An important consideration in the development of vaccines is the mode of delivery. Development of vaccines against RF is focussed on the parenteral and the mucosal delivery of the vaccines.
Administration of adjuvant potentially enhances the efficacy of a vaccine and alum is one of the choices, although the magnitude of the antibody response happens to be suboptimal. Human-compatible adjuvants that induce strong antibody responses are being investigated.
It is generally believed that a mucosal vaccine is an optimal approach because the portal of entry of streptococcus is the nasopharynx. Fischetti38 investigated the role of IgA in immunity to group A streptococcal infection. Mice were protected against intranasal group A streptococcal challenge after passive transfer of affinity-purified human IgA to M protein M6. Mice immunized intranasally with conserved epitopes of M protein conjugated to the B unit of cholera could induce detectable levels of M-protein-specific salivary IgA and serum IgG, and these mice showed significant reduction in colonization by group A streptococcus after challenge with either the M6 or M24 group A streptococci. IgA specific for p145 is capable of opsonizing group A streptococcus in vitro in the presence of complement.158 Other successful oral vaccine strategies include use of genetically altered strains of Salmonella, Escherichia coli heated-labile toxin, and Streptococcus gordonii for delivery of recombinant M-protein antigens. If proven successful, the commensal delivery system would be ideal for developing countries. A live vector would be easy to administer and probably would not require additional doses. Also, since gram-positive bacteria are stable for long periods in the lyophilized state, a cold chain would not be required for S gordonii. S gordonii can persist for more than 2 years and is transmitted to other members of the family. This could be ideal for developing nations. However, it remains to be demonstrated whether the recombinant vaccine will induce a protective immune response in humans to the M-protein fragment expressed on its surface.
In summary, a streptococcal vaccine that evokes broad-spectrum immunity will have significant impact on populations living in areas of high endemicity with group A streptococci. The major problem with developing a vaccine for RF is the complexity of vaccine constructs. Epidemiologic data suggest that numerous serotypes of group A streptococci can induce RF. By using a limited number of serotypes and assuming 100% serotype specificity, the vaccines can at best prevent about three-fourths of the infections causing RF. Strain variation of M-protein structures means that the vaccines will be less efficacious. Another important determinant of serotype-specific M-protein vaccine efficacy is the proportion of strains within a population that is nontypeable. Although future studies in the laboratory should address issues related to strain variation of M proteins and the absolute number of serotypes within the nontypeable strains, ultimate determination of efficacy depends on the outcome of large-scale clinical trials. Clearly, epidemiologic data suggest that it may be necessary to reformulate vaccine constructs periodically to represent the most current serotypes prevalent at any given time, as is currently done for influenza vaccines. Finally, the most effective vaccine strategies may require the combination of M-protein vaccines with non-M-protein vaccines. Such vaccines may not prevent group A streptococcal infections but may have a significant impact on the devastating sequelae, particularly due to RF. Another important area is the ways in which the candidate vaccines can be delivered effectively. Development of an effective vaccine, therefore, is highly complicated but not outside the realm of possibility.
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