Immunologic adjuvant

In immunology, an adjuvant is a component that potentiates the immune responses to an antigen and/or modulates it towards the desired immune responses.[1] The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid.[2] "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 antigens."[3]

A magazine article about vaccine adjuvants in 2007 was headlined "Deciphering Immunology's Dirty Secret"[4] to refer to the early days of vaccine manufacture, when significant variations in the effectiveness of different batches of the same vaccine were observed, correctly assumed to be due to contamination of the reaction vessels. However, it was soon found that more scrupulous attention to cleanliness actually seemed to reduce the effectiveness of the vaccines, and that the contaminants – "dirt" – actually enhanced the immune response. There are many known adjuvants in widespread use, including oils, aluminium salts, and virosomes.

Overview

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 PAMPs, which include liposomes, lipopolysaccharide (LPS), molecular cages for antigen, components of bacterial cell walls, and endocytosed nucleic acids such as double-stranded RNA (dsRNA), single-stranded DNA (ssDNA), and unmethylated CpG dinucleotide-containing DNA.[5] 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 (DCs), lymphocytes, and macrophages by mimicking a natural infection.[6][7]

Inorganic adjuvants

Aluminium salts

There are many adjuvants, some of which are inorganic (such as alum), that also carry the potential to augment immunogenicity.[8][9] Two common salts include aluminium phosphate and aluminium hydroxide. These are the most common adjuvants in human vaccines.

The precise mechanism of alum action remains unclear but a few insights have been gained. For instance, alum can trigger dendritic cells (DC) and other immune cells to secrete interleukin-1β (IL-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 DC picks up the antigen and speeds to a lymph node, where it sticks tightly to a helper T cell and presumably induces 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).[10] A study claims that Docosahexaenoic acid (DHA) may help to prevent aluminum induced biochemical and morphological alteration in the cerebellum.[11]

Organic adjuvants

While aluminium salts are popularly used in human vaccines, the organic compound squalene is also used (e.g. AS03). However, organic adjuvants are more commonly used in animal vaccines.

Oil-based

Oil-based adjuvants are commonly used in some veterinary vaccines. MF59 is an 'oil [squalene] in water' adjuvant used in some human vaccines.

Experimental adjuvants

An increasing number of vaccines with squalene and phosphate adjuvants are being tested on humans.[12] The compound QS21 is under investigation as a possible immunological adjuvant.[13]

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:

This process carried out by both DCs 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.[16][17]

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.[18]

Toll-like receptors

The ability of 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).[19]

The binding of ligands - either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection - to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.[20][21]

As of 2016 several TLR ligands were in clinical development or being tested in animal models as potential adjuvants.[22]

Medical complications

Humans

Aluminium salts used in many human vaccines are generally regarded as safe.[23]

Animals

Aluminum adjuvants have caused motor neuron death in mice[24] 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.[25] Squalene has caused rheumatoid arthritis in rats already prone to arthritis.[26]

In cats, vaccinations have been linked to sarcomas, at a rate of between 1 and 10 per 10,000 injections. No specific types of vaccines, manufacturers or factors have been associated with sarcomas.[27]

In 1993, a causal relationship between VAS and administration of aluminum adjuvanted 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.[28]

Further information: Vaccine-associated sarcoma

Controversy

Recently, 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.[5][29] 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)).[5]

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.

