Successful vaccine discovery is highly dependent on an effective antigen selection process. The best antigen candidates are proteins with the following characteristics (Figure 1):
- Well exposed to immune system (ideally on the bacterial cell surface)
- Stimulate B and T cell activation (are highly immunogenic)
- Induce antibodies capable of mobilizing immune responses, killing the pathogen or otherwise interfering with its function and neutralizing growth
The importance of selecting surface-expressed antigens accessible to the immune system for vaccine development.
- Immune cells primed by vaccine antigens that are easily accessible on the surface of a pathogen, can rapidly detect and respond to the live pathogen when encountered.
- After encountering the target antigen, B cells become activated and secrete antigen-specific antibodies.
- The secreted antibodies bind to the antigen exposed on the bacterial surface, inducing complement activation that leads to opsonization and uptake by phagocytes (or lysis in the case of non-encapsulated Gram negative bacteria which have a thinner cell membrane).
- Phagocytic cells recognize, take up, and digest the opsonized bacteria, generating additional antigenic fragments and mobilizing additional immune defenses.
- This process leads to the amplification of the immune response against the pathogen.
B cell = the immune cell which expresses and secretes antibodies; APC = antigen presenting cell or phagocyte
Identifying the best antigens from thousands of potential candidates is not an easy task. Currently there is no simple and reliable method for rapid screening of thousands of antigen candidates to immediately identify those with a desired protective function.
To reduce the complexity, current antigen discovery technologies initially pre-select a smaller set of potential antigen candidates primarily based on an indirect or a hypothesis-driven approach (sequence analysis, localization and function prediction algorithms, proteomics, serum antibody binding to pathogen encoded cDNA libraries or T cell epitope prediction).
However, selecting antigen candidates initially without functional testing bares the risk of selecting antigens which fail the functional tests which are performed in later stages of the project, after significant resources have been invested.