GROUP A STREPTOCOCCAL VACCINES*
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VACCINE RATIONALE
Streptococcal vaccine development has been ongoing for over 60 years. There are currently several different approaches being investigated, which can be divided into two broad categories of vaccines: (1) those containing virulence determinants that are conserved among the different serotypes of GrAS; and (2) those based on type-specific protective regions of the surface M proteins. Strategies for vaccine development are based on our present understanding of the pathogenesis of GrAS infections
COMMON PROTECTIVE ANTIGENS OF GrAS
Several of the virulence determinants referred to previously contain common epitopes shared by most or all serotypes of GrAS and are actively being evaluated as potential vaccine candidates. C5a-peptidase is expressed by at least 40 different serotypes of GrAS. The peptidase specifically cleaves C5a, which inactivates its ability to attract PMNs into the site of infection. Thus, it is reasoned that the presence of neutralizing antibodies against this streptococcal enzyme would protect against
VACCINES BASED ON TYPE-SPECIFIC, N-TERMINAL REGIONS OF M PROTEINS
All of the vaccine candidates described previously are common antigens or peptides that are designed to evoke broadly protective immune responses after immunization. Although there are sufficient data in animals to suggest that these virulence determinants may contribute to protective immune responses, the observation remains that most individuals acquire more than one streptococcal infection in a lifetime. GrAS have evolved a complex array of type-specific, protective M-protein epitopes that
RATIONALE FOR VACCINES CONTAINING N-TERMINAL M-PROTEIN FRAGMENTS
Early studies had shown that the pepsin-derived fragment of type-5 M protein evoked opsonic antibodies as well as heart cross-reactive antibodies.10, 11 Some of the heart cross-reactive antibodies also reacted with heterologous M proteins, including types 6, 18, and 19, indicating the presence of shared autoimmune epitopes. Structural analyses confirmed that the N-terminal regions of M proteins were hypervariable and could account for type-specific immune responses.16 Thus, it was reasoned that
RECOMBINANT, MULTIVALENT M-PROTEIN–BASED VACCINES
We have used recombinant techniques to produce complex hybrid proteins containing N-terminal peptides of M proteins from different serotypes of GrAS.13, 14, 15 We first constructed a tetravalent gene that encoded defined N-terminal fragments of M24, M5, M6, and M19 (Fig. 2).13 Polymerase chain reaction (PCR) primers were synthesized to amplify specific 5′ sequences of each emm gene, and each primer was extended to contain a unique restriction enzyme site used to ligate the individual PCR
MUCOSAL DELIVERY OF RECOMBINANT M-PROTEIN–BASED VACCINES
The recombinant hybrid proteins described previously were designed to evoke opsonic antibodies following parenteral injection. Another approach is to develop M-protein vaccines that may be delivered via mucosal routes in order to evoke secretory antibodies as well as serum opsonic antibodies. In initial experiments, a hybrid gene was constructed encoding the entire B subunit of E. coli labile toxin (LT-B) linked to 15 N-terminal amino acids of type-5 protein (Fig. 6).12 In this construct, LT-B
COMPLEXITY AND VALENCE OF M-PROTEIN–BASED VACCINES
The approach of using N-terminal fragments of M proteins in multivalent vaccines construct carries with it concerns of complexity and valence. There are currently over 90 different serotypes of GrAS, all of which by definition have different N-terminal M-protein sequences. Certainly, a vaccine designed to prevent all of these infections would be highly complex. Epidemiologic data suggest, however, that not all serotypes of GrAS have the ability to trigger acute rheumatic fever.5 In addition,
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Address reprint requests to James B. Dale, MD, VA Medical Center (11A), 1030 Jefferson Avenue, Memphis, TN 38104
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These studies were supported by research funds from the Department of Veterans Affairs, from the US Public Health Service, NIH grant AI-10085, and from ID Vaccine Corporation, Seattle, Washington
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Division of Infectious Diseases, University of Tennessee, and VA Medical Center, Memphis Tennessee