-for-merck-said-to.html|url-status=live}} was tested in influenza vaccines in the 1970s, but was never released commercially.{{cite journal | vauthors = Smith JW, Fletcher WB, Peters M, Westwood M, Perkins FJ | title = Response to influenza vaccine in adjuvant 65-4 | journal = The Journal of Hygiene | volume = 74 | issue = 2 | pages = 251–259 | date = April 1975 | pmid = 1054729 | pmc = 2130368 | doi = 10.1017/s0022172400024323 }} The oily natural substance squalene is used in the adjuvant MF59.{{cite journal | vauthors = Pulendran B, S Arunachalam P, O'Hagan DT | title = Emerging concepts in the science of vaccine adjuvants | journal = Nature Reviews. Drug Discovery | volume = 20 | issue = 6 | pages = 454–475 | date = June 2021 | pmid = 33824489 | pmc = 8023785 | doi = 10.1038/s41573-021-00163-y }}
• Bacterial products: killed bacteria of the species Bordetella pertussis, Mycobacterium bovis,{{citation needed|date=February 2021}} toxoids. MPL (Monophosphorylated lipid A) is a modified form of a bacterial lipid A protein that is used in several vaccines.
• Plant saponins from Quillaia (soap bark tree), soybean and Polygala senega
• Cytokines: IL-1, IL-2, IL-12
• CpG oligonucleotides
• Combinations: Freund's complete adjuvant, Freund's incomplete adjuvant, AS01 (combining MPL and Quillaia saponins), Matrix-M (combining Quillaia saponins and two types of fat)
• Small molecules: TLR7/8 agonists (imidazoquinolines,{{Cite web |title=COVAXIN® (BBV152) – Inactivated, COVID-19 vaccine |url=https://www.who.int/publications/m/item/covaxin-(bbv152)-inactivated-covid-19-vaccine |access-date=2024-07-14 |website=www.who.int |language=en}} imidazopyrimidines{{cite journal | vauthors = Soni D, Borriello F, Scott DA, Feru F, DeLeon M, Brightman SE, Cheng WK, Melhem G, Smith JA, Ramirez JC, Barman S, Cameron M, Kelly A, Walker K, Nanishi E, van Haren SD, Phan T, Qi Y, Kinsey R, Raczy MM, Ozonoff A, Pettengill MA, Hubbell JA, Fox CB, Dowling DJ, Levy O | title = From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation | journal = Science Advances | volume = 10 | issue = 27 | pages = eadg3747 | date = July 2024 | pmid = 38959314 | pmc = 11221515 | doi = 10.1126/sciadv.adg3747 }})

There are many adjuvants, some of which are inorganic, that carry the potential to augment immunogenicity.{{cite journal | vauthors = Clements CJ, Griffiths E | title = The global impact of vaccines containing aluminium adjuvants | journal = Vaccine | volume = 20 | issue = Suppl 3 | pages = S24–S33 | date = May 2002 | pmid = 12184361 | doi = 10.1016/s0264-410x(02)00168-8 }}{{cite journal | vauthors = Glenny A, Pope C, Waddington H, Wallace U | date = 1926 | title = The antigenic value of toxoid precipitated by potassium alum | journal = J Pathol Bacteriol | volume = 29 | pages = 38–45 }} Alum was the first aluminium salt used for this purpose, but has been almost completely replaced by aluminium hydroxide and aluminium phosphate for commercial vaccines.{{cite journal | vauthors = Marrack P, McKee AS, Munks MW | title = Towards an understanding of the adjuvant action of aluminium | journal = Nature Reviews. Immunology | volume = 9 | issue = 4 | pages = 287–293 | date = April 2009 | pmid = 19247370 | pmc = 3147301 | doi = 10.1038/nri2510 }} 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.{{cite journal | vauthors = Leroux-Roels G | title = Unmet needs in modern vaccinology: adjuvants to improve the immune response | journal = Vaccine | volume = 28 | issue = Suppl 3 | pages = C25–C36 | date = August 2010 | pmid = 20713254 | doi = 10.1016/j.vaccine.2010.07.021 }} However, studies have shown that surgical removal of these depots had no impact on the magnitude of IgG1 response.{{cite journal | vauthors = Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM | title = Antigen depot is not required for alum adjuvanticity | journal = FASEB Journal | volume = 26 | issue = 3 | pages = 1272–1279 | date = March 2012 | pmid = 22106367 | pmc = 3289510 | doi = 10.1096/fj.11-184556 | doi-access = free }}

