Adjuvant

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An adjuvant or adjuvant , plural adjuvants, adjuvants or adjuvants (from Latin adiuvare = to support, to help) is an auxiliary substance that enhances the effect of a reagent (in laboratory medicine) or a drug (in pharmacology ). In chemical and physical terms, they are often solubilizers, emulsions or mixtures thereof. Ideally, an adjuvant should not have any pharmacological effects of its own.

The use of penetration accelerators, such as dimethyl sulfoxide (DMSO) in some drugs for use on the skin, is an example of an improvement in the medicinal effectiveness of adjuvants . The accelerated penetration of the drug means that higher levels of activity are achieved in the tissue.

The adjuvant as a potentiator must be distinguished from adjuvant therapy as a supporting medicinal therapy measure, such as in oncology , pain therapy or rheumatism therapy . This prevents the side effects of the main active ingredient (examples are the administration of antiemetics in pain therapy with opioids or of proton pump inhibitors in the treatment of rheumatism with nonsteroidal anti-inflammatory drugs ) or enables the dose to be reduced (e.g. simultaneous administration of caffeine with paracetamol and / or acetylsalicylic acid ). The medicinal substance used for the accompanying medication, which is itself pharmacologically active but not the main carrier, is also referred to as an adjuvant .

Adjuvants in Immunology

Antigen solution and adjuvant in separate vials

One area of ​​application for adjuvants is immunology . Adjuvants are used in immunology to non-specifically increase the immune response to an administered substance. This means that the antigen is responsible for the specific immune response and the adjuvant is essentially responsible for the strength of the response. Adjuvants cause local tissue irritation and also bind the antigen so that it is only released after a delay. This results in increased antibody formation and an enhanced immune response.

Adjuvants are therapeutically important as components of vaccines. In their function as an active enhancer, they are not a drug, but a pharmaceutical adjuvant . In principle, the rule that to achieve the desired effect, the more the auxiliary effect of an adjuvant is required, the smaller the antigen in question is. The rule does not apply to live vaccines and vaccines from whole bacterial germs, as these do not require any adjuvants to achieve an appropriate immune response.

The antigen components as well as the adjuvants are only approved in the respective composition that forms the vaccine, but not in each case on their own.

Examples of adjuvants for human vaccines
Designation / trade name Type, composition / structure Description, use
Aluminum hydroxide aluminum phosphate

Aluminum hydroxyphosphate sulfate
aluminum potassium sulfate (alum)

Inorganic compound, gel structure. Use as an adsorbent in various inactivated vaccines such as B. Tetanus , diphtheria , pertussis , hepatitis A vaccine. Aluminum-containing adjuvants most often absorb antigens due to electrostatic interactions. The exact mechanism by which the immune response is stimulated is still the subject of research. This was initially explained by a depot function, later the uptake of antigens and finally an immune-stimulating mechanism was proposed:
  • The depot mechanism assumes that the adjuvant gradually releases the absorbed antigen at the injection site. This mechanism is supported by the observation that antigens that bind more strongly to the adjuvant cause a stronger immune response.
  • Alternatively, aluminum-containing adjuvants could ensure an increased uptake of antigens by antigen-presenting cells , a prolonged antigen presentation and increased interactions between CD4-positive T helper cells and dendritic cells .
  • Finally, there is also the possibility that the acquired immune response is stimulated directly, with the NLPR3 inflammasome being activated.

Adjuvants containing aluminum must not be frozen as cold can affect the adjuvant and the absorbed antigen.

