Immunology. Richard Coico
elicits an inflammatory response that nonspecifically increases the immunogenicity of the antigen. When injected, the precipitated antigen is released more slowly at the injection site than antigen alone. Moreover, the increased size of the antigen, which occurs as a consequence of precipitation, increases the probability that the macromolecule will be phagocytized.
Many adjuvants have been used in experimental animals. One commonly used adjuvant is Freund’s complete adjuvant consisting of killed Mycobacterium tuberculosis or M. butyricum suspended in oil, which is then emulsified with an aqueous antigen solution. The oil‐emulsified state of the adjuvant–antigen mixture allows the antigen to be released slowly and continuously, helping sustain the recipient’s exposure to the immunogen. Other microorganisms used as adjuvants are bacille Calmette–Guérin (BCG) (an attenuated Mycobacterium), Corynebacterium parvum, and Bordetella pertussis. In reality, many of these adjuvants exploit the activation properties of microbe‐expressed molecules including lipopolysaccharide (LPS), bacterial DNA containing unmethylated CpG dinucleotide motifs, and bacterial heat‐shock proteins. Many of these microbial cell adjuvants bind to pattern‐recognizing signaling receptors such as the TLRs. Ligation of TLRs indirectly activates adaptive B‐ and T‐cell responses. Dendritic cells are important APCs involved in the activity of microbial adjuvants. They respond by secreting cytokines and expressing co‐stimulatory molecules that, in turn, stimulate the activation and differentiation of antigen‐specific T cells.
Table 5.2 lists the majority of currently used adjuvants, some of which are still being tested in clinical trials.
TABLE 5.2. Adjuvants Currently Licensed for Use in the United States and Those Under Development for Clinical Trials
| Adjuvant name (year licensed) | Adjuvant class | Components | Vaccines (disease) |
|---|---|---|---|
| Adjuvants licensed for use in human vaccines | |||
| Aluma(1924) | Mineral salts | Aluminum phosphate/aluminum hydroxide | Various |
| MF (Novartis; 1997) | Oil in water emulsion | Squalene, polysorbate 80 (Tween 80; ICI Americas), sorbitan trioleate (Span 85; Croda International) | Fluad (seasonal influenza), Aflunov (prepandemic influenza) |
| AS03 (GlaxoSmithKline; 2009 | Oil in water emulsion | Squalene, Tween 80, α‐tocopherol | Pandremix (pandemic influenza), Prepandrix (prepandemic influenza) |
| Virosomes (Berna Biotech; 2000 | Liposomes | Lipids, hemagglutinin | Inflexal (seasonal influenza), Epaxal (hepatitis A) |
| AS04a (GlaxoSmithKline; 2005) | Alum‐absorbed TLR4 agonist | Aluminum hydroxide, MPL | Fendrix (hepatitis B), Cervarix (human papilloma virus) |
| Adjuvants under development or being tested in clinical trials but not licensed for use | |||
| Cp 7909, CpG 1018 | TLR agonist | CpG oligonucleotides alone or combined with alum/emulsions | — |
| Imidazoquinolines | TLR7 and TLR8 agonists | Small molecules | — |
| PolyI:C | TLR3 agonist | Double‐stranded RNA analogs | — |
| Pam3Cys | TLR2 agonist | Lipopeptide | — |
| Flagellin | TLR5 agonist | Bacterial protein linked to antigen | — |
| Iscomatrix | Combination | Saponin, cholesterol, dipalmitoylphosphatidylcholine | — |
| AS01 | Combination | Liposome, MPL, saponin (QS21) | — |
| AS02 | Combination | Oil in water emulsion, MPL, saponin (QS21) | |
| AF03 | Oil in water emulsion | Squalene, Montane 80, Eumulgin B1 PH | — |
| CAF01 | Combination | Liposome, DDA, TDB | — |
| Chitosan | Induced type I interferons | Cationic polysaccharide | |
a Adjuvants licensed in the United States. AF03 adjuvant formulation 03; CAF01, catonic adjuvant formulation 01; DDA, dimethyldioctadecylammonium; MPL, monophosphoryl lipid A; Pam3Cys, tripalmitoyl‐S‐gylceryl systeine; PolyI:C, polyinosinic‐polycytidylic acid; TDB trehalose dibehenate; TLR, Toll‐like receptor.
SUMMARY
1 Immunogenicity is the capacity of a compound to induce an immune response. Immunogenicity requires that a compound (a) be foreign to the immunized individual, (b) possesses a certain minimal molecular weight, (c) possesses a certain degree of chemical complexity, and (d) be degradable or susceptible to antigen processing and presentation through its interaction with MHC.
2 Antigenicity refers to the ability of a compound to bind with antibodies or with cells of the immune system. This binding is highly specific; the immune components are capable of recognizing various physicochemical aspects of the compound. The binding between antigen and immune components involves several weak forces operating over short distances (van der Waals forces, electrostatic interactions, hydrophobic interactions, and hydrogen bonds); it does not involve covalent bonds.
3 The smallest unit of antigen that is capable of binding with antibodies and T cells is called an antigenic determinant or epitope. Compounds may have one or more epitopes capable of reacting with immune components. The immune response against these compounds involves the production of antibodies or the generation of cells with specificities directed against most or all of the epitopes.
4 B‐cell membrane immunoglobulin or secreted antibody tends to recognize amino acid sequences that are accessible, usually hydrophilic, and mobile.