Alum can trigger dendritic cells and other immune cells to secrete Interleukin 1 beta (IL{{nbh}}1β), 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 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).{{cite journal | vauthors = Leslie M | title = Solution to vaccine mystery starts to crystallize | journal = Science | volume = 341 | issue = 6141 | pages = 26–27 | date = July 2013 | pmid = 23828925 | doi = 10.1126/science.341.6141.26 | bibcode = 2013Sci...341...26L }} 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.{{cite journal | vauthors = Nazarizadeh A, Staudacher AH, Wittwer NL, Turnbull T, Brown MP, Kempson I | title = Aluminium Nanoparticles as Efficient Adjuvants Compared to Their Microparticle Counterparts: Current Progress and Perspectives | journal = International Journal of Molecular Sciences | volume = 23 | issue = 9 | pages = 4707 | date = April 2022 | pmid = 35563097 | pmc = 9101817 | doi = 10.3390/ijms23094707 | doi-access = free }}

Freund's complete adjuvant is a solution of inactivated Mycobacterium tuberculosis 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.{{cite journal | vauthors = Apostólico JD, Lunardelli VA, Coirada FC, Boscardin SB, Rosa DS | title = Adjuvants: Classification, Modus Operandi, and Licensing | journal = Journal of Immunology Research | volume = 2016 | pages = 1459394 | date = 2016 | pmid = 27274998 | pmc = 4870346 | doi = 10.1155/2016/1459394 | doi-access = free }}

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 and is present in human sebum.{{cite journal | vauthors = Del Giudice G, Fragapane E, Bugarini R, Hora M, Henriksson T, Palla E, O'hagan D, Donnelly J, Rappuoli R, Podda A | title = Vaccines with the MF59 adjuvant do not stimulate antibody responses against squalene | journal = Clinical and Vaccine Immunology | volume = 13 | issue = 9 | pages = 1010–1013 | date = September 2006 | pmid = 16960112 | pmc = 1563566 | doi = 10.1128/CVI.00191-06 }} MF59 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.{{Cite web|url=https://www.who.int/vaccine_safety/committee/topics/adjuvants/squalene/questions_and_answers/en/|archive-url=https://web.archive.org/web/20121104105400/http://www.who.int/vaccine_safety/committee/topics/adjuvants/squalene/questions_and_answers/en/|url-status=dead|archive-date=November 4, 2012|title= Squalene-based adjuvants in vaccines|website=WHO|access-date=2019-01-10}} AS03 is another squalene-containing adjuvant.[http://www.emea.europa.eu/humandocs/PDFs/EPAR/pandemrix/emea-combined-h832en.pdf Pandemrix – Summary of product characteristics] {{webarchive|url=https://web.archive.org/web/20091007191040/http://www.emea.europa.eu/humandocs/PDFs/EPAR/pandemrix/emea-combined-h832en.pdf |date=October 7, 2009 }}, European Medicines Agency website [http://www.emea.europa.eu/ European Medicines Agency website] {{Webarchive|url=https://web.archive.org/web/20130715075412/http://www.emea.europa.eu/ |date=2013-07-15 }} 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.