AS01 Combined adjuvant.
Liposomes , MPL and QS21.		 Activation of the CD4 + T-cell and humoral immune response, component in the inactivated vaccine Shingrix against herpes zoster vaccine (there in the formulation AS01 B ), experimental use in malaria and TB vaccines under investigation (in the formulation AS01 E which contains half as much MPL and QS-21 as AS01 B )
AS02 Combined adjuvant.
Oil-in-water emulsion, MPL and QS21.		 Activation of toll-like receptors, experimental use (development of malaria vaccine)
AS03 Oil-in-water emulsion.
Ingredients: squalene , polysorbate 80 , DL-α- tocopherol 		Use as a potentiator in influenza vaccines such. B. Pandemic Influenza Vaccine A / H1N1 ( Pandemrix )
AS04 Combined adjuvant.
Complex of MPL and aluminum hydroxide or aluminum phosphate		 Activation of the toll-like receptor TLR4. Part of Fendrix ( hepatitis B vaccine ), Cervarix ( HPV vaccine )
CpG oligonucleotide Immunostimulating DNA sequences ( ISS ) from synthetically produced oligonucleotides with CpG motifs experimental use in the development of hepatitis B and influenza vaccines
IC31 Combination of the peptide KLK with the oligodeoxynucleotide ODN1 Activation of the toll-like receptor TLR9. Experimental use (development of vaccines against malaria, influenza, tuberculosis )
ISCOMATRIX Manufacturer: CSL Behring. Consists of the purified quillary saponin QS21, cholesterol and phospholipids of the cell membrane, which, under suitable conditions, form “cage structures” of 40–50 nm experimental use in human vaccines (approved in vaccines against equine influenza )
MF59 Oil-in-water emulsion.
Ingredients: squalene , polysorbate 80 , sorbitan trioleate (Span 85), sodium citrate and citric acid 		After injection, MF59 quickly passes into the lymphatic system and accelerates the absorption of the antigens into the immune system . Use as an enhancer in influenza vaccines (e.g. Fluad )
MPL Monophosphoryl lipid A , a purified derivative of lipopolysaccharides from bacterial cell walls of Salmonella minnesota Part of combined adjuvants ( Adjuvant Systems, AS )
QS-21 Surface-active substance ( saponin ) from the bark of the South American soap bark tree ( Quillaja saponaria ) Use as a matrix in the so-called ISCOMs ( immunostimulating complexes ) and in the combined adjuvants
Virosomes Double membrane made of phospholipids ( liposomes ) into which the viral antigen structures (e.g. influenza virus A hemagglutinin and neuraminidase ) are incorporated; reconstituted ("artificial") virus envelope . Use in hepatitis A vaccines such as HAVpur and Epaxal

The oldest immunological emulsion adjuvants still in use today include aluminum salts (from 1931) and the incomplete Freund's adjuvant (IFA), an experimentally used water-in-oil emulsion based on mineral oil that is stabilized with an emulsifier . Due to their pronounced oily properties, both lead to severe tissue irritation.

In addition, the so-called adjuvant 65 was used in clinical trials for influenza vaccines until the 1970s . This adjuvant was developed by MSD and is a water-in-oil emulsion with 86% peanut oil , 10% Arlacel A (mannitol monooleate) as an emulsifier and 4% aluminum monostearate as a stabilizer . However, due to its reactogenicity, it was never approved, especially since an animal study indicated a possible carcinogenic potential of Arlacel A. Thus, Adjuvant 65 is not included in any approved vaccine.

In France, various dead vaccines (mainly those of the DTP group and a pentavalent vaccine against smallpox, yellow fever, measles, BCG and tetanus) contained the adjuvant calcium phosphate developed by the Pasteur Institute . It was finally substituted with aluminum adjuvants in the late 1980s. Calcium phosphate is still a WHO- approved adjuvant (up to 1.3 mg calcium per dose) and is also listed in the European Pharmacopoeia.

Other known and used adjuvants are slotted snail hemocyanin (KLH) and Bacillus Calmette-Guérin (BCG).

