Adjuvants are ingredients used in some vaccines to enhance the immunogenicity of antigens (immunogens). Adjuvants are used to boost the immune response when an antigen has low immunogenicity or when a small amount of antigen is available. For example, the antibody response of mice to immunization with bovine serum albumin (BSA) can be increased fivefold or more if the BSA is administered with an adjuvant.
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Functions of Adjuvants
The precise mechanism of action of adjuvants is not entirely known but it is postulated that adjuvants exert one or more of the following effects to augment immune response;
- Prolongs antigen persistence
- Enhance co-stimulatory signals
- Increases local inflammation and formation of granuloma
- Stimulate nonspecific proliferation of lymphocytes
- Stimulate Toll-like receptors on the surface of macrophages. This results in cytokine production (such as IL-12) that enhances the response of T cells and B cells to the immunogen.
Types of Adjuvants
Several different adjuvants are now available and have been used safely in vaccines. Some of the commonly used adjuvants are as follows;
- Freund’s incomplete adjuvant
- Freund’s complete adjuvant
- Mycobacterium tuberculosis
- Bordetella pertusis
- Bacterial lipopolysaccharide (LPS)
- Synthetic polynucleotides (poly IC/poly AU)
- Other adjuvants
For example, aluminum salts and Freund’s adjuvants stimulate a local chronic inflammatory response that attracts both phagocytes and lymphocytes. This infiltration of cells at the site of injection results in the formation of a dense, macrophage-rich mass of cells called a granuloma. The formation of granuloma enhances the activation of TH cells.
Aluminum salts such as aluminum potassium sulfate (alum), aluminum phosphate, aluminum hydroxide, and aluminum hydroxyphosphate sulfate (AAHS) are being used safely in vaccines since the 1930s to enhance the body’s immune response to vaccines. Aluminum is not used by the body and is gradually eliminated through the kidneys.
Alum prolongs the persistence of antigen. When an antigen is mixed with alum, the salt precipitates the antigen. Injection of this alum precipitate results in a slower release of antigen from the injection site so that the effective time of exposure to the antigen increases from a few days without adjuvant to several weeks with adjuvant. The alum precipitate also increases the size of the antigen, thus increasing the probability of phagocytosis.
Aluminum adjuvants are used in various vaccines such as Hepatitis A (Havrix), Hepatitis B (Recombivax), HPV (Gardasil 9), Japanese encephalitis (Ixiaro), and pneumococcal vaccine (Prevnar 13), etc.
Freund’s Incomplete Adjuvant
It contains antigen in an aqueous solution, mineral oil, and emulsifying agents such as mannide monooleate. Mannide monooleate disperses the oil into small droplets which surround the antigen. This causes a slow release of antigen from the site of injection.
Freund’s adjuvants are prohibited for human use.
Freund’s Complete Adjuvant
Freund’s complete adjuvant, formulated by Jules Freund, contains heat-killed Mycobacteria as an additional ingredient to Freund’s incomplete adjuvant. Muramyl dipeptide which is a component of mycobacterial cell wall activates macrophages. Activated macrophages express higher levels of class II MHC molecules and the membrane molecules of the B7 family. These changes increase antigen presentation and enhancement of co-stimulatory signals respectively, making Freund’s complete adjuvant far more potent than the incomplete form.
Bacterial lipopolysaccharide (LPS)
Bacterial lipopolysaccharides stimulate the nonspecific proliferation of lymphocytes. This increases the likelihood of antigen-induced clonal selection of lymphocytes.
Cervarix contains an adjuvant called AS04 (monophosphoryl lipid A + aluminum salt) that stimulates Toll-like receptors and thereby enhances antibody production.
MF59 is an oil-in-water emulsion adjuvant and licensed for use in pandemic and seasonal influenza vaccines in many countries. A virosome (or IRIV, immunopotentiating reconstituted influenza virosome) is a type of “artificial virus” that can be used to deliver vaccine antigens directly into a host cell. Influenza virosomes have been used for more than 10 years in commercial vaccines.
References and further readings