100,000 to 10 or 15 per 100,000. An outbreak of rheumatic fever in Utah has been continuing since the mid-1980s. At the same time, there has been an increase in more serious infections—not just pharyngitis and impetigo without complications, but loss of limbs and even of lives. CDC estimates that there are 15,000 to 20,000 cases of serious streptococcal infection per year in the United States, with mortality of anywhere from 30 to 50 percent. In developing nations, meantime, acute rheumatic fever and life-threatening streptococcal infections continue to be as serious a problem as ever.

Rationale for a Surface M Protein-Based Vaccine. There are several potential antigens for vaccines, but over the years the surface M protein has produces the best evidence for protective immune responses. The surface M protein is a major virulence factor of Group A streptococci, since organisms that are rich in M protein are able to resist phagocytosis in the nonimmune host. Significantly, antibodies to M protein are opsonic.

Given these characteristics, the logical approach would be to extract M proteins from the various serotypes of Group A streptococci and combine them into a vaccine. There are three significant obstacles to this approach:

1. Some of the extracellular products that co-purify with M protein preparations are highly toxic. This obstacle has been overcome by recombinant vaccine technology.

2. There are over 80 serotypes of Group A streptococci, all of which express slightly different M proteins, and it would be extremely difficult to concoct a vaccine containing all 80 M proteins. However, there is evidence that the most serious infections can be prevented by a vaccine containing as few as 14 or 16 different M proteins.

3. Most serious of all, some M proteins contain autoimmune (tissue-crossreactive) epitopes and could theoretically trigger acute rheumatic fever, although there is no direct evidence of their role in the pathogenesis of that disease. For example, antibodies to type 5 M protein bind to human myocardium; antibodies to type 6 bind to neurofibers in human brain tissue; and antibodies to type 18 bind to the surface and chondrocytes of mouse joint bone. Among the other host antigens with which M proteins crossreact are myosin, vimentin, keratin, actin, tropomyosin, phosphorylase, DNA, and a large number of undefined antigens.

The latter obstacle led researchers to undertake 15 years of studies to identify which regions of the M protein evoke opsonic (i.e., protective) antibodies and which regions contain autoimmune or potentially harmful epitopes.

Structural and Functional Domains of M Proteins. A generic M protein, which protrudes from the surface of a Group A streptococcus with the amino terminus outward and the carboxy terminus buried in the cytoplasm, is a highly alpha-helical (coiled coil) molecule whose central rod typically contains internal repeats. However, the exposed amino terminus is nonhelical.

In general, the amino terminus usually contains the epitopes that evoke antibodies with the greatest serotypic specificity and bacteriocidal activity. By