Immunology. Richard Coico
of antigen with both B and T cells and subsequent activation events are discussed in Chapters 9 and 10. At this point, it is only important to emphasize that the binding of antigen with antibodies or TCRs does not involve covalent bonds. The noncovalent binding may involve electrostatic interactions, hydrophobic interactions, hydrogen bonds, and van der Waals forces. Since these interactive forces are relatively weak, the fit between antigen and its complementary site on the antigen receptor must occur over an area large enough to allow the summation of all the possible available interactions. This requirement is the basis for the exquisite specificity observed in immunological interactions.
CROSS‐REACTIVITY
Since macromolecular antigens contain several distinct epitopes, some of these antigens can be altered without totally changing the immunogenic or antigenic structure of the entire molecule. This concept is important in relation to immunization against highly pathogenic microorganisms or highly toxic compounds. Obviously, immunization with the pathogenic toxin is unwise. However, it is possible to destroy the biological activity of such toxins and a broad variety of other toxins (e.g., snake venoms) without appreciably affecting their immunogenicity.
A toxin that has been modified to the extent that it is no longer toxic but still maintains some of its immunochemical characteristics is called a toxoid. Thus we can say that a humoral immune response to a toxoid cross‐reacts immunologically with the toxin. Accordingly, it is possible to immunize individuals with the toxoid and thereby induce immune responses to some of the epitopes that the toxoid still shares with the native toxin because these epitopes have not been destroyed by the modification. Although the molecules of toxin and toxoid differ in many physicochemical and biological respects, they nevertheless cross‐react immunologically; they share enough epitopes to allow the immune response to the toxoid to mount an effective defense against the toxin itself.
An immunological reaction in which the immune components, either cells or antibodies, react with two molecules that share epitopes but are otherwise dissimilar, is called a cross‐reaction. When two compounds cross‐react immunologically, the compounds will have one or more epitopes in common, and the immune response to one of the compounds will recognize one or more of the same epitope(s) on the other compound and react with it. Another form of cross‐reactivity is seen when antibodies or cells with specificity to one epitope bind, usually more weakly, to another epitope that is not quite identical but has a structural resemblance to the first epitope.
To denote that the antigen used for immunization is different from the one with which the induced immune components are then allowed to react, the terms homologous and heterologous are used. Homologous denotes that the antigen and the immunogen are the same; heterologous denotes that the substance used to induce the immune response is different from the substance that is then used to react with the products of the induced response. In the latter case, the heterologous antigen may or may not react with the immune components. If reaction does take place, it may be concluded that the heterologous and homologous antigens exhibit immunological cross‐reactivity.
Although the hallmark of immunology is specificity, immunological cross‐reactivity has been observed on many levels. This does not mean that the immunological specificity has been diminished but rather that the substances that cross‐react share antigenic determinants (epitopes). In cases of cross‐reactivity, the antigenic determinants of the cross‐reacting substances may have identical chemical structures, or they may be composed of similar but not identical physicochemical configurations. In the example described above, a toxin and its corresponding toxoid represent two molecules: the toxin is the native molecule and the toxoid is a modified molecule, the response to which cross‐reacts with the native molecule.
There are other examples of immunological cross‐reactivity, wherein the two cross‐reacting substances are unrelated to each other except that they have one or more epitopes in common, specifically, one or more areas that have similar three‐dimensional characteristics. These substances are referred to as heterophile antigens. For example, human blood group A antigen reacts with antiserum raised against pneumococcal capsular polysaccharide (type XIV). Similarly, human blood group B antigen reacts with antibodies to certain strains of Escherichia coli. In these examples of cross‐reactivity, the antigens of the microorganisms are referred to as the heterophile antigens (with respect to the blood group antigen).
ADJUVANTS
To 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