Vaccine Design in Relation with theImmune Response
For the rational design of a new vaccine, under-standing of the mechanisms of the protective immunity to the pathogen against which the vaccine is developed is crucial. For instance, to prevent tetanus a high blood titer of antibody against tetanus toxin is required; in mycobacterial diseases such as tubercu-losis a macrophage-activating CMI is most effective; in case of an influenza virus infection CTLs probably play a significant role. Importantly, the immune effector mechanisms triggered by a vaccine and, hence, the success of immunization not only depend on the nature of the protective components but also on their presentation form, the presence of adjuvants, and the route of administration.
The presentation form of the vaccine is one of the determinants that influence the extent and type of immune response that will be evoked (Pashine et al., 2005; Pulendran and Ahmed, 2006). DCs and other APCs play a pivotal role in how the antigenic determinants of a vaccine will be processed and presented to T-cells in the peripheral lymphoid organs. Through various PRRs, DCs are more or less able to “sense” the type of pathogen that is encoun-tered. This determines the set of co-stimulatorysignals and pro-inflammatory cytokines that will be generated by APCs when presenting the antigen to Th-cells in the peripheral lymphoid organs. For instance, pathogens or vaccines containing lipopro-teins or peptidoglycans will trigger DCs via TLR-2, which predominantly generates a Th2 response, whereas stimulation of DCs through TLR-3, -4, -5 or -8 is known to yield robust Th1 responses. Therefore, vaccines should be formulated in such a way that the appropriate Th response will be triggered. This can be done by presenting the antigen in its native format, as is the case for the conventional vaccines, or by adding adjuvants that stimulate the desired response (see below).
The response by B-cells is dependent upon the nature of the antigen and two types of antigens can be distinguished:
1. Thymus-independent antigens include certain linear antigens that are not readily degraded in the body and have a repeating determinant, such as bacterial polysaccharides. They are able to stimulate B-cells without the Th-cell involvement. Thymus-independent antigens do not induce immunological memory.
2. Thymus-dependent antigens provoke little or no antibody response in animals with few T-cells. Proteins are the typical representatives of thymus-dependent antigens. A prerequisite for thymus-dependency is that a physical linkage exists between the sites recognized by B-cells and those by Th-cells. When a thymus-independent antigen is coupled to a carrier protein containing Th-epitopes, it becomes thymus-dependent. As a result, these conjugates are able to induce memory.
When the antigen is a protein, the epitopes can be continuous or discontinuous. Continuous epitopes involve linear peptide sequences (usually consisting of up to ten amino acid residues) of the protein (Fig. 7A). Discontinuous epitopes comprise amino acid residues sometimes far apart in the primary sequence, which are brought together through the unique folding of the protein (Fig. 7B). Antibody recognition of B-cell epitopes, whether continuous or discontinuous, is usually dependent on the conforma-tion (¼ three-dimensional structure). T-cell epitopes, on the other hand, are continuous peptide sequences, the conformation of which does not seem to play a role in T-cell recognition.