Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents. Adjuvants may be added to a vaccine to boost the immune response to produce more antibodies and longer-lasting immunity, thus minimizing the dose of antigen needed. Adjuvants may also be used to enhance the efficacy of a vaccine by helping to modify the immune response to particular types of immune system cells: for example, by activating T cells instead of antibody-secreting B cells depending on the purpose of the vaccine.[1][2] Adjuvants are also used in the production of antibodies from immunized animals. There are different classes of adjuvants that can push immune response in different directions, but the most commonly used adjuvants include aluminum hydroxide and paraffin oil.[1][2]
Immunologic adjuvants
Immunologic adjuvants are added to vaccines to stimulate the immune system's response to the target antigen, but do not provide immunity themselves. Adjuvants can act in various ways in presenting an antigen to the immune system. Adjuvants can act as a depot for the antigen, presenting the antigen over a longer period of time, thus maximizing the immune response before the body clears the antigen. Examples of depot type adjuvants are oil emulsions. An adjuvant can also act as an irritant, which engages and amplifies the body's immune response.[3] A tetanus, diphtheria, and pertussis (DPT) vaccine, for example, contains small quantities of inactivated toxins produced by each of the target bacteria, but also contains some aluminium hydroxide.[4] Such aluminium salts are common adjuvants in vaccines sold in the United States and have been used in vaccines for more than 70 years.[5]
Mechanism
Adjuvants are needed to improve routing and adaptive immune responses to antigens. This reaction is mediated by two main types of lymphocytes, B and T lymphocytes. Adjuvants apply their effects through different mechanisms. Some adjuvants, such as alum, 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.[6] This is now under debate, as studies have shown that surgical removal of these depots had no impact on the magnitude of IgG1 response.[7]
Adjuvants as stabilizing agents
Although immunological adjuvants have traditionally been viewed as substances that aid the immune response to the antigen, adjuvants have also evolved as substances that can aid in stabilizing formulations of antigens, especially for vaccines administered for animal health.[3]
Types of adjuvants
- Analgesic adjuvants
- Inorganic compounds: alum, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide
- Mineral oil: paraffin oil
- Bacterial products: killed bacteria Bordetella pertussis, Mycobacterium bovis, toxoids
- Nonbacterial organics: squalene
- Delivery systems: detergents (Quil A)
- Plant saponins from Quillaja (See Quillaia), Soybean, Polygala senega
- Cytokines: IL-1, IL-2, IL-12
- Combination: Freund's complete adjuvant, Freund's incomplete adjuvant
- Food-based oil: Adjuvant 65, which is a product based on peanut oil.[8] Adjuvant 65 was tested in influenza vaccines in the 1970s, but was never released commercially.[9]
The mechanism of immune stimulation by adjuvants
Adjuvants can enhance the immune response to the antigen in different ways:
- Extend the presence of antigen in the blood
- Help the antigen presenting cells absorb antigen
- Activate macrophages and lymphocytes
- Support the production of cytokines
Alum as an adjuvant
Alum was the first aluminium salt used as an adjuvant, but has been almost completely replaced by aluminium hydroxide and aluminium phosphate for commercial vaccines.[10]
Concerns
Adjuvants may make vaccines too reactogenic, which often leads to fever. This is often an expected outcome upon vaccination and is usually controlled in infants by over-the-counter medication if necessary.
An increased number of narcolepsy (a chronic sleep 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.[11]
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 12 times higher risk of developing the disease. 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, leading to the hypothesis that autoimmunity may arise in genetically susceptible individuals,[11] but there is no clinical data to support this hypothesis yet.
References
- ^ a b "ABC News: Swine Flu Vaccine: What The Heck Is an Adjuvant, Anyway? (2009)". Abcnews.go.com. 2009-08-11. Retrieved 2010-06-14.
- ^ a b "Definition of immunological adjuvant -- NCI Dictionary of Cancer Terms". www.cancer.gov. Retrieved 2010-08-27.
- ^ a b "Adjuvants as stabilizing agents". Benchmark Biolabs, Inc. Archived from the original on 2012-09-01. Retrieved 2013-05-19.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - ^ "Boostrix Prescribing Information" (pdf). GlaxoSmithKline. 2009. Retrieved 2013-05-19.
- ^ Clapp, Tanya; Siebert, Paul; Chen, Dexiang; Jones Braun, Latoya (2011). "Vaccines with aluminium-containing adjuvants: Optimizing vaccine efficacy and thermal stability". Journal of Pharmaceutical Sciences. 100 (2): 388–401. doi:10.1002/jps.22284. PMC 3201794. PMID 20740674.
- ^ Leroux-Roels G (31 August 2010). "Unmet needs in modern vaccinology adjuvants to improve the immune response". Vaccine. 28 (S3): C25-3. doi:10.1016/j.vaccine.2010.07.021. PMID 20713254.
- ^ Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM (March 2012). "Antigen depot is not required for alum adjuvanticity". FASEB J. 26: 1272–1279. doi:10.1096/fj.11-184556. PMC 3289510. PMID 22106367.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Jones, Stacy V. (19 September 1964). "Peanut Oil Used in a New Vaccine". New York Times. Retrieved 27 August 2017.
- ^ Smith JW, Fletcher WB, Peters M, Westwood M, Perkins FJ (1975). "Response to influenza vaccine in adjuvant 65-4". J Hyg (Lond). 74: 251–9. doi:10.1017/s0022172400024323. PMC 2130368. PMID 1054729.
- ^ Marrack, Philippa; Amy S. McKee; Michael W. Munks (2009). "Towards an understanding of the adjuvant action of aluminium". Nature Reviews Immunology. 9 (4): 287–293. doi:10.1038/nri2510. ISSN 1474-1733. PMC 3147301.
- ^ a b Masoudi, Sanita; Daniela Ploen; Katharina Kunz (23 May 2014). "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". Vaccine. 32 (5): 2980–2988. doi:10.1016/j.vaccine.2014.03.085. ISSN 1474-1733. PMID 24721530.