See also

External links

References

  1. ↑ "Guideline on Adjuvants in Vaccines for Human Use" (PDF). The European Medicines Agency. Retrieved 8 May 2013.
  2. ↑ DNA Vaccines: Methods and Protocols, D.B. Lowrie and R.G. Whalen, Humana Press, 2000. ISBN 978-0-89603-580-5.
  3. ↑ The Use of Conventional Immunologic Adjuvants in DNA Vaccine Preparations, by Shin Sasaki and Kenji Okuda. In D.B. Lowrie and R.G. Whalen (editors), DNA Vaccines: Methods and Protocols, Humana Press, 2000. ISBN 978-0-89603-580-5.
  4. ↑ The Scientist "Deciphering Immunology's Dirty Secret."
  5. 1 2 3 Gavin A, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D (2006). "Adjuvant-enhanced antibody responses occur without Toll-like receptor signaling". Science 314 (5807): 1936–8. Bibcode:2006Sci...314.1936G. doi:10.1126/science.1135299. PMC 1868398. PMID 17185603.
  6. ↑ Majde JA. 1987. Progress in leukocyte biology. Alan R. Liss, Inc. vol. 6.
  7. ↑ "Immunization schedule in India 2016". Superbabyonline. Retrieved 5 May 2016.
  8. ↑ Clements C, Griffiths E (2002). "The global impact of vaccines containing aluminium adjuvants". Vaccine. 20 Suppl 3: S24–33. doi:10.1016/s0264-410x(02)00168-8. PMID 12184361.
  9. ↑ Glenny A, Pope C, Waddington H, and Wallace U. 1926. The antigenic value of toxoid precipitated by potassium alum. J Pathol Bacteriol. 29: 38-45.
  10. ↑ Leslie, M. (2013) Solution to Vaccine Mystery Starts to Crystallize" Science 341: 26-27
  11. ↑ Chaudhary M, Joshi DK, Tripathi S, Kulshrestha S, Mahdi AA (2014). "Docosahexaenoic acid ameliorates aluminum induced biochemical and morphological alteration in rat cerebellum". Annals of Neurosciences 21 (1): 5–9. doi:10.5214/ans.0972.7531.210103. PMC 4117144. PMID 25206046.
  12. ↑ "Immunologic adjuvants for modern vaccine formulations," F. R. Vogel, Annals of the New York Academy of Sciences, Vol 754, Issue 1, 1995, pp. 153-160
  13. ↑ Ghochikyan A, Mkrtichyan M, Petrushina I, Movsesyan N, Karapetyan A, Cribbs D, Agadjanyan M (2006). "Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch". Vaccine 24 (13): 2275–82. doi:10.1016/j.vaccine.2005.11.039. PMC 2081151. PMID 16368167.
  14. ↑ Bousso P, Robey E (2003). "Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes". Nat Immunol 4 (6): 579–85. doi:10.1038/ni928. PMID 12730692.
  15. ↑ Mempel T, Henrickson S, Von Andrian U (2004). "T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases". Nature 427 (6970): 154–9. Bibcode:2004Natur.427..154M. doi:10.1038/nature02238. PMID 14712275.
  16. ↑ Gaboury J, Johnston B, Niu X, Kubes P (1995). "Mechanisms underlying acute mast cell-induced leukocyte rolling and adhesion in vivo". J Immunol 154 (2): 804–13. PMID 7814884.
  17. ↑ Kashiwakura J, Yokoi H, Saito H, Okayama Y (2004). "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". J Immunol 173 (8): 5247–57. doi:10.4049/jimmunol.173.8.5247. PMID 15470070.
  18. ↑ Schijns V (2000). "Immunological concepts of vaccine adjuvant activity". Curr Opin Immunol 12 (4): 456–63. doi:10.1016/S0952-7915(00)00120-5. PMID 10899018.
  19. ↑ Delneste Y, Beauvillain C, Jeannin P (2007). "Innate immunity: structure and function of TLRs". Med Sci (Paris) 23 (1): 67–73. doi:10.1051/medsci/200723167. PMID 17212934.
  20. ↑ Takeda, Kiyoshi; Akira, Shizuo (2005). "Toll-like receptors in innate immunity". International Immunology 17 (1): 1–14. doi:10.1093/intimm/dxh186. PMID 15585605.
  21. ↑ Medzhitov R, Preston-Hurlburt P, Janeway C (1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature 388 (6640): 394–7. doi:10.1038/41131. PMID 9237759.
  22. ↑ Toussi DN, Massari P Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands. Vaccines (Basel). 2014 Apr 25;2(2):323-53. PMID 26344622 PMC 4494261/
  23. ↑ Baylor N, Egan W, Richman P (2002). "Aluminum salts in vaccines--US perspective". Vaccine 20 (Suppl 3): S18–23. doi:10.1016/S0264-410X(02)00166-4. PMID 12184360.
  24. ↑ Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA (2007). "Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice". Neuromolecular Med 9 (1): 83–100. doi:10.1385/NMM:9:1:83. PMID 17114826.
  25. ↑ Satoh, M; et al. (2003). "Induction of lupus autoantibodies by adjuvants". J Autoimmun 21 (1): 1–9. doi:10.1016/S0896-8411(03)00083-0. PMID 12892730.
  26. ↑ Carlson, BC; Jansson AM; Larsson A; Bucht A; Lorentzen JC (2000). "The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis in Rats". American Journal of Pathology 156 (2057–2065): 2057–65. doi:10.1016/S0002-9440(10)65077-8. PMC 1850095. PMID 10854227.
  27. ↑ Kirpensteijn, J (2006). "Feline injection site-associated sarcoma: Is it a reason to critically evaluate our vaccination policies?". Veterinary Microbiology 117 (1): 59–65. doi:10.1016/j.vetmic.2006.04.010. PMID 16769184.
  28. ↑ Richards J, Elston T, Ford R, Gaskell R, Hartmann K, Hurley K, Lappin M, Levy J, Rodan I, Scherk M, Schultz R, Sparkes A (2006). "The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Panel report". J Am Vet Med Assoc 229 (9): 1405–41. doi:10.2460/javma.229.9.1405. PMID 17078805.
  29. ↑ Wickelgren I (2006). "Immunology. Mouse studies question importance of toll-like receptors to vaccines". Science 314 (5807): 1859–60. doi:10.1126/science.314.5807.1859a. PMID 17185572.
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