The plant extract QS-21 is a liposome loaded with saponins extracted from the tree Quillaja saponaria.{{cite journal | vauthors = Alving CR, Beck Z, Matyas GR, Rao M | title = Liposomal adjuvants for human vaccines | journal = Expert Opinion on Drug Delivery | volume = 13 | issue = 6 | pages = 807–816 | date = June 2016 | pmid = 26866300 | doi = 10.1517/17425247.2016.1151871 | s2cid = 30639153 }}{{cite journal | vauthors = Stertman L, Palm AE, Zarnegar B, Carow B, Lunderius Andersson C, Magnusson SE, Carnrot C, Shinde V, Smith G, Glenn G, Fries L, Lövgren Bengtsson K | title = The Matrix-M™ adjuvant: A critical component of vaccines for the 21st century | journal = Human Vaccines & Immunotherapeutics | volume = 19 | issue = 1 | pages = 2189885 | date = December 2023 | pmid = 37113023 | pmc = 10158541 | doi = 10.1080/21645515.2023.2189885 }}

Monophosphoryl lipid A (MPL), a detoxified version of the lipopolysaccharide toxin from the bacterium Salmonella Minnesota, interacts with the receptor TLR4 to enhance immune response.{{cite web |title=Shingrix package insert |url=https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm581605.pdf |access-date=7 April 2019 |publisher=Food and Drug Administration |archive-date=24 April 2019 |archive-url=https://web.archive.org/web/20190424160644/https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM581605.pdf |url-status=dead }}

The combination of QS-21, cholesterol and MPL forms the adjuvant AS01 which is used in the Shingrix vaccine approved in 2017, as well as in the approved malaria vaccine Mosquirix.

The adjuvant Matrix-M is an immune stimulating complex (ISCOM) consisting of nanospheres made of QS-21, cholesterol and phospholipids. It is used in the approved Novavax Covid-19 vaccine and in the malaria vaccine R21/Matrix-M.

Several unmethylated cytosine phosphoguanosine (CpG) oligonucleotides activate the TLR9 receptor that is present in a number of cell types of the immune system. The adjuvant CpG 1018 is used in an approved Hepatitis B vaccine.

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 dendritic cells engulf pathogens through a process called phagocytosis.
• Dendritic cells then migrate to the lymph nodes where T cells (adaptive immune cells) wait for signals to trigger their activation.{{cite journal | vauthors = Bousso P, Robey E | title = Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes | journal = Nature Immunology | volume = 4 | issue = 6 | pages = 579–585 | date = June 2003 | pmid = 12730692 | doi = 10.1038/ni928 | s2cid = 26642061 | doi-access = free }}
• 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.
• T cells can then recognize these clippings and undergo a cellular transformation resulting in their own activation.{{cite journal | vauthors = Mempel TR, Henrickson SE, Von Andrian UH | title = T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases | journal = Nature | volume = 427 | issue = 6970 | pages = 154–159 | date = January 2004 | pmid = 14712275 | doi = 10.1038/nature02238 | doi-access = free | bibcode = 2004Natur.427..154M }}
• γδ T cells possess characteristics of both the innate and adaptive immune responses.
• Macrophages 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 and represents a physical link between the innate and adaptive immune responses.

Upon activation, mast cells release heparin and histamine to effectively increase trafficking to and seal off the site of infection 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 of other immune cells of both the innate and adaptive immune responses to the infected area.{{cite journal | vauthors = Gaboury JP, Johnston B, Niu XF, Kubes P | title = Mechanisms underlying acute mast cell-induced leukocyte rolling and adhesion in vivo | journal = Journal of Immunology | volume = 154 | issue = 2 | pages = 804–813 | date = January 1995 | pmid = 7814884 | doi = 10.4049/jimmunol.154.2.804 | s2cid = 17839603 | doi-access = free }}{{cite journal | vauthors = Kashiwakura J, Yokoi H, Saito H, Okayama Y | title = T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells: comparison of gene expression profiles between human tonsillar and lung-cultured mast cells | journal = Journal of Immunology | volume = 173 | issue = 8 | pages = 5247–5257 | date = October 2004 | pmid = 15470070 | doi = 10.4049/jimmunol.173.8.5247 | doi-access = free }}

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.{{cite journal | vauthors = Schijns VE | title = Immunological concepts of vaccine adjuvant activity | journal = Current Opinion in Immunology | volume = 12 | issue = 4 | pages = 456–463 | date = August 2000 | pmid = 10899018 | doi = 10.1016/S0952-7915(00)00120-5 }}

