Vaccine Approaches To Protect against Group A Streptococcal Pharyngitis

Abstract

Streptococcal pharyngitis (or strep throat) is a common childhood disease affecting millions of children each year, but it is one of the only childhood diseases for which a vaccine does not exist. While for decades the development of a vaccine has been the center of attention in many laboratories worldwide, with some successes, no corporate development has yet to be initiated. The reason for this probably lies in our inability to conclusively identify the streptococcal molecule or molecules responsible for the heart cross-reactive antibodies observed in the serum of rheumatic fever patients. Without this specific knowledge, any streptococcal vaccine antigen is suspect and thus not the target for a billion-dollar investment, despite the fact that the exact role of cross-reactive antibodies in rheumatic fever is still questionable. This article will describe the development of several approaches to protect against Streptococcus pyogenes infections over the past several decades.

FIGURE 1

Proposed model of the M protein from M6 strain D471 (29, 85). The coiled-coil rod region extends about 60 nm from the cell wall with a short nonhelical domain at the NH2 terminus. The Pro/Gly-rich region of the molecule is found within the peptidoglycan (86). The membrane-spanning segment is composed of predominantly hydrophobic amino acids, and a short charged tail extends into the cytoplasm. Data suggest that the membrane anchor may be cleaved shortly after synthesis (86). The A-, B-, and C-repeat regions are indicated along with those segments containing conserved, variable, and hypervariable epitopes among heterologous M serotypes. Pepsin designates the position of a pepsin-susceptible site near the center of the molecule.

FIGURE 2

The extent of colonization and death of mice challenged with group A streptococci after oral immunization with M-protein conserved-region M6 peptides linked to CTB. The throats of orally immunized mice were swabbed each day after challenge with M14 streptococci, and the specimens were plated on blood plates to determine the extent of colonization compared with that of mice vaccinated with CTB only. Plates showing group A streptococci were scored as positive.

FIGURE 3

The extent of colonization and death of mice challenged with group A streptococci after oral immunization with recombinant vaccinia virus containing the gene for the whole conserved region of the M6 protein. The throats of orally immunized mice were swabbed each day after challenge with M14 streptococci, and the specimens were plated on blood plates to determine the extent of colonization compared with that of mice vaccinated with wild-type vaccinia only. Plates showing group A streptococci were scored as positive.

FIGURE 4

M protein-specific salivary IgA in rabbits colonized with S. gordonii expressing the conserved region on the cell surface. Salivary samples were taken after pilocarpine induction and tested in an enzyme-linked immunosorbent assay against the M protein.

FIGURE 5

M protein-specific serum IgG in rabbits colonized with S. gordonii expressing the conserved region on the cell surface. Blood samples were taken at weekly intervals and tested in ELISA against the M protein.