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Vaccines for the 21st Century: A Tool for Decisionmaking
are highly conserved from one serotype to another. These conserved epitopes are exposed on the surface of the organism and available for antibody binding. Researchers have shown that antibodies to these C-repeat epitopes can block adherence and colonization, and thus prevent infection, in the mouse model. In this experiment, mice were immunized intranasally with peptide from the C-repeat region of type 5 streptococcus and then challenged with the heterologous type 24 streptococcus. The experimental group showed a higher level of survival and a lower level of colonization compared with controls. While this approach will work, however, it is questionable whether it should be the sole basis for streptococcal vaccines.
There are potential vaccine constructs that might be effective against Type A streptococci. Data on the octavalent vaccine suggest that these high complex hybrid molecules can maintain the conformations that stimulate B-cells to produce the relevant antibodies, and researchers have plans to construct a dodecavalent gene and protein. Linking this multivalent protein to LT-B or another carrier that serves as a mucosal adjuvant would provide for both opsonic and secretory antibodies, or a “cocktail” of monovalent terminal fragments could be mixed together according the epidemiology of the organism. C-repeat fragments linked to a carrier might provide broader, more flexible protection. A strategy that deserves attention in the future is the combination of amino terminal fragments (which evoke opsonic antibodies) and C-repeat epitopes (which evoke IgA that can block colonization); this combination might afford the broadest protective immunity in ultimate vaccine trials.
In response to questions from the audience, Dr. Dale added the following:
The best candidate at present is the type-specific amino terminal approach. Researchers have had unexpected success with these epitopes, which often evoke a better immune response when buried in the middle of a hybrid molecule than when they are on the end.
Researchers have not yet tested any of these approaches in humans. A great deal of pure development remains to be done, including the preclinical studies that will be needed to convince FDA that these complex constructs are safe.
It would be desirable to take a candidate vaccine into limited Phase I trials within 5 years.
The goal of the vaccine is not just to prevent rheumatic fever and other serious disease, but to prevent streptococcus infection in general. Types 2, 4, and 12 are not particularly rheumatogenic but are highly prevalent; by incorporating them in a multivalent vaccine, it might be possible to have a broad impact on disease.
The target population for the vaccine is preschool children. If they can be immunized before kindergarten, it might be possible to have an impact on overall incidence.
In addition to common C-repeats, the so-called M5 family (M5, M6, M18, M19, and others) also has common B-repeats, and these conserved epitopes are opsonic.