• First, adjuvants may help in the translocation of antigens to the lymph nodes where they can be recognized by T cells. This will ultimately lead to greater T cell activity resulting in a heightened clearance of pathogen throughout the organism.
• 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 in the adaptive immune response.
• Third, adjuvants may help to increase the capacity to cause local reactions at the injection site (during vaccination), inducing greater release of danger signals by chemokine releasing cells such as helper T cells and mast cells.
• Fourth, they may induce the release of inflammatory cytokines which helps to not only recruit B and T cells at sites of infection but also to increase transcriptional events leading to a net increase of immune cells as a whole.
• Finally, adjuvants are believed to increase the innate immune response to antigen by interacting with pattern recognition receptors (PRRs) on or within accessory cells.

The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called toll-like receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity (T and B lymphocytes) and non-immune cells (epithelial and endothelial cells, and fibroblasts).{{cite journal | vauthors = Delneste Y, Beauvillain C, Jeannin P | title = [Innate immunity: structure and function of TLRs] | journal = Médecine/Sciences | volume = 23 | issue = 1 | pages = 67–73 | date = January 2007 | pmid = 17212934 | doi = 10.1051/medsci/200723167 | doi-access = free }}

The binding of ligands{{snd}}either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection{{snd}} to TLRs mark the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.{{cite journal | vauthors = Takeda K, Akira S | title = Toll-like receptors in innate immunity | journal = International Immunology | volume = 17 | issue = 1 | pages = 1–14 | date = January 2005 | pmid = 15585605 | doi = 10.1093/intimm/dxh186 | doi-access = }}{{cite journal | vauthors = Medzhitov R, Preston-Hurlburt P, Janeway CA | title = A human homologue of the Drosophila Toll protein signals activation of adaptive immunity | journal = Nature | volume = 388 | issue = 6640 | pages = 394–397 | date = July 1997 | pmid = 9237759 | doi = 10.1038/41131 | s2cid = 4311321 | doi-access = free | bibcode = 1997Natur.388..394M }}

As of 2016, several TLR ligands were in clinical development or being tested in animal models as potential adjuvants.{{cite journal | vauthors = Toussi DN, Massari P | title = Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands | journal = Vaccines | volume = 2 | issue = 2 | pages = 323–353 | date = April 2014 | pmid = 26344622 | pmc = 4494261 | doi = 10.3390/vaccines2020323 | doi-access = free }}

Aluminium salts used in many human vaccines are regarded as safe by Food and Drug Administration.{{cite journal | vauthors = Baylor NW, Egan W, Richman P | title = Aluminum salts in vaccines--US perspective | journal = Vaccine | volume = 20 | issue = Suppl 3 | pages = S18–S23 | date = May 2002 | pmid = 12184360 | doi = 10.1016/S0264-410X(02)00166-4 }} Although there are studies suggesting the role of aluminium, especially injected highly bioavailable antigen-aluminium complexes in Alzheimer's disease development,{{cite journal | vauthors = Tomljenovic L | title = Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link? | journal = Journal of Alzheimer's Disease | volume = 23 | issue = 4 | pages = 567–598 | date = 2010 | pmid = 21157018 | doi = 10.3233/JAD-2010-101494 }} most researchers do not support a causal connection with aluminium.{{cite journal | vauthors = Lidsky TI | title = Is the Aluminum Hypothesis dead? | journal = Journal of Occupational and Environmental Medicine | volume = 56 | issue = 5 Suppl | pages = S73–S79 | date = May 2014 | pmid = 24806729 | pmc = 4131942 | doi = 10.1097/jom.0000000000000063 }} Adjuvants may make vaccines too reactogenic, which often leads to fever. This is often an expected outcome upon vaccination and is usually controlled by oral paracetamol if necessary.

