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Appendix D-16: The Prospects for Immunizing Against Streptococcus Group A
Pages 338-356

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From page 338...
... The impetus for vaccine development, however, stems from the propensity of the organism to elicit the delayed nonsuppurative sequelae of acute rheumatic fever (ARF) and acute post-streptococcal glomerulonephritis (AGN)
From page 339...
... Individuals with "pure" chorea represent an exception to this rule, because 25 percent of them may go on to develop rheumatic heart disease. Although the figures vary widely, in most modern studies about 50 percent of patients diagnosed as having ARF experience some carditis during the acute attack.
From page 340...
... The manner in which M protein exerts its anti-phagocytic effect is under investigation. The protein prevents interaction of the streptococcal cell wall with complement components, an effect that is enhanced by the ability of M protein to precipitate fibrinogen directly onto the bacterial surface.
From page 341...
... HOST IMMUNE RESPONSE During the course of human infection, the host mounts both humor al and delayed immune responses to a wide variety of streptococcal somatic and extracellular products. Patients with ARF are apparently hypersensitive to streptococcal antigens, because their mean antibody titers are significantly higher than similar titers among individuals with uncomplicated GrAS infection.
From page 342...
... Details of such studies are outlined below in the section on prospects for vaccine development. Although the pathogenesis of ARF remains unknown, most authorities believe that the disease results from host immune responses to certain streptococcal antigens that share antigenic determinants with human host tissues.
From page 343...
... In contrast, morbidity and mortality of ARF and rheumatic heart disease have declined markedly in western Europe and North America, a decline that appears to have begun prior to the antibiotic era and is best documented in the Scandinavian data (Stollerman, 1975~. While similar sequential data are lacking for most cities in the United States, one has only to query older physicians or to observe the closing of the famous rheumatic fever sanatoriums of the past to perceive how much the rate has fallen in certain areas.
From page 344...
... . The contribution of minor GrAS infections to the total disease burden has not been considered in this analysis.
From page 345...
... . Already, the WHO has major programs in most developing countries of the world related to prevention of rheumatic heart disease by secondary prophylaxis.
From page 347...
... SUITABILITY FOR VACCINE CONTROL Because of the limitations inherent in currently available preventive measures and because of the devastating consequences of rheumatic fever throughout the developing world, new and innovative approaches to control are required. Clearly, the most appealing of such approaches, both theoretically and practically, would be the development of a safe and effective GrAS vaccine.
From page 348...
... Recent studies of the immunogenicity of polypeptide fragments of M protein liberated from whole type 24 group A streptococci by limited peptic digestion have been promising. The purified extracts lacked detectable heart cross-reactive antigens, but retained protective determinants as demonstrated by vaccination of laboratory animals (Beachey et al., 1974, 1977)
From page 349...
... Third, purified subpeptides derived by cyanogen bromide cleavage of type 24 M protein each evoked protective antibodies against the homologous serotype of streptococci (Beachey et al., 1980~. Finally, two chemically synthesized, 35-residue peptide fragments of pep M24 were shown to evoke similar type-specific protective antibodies without eliciting heart-reactive antibodies (Beachey et al., 1981a, 1983~.
From page 350...
... In opsono-bactericidal assays using types 5, 6, and 24 streptococci, the immune sera were capable of promoting phagocytosis of and killing only the type 24 streptococc', indicating that the humoral immune responses to S-CB7 were type-specific (Beachey et al., 1980~. Immunodiffusion tests of the immune sera revealed precipitin arcs of identity between w~lls containing polylysine conjugates of native and synthetic CB7, as well as with the intact pep M24.
From page 351...
... rendered this protective peptide nonprotective (Dale et al., 1980~. In contrast to the high degree of type-specificity of the humoral immune responses to each of the synthetic peptides, the cellular immune responses were highly cross-reactive.
From page 352...
... that predict which antigenic regions to isolate or synthesize based on the relative hydrophilicity of various peptide regions as determined by their amino acid sequences. At the time of publication, phase 1 studies in humans on tetanus toxoid conjugated M protein peptides were expected to begin shortly and plans for more extensive efficacy trials, possibly to be conducted in India and Chile, were being prepared (National Institute of Allergy and Infectious Diseases, 19851.
From page 353...
... 1983. Repeating covalent structure and protective immunogenicity of native and synthetic polypeptide fragments of type 24 streptococcal M protein.
From page 354...
... 1982. Hybridoma antibodies against protective and nonprotective antigenic determinants of a structurally defined polypeptide fragment of streptococcal M protein.
From page 355...
... 1980a. Studies on group A streptococcal M-proteins: Purification of type 5 M-protein and comparison of its amino terminal sequence with two immunogenically unrelated M-protein molecules.
From page 356...
... 1980. Community control of rheumatic heart disease in developing countries.


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