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ADJUVANTS
ОглавлениеTo enhance the immune response to a given immunogen, various additives or vehicles are often used. An adjuvant (from the Latin adjuvare, “to help”) is a substance that, when mixed with an immunogen, enhances the immune response against the immunogen. It is important to distinguish between a carrier for a hapten and an adjuvant. A hapten will become immunogenic when conjugated covalently to a carrier; it will not become immunogenic if mixed with an adjuvant. Thus an adjuvant enhances the immune response to immunogens but does not confer immunogenicity on haptens.
Adjuvants have been used to augment immune responses to antigens for more than 80 years. Interest in the identification of adjuvants for use with vaccines is growing because many new vaccine candidates lack sufficient immunogenicity. This is particularly true of peptide‐based vaccines. Adjuvant mechanisms include (1) increasing the biological or immunological half‐life of vaccine antigens; (2) increasing the production of local inflammatory cytokines; and (3) improving antigen delivery and antigen processing and presentation by APCs, especially the dendritic cells. Empirically, it has been found that adjuvants containing microbial components (e.g., mycobacterial extracts) are the best adjuvants. Pathogen components induce macrophages and dendritic cells to express co‐stimulatory molecules and to secrete cytokines. More recently, it has been shown that such induction by microbial components involves pattern recognition molecules (e.g., Toll‐like receptors [TLRs]) expressed by these cells. Thus binding of microbial components to TLRs signals the cells to express co‐stimulatory molecules and to release cytokines.
Over the past decades, strategies for the development and delivery of vaccine antigens have expanded. Some of these antigens are weakly immunogenic and require the presence of adjuvants for the induction or enhancement of an adequate immune response. Vaccines with aluminum‐based adjuvants have been extensively used in immunization programs worldwide and a significant body of safety information has accumulated for them. As knowledge of immunology and the mechanisms of adjuvant action have expanded, the number of vaccines containing novel adjuvants being evaluated in clinical trials has increased. Vaccines containing adjuvants other than aluminum‐containing compounds have been authorized for use in several countries, and a number of vaccines with novel adjuvants are currently under development, including, but not limited to, vaccines against human papillomavirus (HPV), human immunodeficiency virus (HIV), malaria, and tuberculosis, as well as next‐generation vaccines against influenza and other diseases.
However, the development and evaluation of new adjuvants, as well as so‐called adjuvanted vaccines (compound reagents administered as a single reagent compared with vaccines that are mixed with an adjuvant right before they are used for vaccination), present regulatory challenges. Vaccine manufacturers and regulators have questions about the type of information and extent of data that would be required to support proceeding to clinical trials with adjuvanted vaccines and to their eventual authorization. Obviously, this is beyond the scope of our discussion here, but it is important to understand that we face scientific and regulatory challenges in our efforts to develop new, efficacious, and safe adjuvants for future use.
While many adjuvants have been developed in animal models and tested experimentally in humans, only one type of adjuvant has been approved by the US Food and Drug Administration (USFDA) for routine vaccination. Currently, aluminum hydroxide and aluminum phosphate (alum) are the major adjuvants used for licensed human vaccines administered to normal individuals in the United States. As an inorganic salt, alum binds to proteins, causing them to precipitate, and 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.