An increased number of narcolepsy (a chronic neurological 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. 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.{{cite journal | vauthors = Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, Verity C | title = Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis | journal = BMJ | volume = 346 | issue = feb26 2 | pages = f794 | date = February 2013 | pmid = 23444425 | doi = 10.1136/bmj.f794 | doi-access = free }}{{cite journal | vauthors = Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, Himanen SL, Hublin C, Julkunen I, Olsén P, Saarenpää-Heikkilä O, Kilpi T | title = AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland | journal = PLOS ONE | volume = 7 | issue = 3 | pages = e33536 | date = 2012-03-28 | pmid = 22470453 | pmc = 3314666 | doi = 10.1371/journal.pone.0033536 | doi-access = free | bibcode = 2012PLoSO...733536N | others = Benjamin J. Cowling (ed.) }} The adjuvant of the vaccine contained vitamin E that was no more than a day's normal dietary intake. Vitamin E increases hypocretin-specific fragments that bind to DQB1*602 in cell culture experiments, leading to the hypothesis that autoimmunity may arise in genetically susceptible individuals,{{cite journal | vauthors = Masoudi S, Ploen D, Kunz K, Hildt E | title = The adjuvant component α-tocopherol triggers via modulation of Nrf2 the expression and turnover of hypocretin in vitro and its implication to the development of narcolepsy | journal = Vaccine | volume = 32 | issue = 25 | pages = 2980–2988 | date = May 2014 | pmid = 24721530 | doi = 10.1016/j.vaccine.2014.03.085 }} but there is no clinical data to support this hypothesis. The third AS03 ingredient is polysorbate 80. Polysorbate{{spaces}}80 is also found in both the Oxford–AstraZeneca and Janssen COVID-19 vaccines.{{Cite web|title=Emergency Use Authorization (EUA) of the Jansen COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) in Individuals 18 Years of Age and Older|website=Food and Drug Administration|url=https://www.fda.gov/media/146305/download|access-date=2021-04-06|archive-date=2023-08-02|archive-url=https://web.archive.org/web/20230802194225/https://www.fda.gov/media/146305/download|url-status=dead}}{{Cite web|title=AstraZeneca COVID-19 Vaccine|url=https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1f0531bd-4e0a-4246-8c1e-11fc5658e950|access-date=2021-04-06|website=dailymed.nlm.nih.gov|archive-date=2022-10-13|archive-url=https://web.archive.org/web/20221013182002/https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1f0531bd-4e0a-4246-8c1e-11fc5658e950|url-status=live}}

Aluminium adjuvants have caused motor neuron death in mice{{cite journal | vauthors = Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA | title = Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice | journal = Neuromolecular Medicine | volume = 9 | issue = 1 | pages = 83–100 | year = 2007 | pmid = 17114826 | doi = 10.1385/NMM:9:1:83 | s2cid = 15839936 | doi-access = free }} 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 in mice.{{cite journal | vauthors = Satoh M, Kuroda Y, Yoshida H, Behney KM, Mizutani A, Akaogi J, Nacionales DC, Lorenson TD, Rosenbauer RJ, Reeves WH | title = Induction of lupus autoantibodies by adjuvants | journal = Journal of Autoimmunity | volume = 21 | issue = 1 | pages = 1–9 | date = August 2003 | pmid = 12892730 | doi = 10.1016/S0896-8411(03)00083-0 }} Squalene has caused rheumatoid arthritis in rats already prone to arthritis.{{cite journal | vauthors = Carlson BC, Jansson AM, Larsson A, Bucht A, Lorentzen JC | title = The endogenous adjuvant squalene can induce a chronic T-cell-mediated arthritis in rats | journal = The American Journal of Pathology | volume = 156 | issue = 6 | pages = 2057–2065 | date = June 2000 | pmid = 10854227 | pmc = 1850095 | doi = 10.1016/S0002-9440(10)65077-8 | url = http://ajp.amjpathol.org/cgi/content/full/156/6/2057 | url-status = dead | archive-url = https://archive.today/20031121095334/http://ajp.amjpathol.org/cgi/content/full/156/6/2057 | archive-date = 2003-11-21 }}