Individual evidence

  1. ↑ Adjuvant in the Lexicon of Biology, Wissenschaft-Online .
  2. ^ PC Schmidt: Fiedler Encyclopedia of Excipients. Editio Cantor, 2007, p. 154.
  3. ↑ K.-J. Steffens: Vaccines: Innovation through pharmaceutical development. In: Pharmaceutical newspaper. 04/2002.
  4. ^ A b Kenneth Murphy, Casey Weaver: Janeway Immunology . 9th edition. Springer-Verlag, 2018, ISBN 978-3-662-56004-4 , pp. 960 .
  5. ↑ a b H. Giessen: Adjuvants. Auxiliary materials for better vaccines . In: Pharmaceutical newspaper. 48/2007.
  6. ^ Dose Optimization Strategies for Vaccines: The Role of Adjuvants and New Technologies. February 2008. Report of The National Vaccine Advisory Committee (NVAC) ( Memento of 25 September 2012 at the Web archive archive.today ) in the US Department of Health & Human Services.
  7. ↑ a b Armando A Paneque-Quevedo: Inorganic compounds as vaccine adjuvants . Ed .: Biotecnología Aplicada. tape 30 , no. 4 , 2013, ISSN  1027-2852 , p. 250–256 (English, sld.cu ).
  8. ^ Stanley A. Plotkin et al .: Plotkin's Vaccines . 7th edition. Elsevier, Philadelphia 2017, ISBN 978-0-323-35761-6 , pp. 61 ( elsevier.com ).
  9. ↑ Commentary on the European Pharmacopoeia. 4.08, loose-leaf collection, volume 21, 2005.
  10. ↑ a b c Stanley A. Plotkin et al .: Plotkin's Vaccines . 7th edition. Elsevier, Philadelphia 2017, ISBN 978-0-323-35761-6 , pp. 66 ( elsevier.com ).
  11. ^ S. Hutchison, RA Benson, VB Gibson, AH Pollock, P. Garside, JM Brewer: Antigen depot is not required for alum adjuvanticity. In: FASEB J. Volume 26, Edition 3, 2012, pp. 1272-1279. doi: 10.1096 / fj.11-184556 . PMID 22106367 ; PMC 3289510 (free full text).
  12. ↑ TR Ghimire, RA Benson, P. Garside, JM Brewer: Alum Increases antigen uptake, Reduces antigen degradation and sustains antigen presentation by DCs in vitro. In: Immunol Lett. Volume 147, Issue 1-2, 2012, pp. 55–62. doi: 10.1016 / j.imlet.2012.06.002 . PMID 22732235 ; PMC 3477319 (free full text).
  13. ^ AS McKee, MA Burchill, MW Munks, L. Jin, JW Kappler, RS Friedman, J. Jacobelli, P. Marrack: Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. In: Proc Natl Acad Sci US A. Volume 110, Issue 12, 2013, pp. E1122-E1131. doi: 10.1073 / pnas.1300392110 . PMID 23447566 ; PMC 3607057 (free full text).
  14. ^ Stanley A. Plotkin et al .: Plotkin's Vaccines . 7th edition. Elsevier, Philadelphia 2017, ISBN 978-0-323-35761-6 , pp. 64 ( elsevier.com ).
  15. ↑ Innocent Valéa et al .: Long-term immunogenicity and immune memory response to the hepatitis B antigen in the RTS, S / AS01E malaria vaccine in African children: a randomized trial . In: Human Vaccines & Immunotherapeutics . January 17, 2020, p. 1–7 , doi : 10.1080 / 21645515.2019.1695457 , PMID 31951771 .
  16. ^ Dereck R. Tait et al .: Final Analysis of a Trial of M72 / AS01E Vaccine to Prevent Tuberculosis . In: New England Journal of Medicine . tape 381 , no. 25 , 19 December 2019, p. 2429-2439 , doi : 10.1056 / NEJMoa1909953 .
  17. ↑ Michel Fochesato et al .: Comparative preclinical evaluation of AS01 versus other Adjuvant Systems in a candidate herpes zoster glycoprotein E subunit vaccine . In: Human Vaccines & Immunotherapeutics . tape 12 , no. 8 , August 2, 2016, p. 2092-2095 , doi : 10.1080 / 21645515.2016.1154247 , PMID 26933767 , PMC 4994747 (free full text).
  18. ↑ Pandemrix : Summary of the product characteristics (PDF file; 374 kB), as of October 2, 2009.
  19. ↑ adjuvant IC31 ® . ( Memento from January 26, 2013 in the web archive archive.today ) on the website of the manufacturer, Intercell AG.
  20. ↑ a b CSL Behring ISCOMATRIX ® adjuvant ( Memento of 30 April 2009 at the Internet Archive ) .
  21. ↑ Novartis MF59 ® Adjuvant Fact Sheet ( Memento from October 12, 2013 in the Internet Archive ) (PDF file; 48 kB) .
  22. ↑ Adjuvants: Boosters for vaccination. Pharmaceutical newspaper , March 29, 2017, accessed May 22, 2019 .
  23. ↑ Ernst Maschmann, Emil Küster, Werner Fischer: About the ability of clay preparation B to adsorb diphtheria toxin. In: Reports of the German Chemical Society. 64, 1931, p. 2174, doi: 10.1002 / cber.19310640851 .
  24. ↑ a b c Alex Kasprak: Are Pharmaceutical Companies Hiding the Presence of Peanut Oil in Vaccines? In: Snopes. February 16, 2017, Retrieved April 28, 2020 (American English).
  25. ^ Rajesh K. Gupta et al .: Adjuvants - a balance between toxicity and adjuvanticity . In: Vaccine . tape 11 , no. 3 , January 1, 1993, p. 293-306 , doi : 10.1016 / 0264-410X (93) 90190-9 .
  26. ^ Gary Ott et al .: MF59 Design and Evaluation of a Safe and Potent Adjuvant for Human Vaccines . In: Vaccine Design: The Subunit and Adjuvant Approach (=  Pharmaceutical Biotechnology ). Springer US, Boston, MA 1995, p. 277-296 , doi : 10.1007 / 978-1-4615-1823-5_10 .
  27. ^ A b Jean-Daniel Masson et al .: Calcium phosphate: a substitute for aluminum adjuvants? In: Expert Review of Vaccines . tape 16 , no. 3 , March 4, 2017, p. 289-299 , doi : 10.1080 / 14760584.2017.1244484 , PMID 27690701 .

further reading

Web links

Wiktionary: Adjuvans  - explanations of meanings, word origins, synonyms, translations