New multi-determinant strategy for a group A streptococcal vaccine designed for the Australian Aboriginal population

Infection with group A streptococci can result in acute and postinfectious pathology, including rheumatic fever and rheumatic heart disease. These dis eases are associated with poverty and are increasing in incidence, particul arly in developing countries and amongst indigenous populations, such as Au stralia's Aboriginal population, who suffer the highest incidence worldwide (1). Immunity to group A streptococci is mediated by antibodies against the M protein, a coiled-coil alpha helical surface protein of the bacterium(2) . Vaccine development(3-5) faces two substantial obstacles. Although opsoni c antibodies directed against the N terminus of the protein are mostly resp onsible for serotypic immunity, more than 100 serotypes exist. Furthermore, whereas the pathogenesis of rheumatic fever is not well understood, increa sing evidence indicates an autoimmune process(6,7). To develop a suitable v accine candidate, we first identified a minimum, helical, non-host-cross-re active peptide from the conserved C-terminal half of the protein and displa yed this within a non-M-protein peptide sequence designed to maintain helic al folding and antigenicity, J14 (refs. 8,9). As this region of the M prote in is identical in only 70% of group A streptococci isolates(10), the optim al candidate might consist of the conserved determinant with common N-termi nal sequences found in communities with endemic group A streptococci. We li nked seven serotypic peptides with J14 using a new chemistry technique that enables the immunogen to display all the individual peptides pendant from an alkane backbone. This construct demonstrated excellent immunogenicity an d protection in mice.