In cats, vaccine-associated sarcoma (VAS) occurs at a rate of 1–10 per 10,000 injections. 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.{{cite journal | vauthors = Richards JR, Elston TH, Ford RB, Gaskell RM, Hartmann K, Hurley KF, Lappin MR, Levy JK, Rodan I, Scherk M, Schultz RD, Sparkes AH | title = The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Panel report | journal = Journal of the American Veterinary Medical Association | volume = 229 | issue = 9 | pages = 1405–1441 | date = November 2006 | pmid = 17078805 | doi = 10.2460/javma.229.9.1405 | doi-access = free }} However, evidence conflicts on whether types of vaccines, manufacturers or factors have been associated with sarcomas.{{cite journal | vauthors = Kirpensteijn J | title = Feline injection site-associated sarcoma: Is it a reason to critically evaluate our vaccination policies? | journal = Veterinary Microbiology | volume = 117 | issue = 1 | pages = 59–65 | date = October 2006 | pmid = 16769184 | doi = 10.1016/j.vetmic.2006.04.010 }}

{{As of|2006}}, 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 in the absence of TLR signaling.{{cite journal | vauthors = Wickelgren I | title = Immunology. Mouse studies question importance of toll-like receptors to vaccines | journal = Science | volume = 314 | issue = 5807 | pages = 1859–1860 | date = December 2006 | pmid = 17185572 | doi = 10.1126/science.314.5807.1859a | s2cid = 31553418 | doi-access = free }} One researcher found that in the absence of MyD88 and Trif (essential adapter proteins in TLR signaling), they were still able to induce inflammatory responses, increase T cell activation and generate greater B cell abundancy using conventional adjuvants (alum, 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 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.

Reports after the first Gulf War linked anthrax vaccine adjuvants{{cite journal | vauthors = Butler D | title = Admission on Gulf War vaccines spurs debate on medical records | journal = Nature | volume = 390 | issue = 6655 | pages = 3–4 | date = November 1997 | pmid = 9363878 | doi = 10.1038/36158 | s2cid = 5116290 | doi-access = free | bibcode = 1997Natur.390Q...3B }} to Gulf War syndrome in American and British troops.{{cite web|title=Illegal vaccine link to Gulf war syndrome|website=TheGuardian.com|date=30 July 2001|url=https://www.theguardian.com/environment/2001/jul/30/internationalnews|access-date=20 September 2020|archive-date=10 May 2023|archive-url=https://web.archive.org/web/20230510112450/https://www.theguardian.com/environment/2001/jul/30/internationalnews|url-status=live}} The United States Department of Defense 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."{{cite web|title=Squalene-based adjuvants in vaccines|date = 21 July 2006 |author=The Global Advisory Committee on Vaccine Safety|url=https://www.who.int/vaccine_safety/committee/topics/adjuvants/squalene/questions_and_answers/en/|archive-url=https://web.archive.org/web/20121104105400/http://www.who.int/vaccine_safety/committee/topics/adjuvants/squalene/questions_and_answers/en/|url-status=dead|archive-date=November 4, 2012}} 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."{{cite journal | vauthors = Petrovsky N | title = Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs | journal = Drug Safety | volume = 38 | issue = 11 | pages = 1059–1074 | date = November 2015 | pmid = 26446142 | pmc = 4615573 | doi = 10.1007/s40264-015-0350-4 }}

• Beta-glucan
• Immunomodulator
• Immunostimulant
• Pharmaceutic adjuvant

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{{Wiktionary|adjuvant}}

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• [http://www.mayoclinic.com/health/adjuvant-therapy/CA00012 Adjuvant therapy]
• [http://research.uiowa.edu/animal/?get=adjuvant Animal research] {{Webarchive|url=https://web.archive.org/web/20120227081855/http://research.uiowa.edu/animal/?get=adjuvant |date=2012-02-27 }}
• [http://www.violinet.org/vaxjo Vaxjo database] {{Webarchive|url=https://web.archive.org/web/20200514012615/http://www.violinet.org/vaxjo |date=2020-05-14 }}

{{Vaccines}}

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Category:Adjuvants

Category:Immunology