Group A Streptococcus Epidemiology and Vaccine Implications

Group A Streptococcus (GAS ) species are responsible for a wide variety of human diseases that range from noninvasive, mild infections, such as pharyngitis and impetigo, to life-threatening, invasive conditions, such as bacteremia, pneumonia, necrotizing fasciitis (NF), and streptococcal toxic shock syndrome (STSS). In addition, GAS is responsible for nonsuppurative sequelae of infection—specifically, acute rheumatic fever and poststreptococcal glomerulonephritis. The global impact of disease has been estimated to be >500,000 deaths per year, primarily due to rheumatic fever, rheumatic heart disease, and invasive GAS infection. These figures place GAS among the world's major human pathogens, exceeded only by HIV, Mycobacterium tuberculosis, Plasmodium falciparum, and Streptococcus pneumoniae, with mortality rates comparable to those for rotavirus infection, measles, Haemophilus influenzae type b infection, and hepatitis [1]. A previous report by the Centers for Disease Control and Prevention Active Bacterial Core surveillance (ABCs) system estimated that the rate of invasive GAS disease in the United States during 1995–1999 was 3.1–3.8 cases per 100,000 population, resulting in 9000–11,000 cases and 1000–1700 deaths per year, with a case-fatality rate of 11.7%–14.8% [2]. These rates are comparable to those reported in other developed countries in North America and Europe [3, 4]. GAS is the most common bacterial cause of acute pharyngitis, accounting for 15%–30% of childhood cases and 10% of adult cases. These cases place a high burden on the health care system and society as a result of doctor's visits, treatment costs, and the loss of working days. Although the incidence of acute rheumatic fever in the industrialized world has decreased during the past 50 years, several outbreaks in civilian communities and military camps have been reported [5,6,7,8,9–10], and acute rheumatic fever remains a major cause of morbidity in the developing world, with an estimated 471,000 cases annually [1]. Primary prevention of acute rheumatic fever with early antibiotic treatment is beneficial in individual cases but not for controlling the disease in the developing world; secondary prevention of acute rheumatic fever is not yet feasible in the developing world. Strategies for prevention of invasive GAS disease, although limited, include infection-control measures and prevention of secondary cases among postpartum and postsurgical patients [11]. These facts, together with the high global disease burden, provide the rationale and emphasize the need for further vaccine development. Attempts to immunize humans against GAS started in the 1930s. Intravenous administration of killed GAS to children with rheumatic fever resulted in a decrease in recurrence rates [12]. Rebecca Lancefield's [13] recognition of the role of the GAS surface M protein in both virulence and immunity led to studies of humans that demonstrated a protective immune response evoked by vaccines that contained purified M protein [14, 15]. Although research directed toward the development of effective vaccines started ∼70 years ago, a commercial vaccine is still not available. For many years, the development of vaccines based on the M protein was hindered by presumed “molecular mimicry” caused by antibodies raised against purified M protein that cross-reacted with human tissues, including the heart, skeletal muscle, brain, and glomerular basement membrane, thereby causing concern about the potential for induction of autoimmunity [16, 17]. Three cases of probable or definite rheumatic fever were reported after a trial of M3 partially purified vaccine [18]. The understanding that the type-specific N terminus of the M protein responsible for induction of bactericidal antibodies can be separated from cross-reactive epitopes led to the development of 2 multivalent vaccines, which were tested in clinical trials. A hexavalent vaccine evaluated in a phase 1 clinical trial involving 28 healthy adults was well tolerated and stimulated bactericidal antibodies that were not cross-reactive with human tissues [19]. A 26-valent vaccine that included 80%–90% of the serotypes that cause pharyngitis and invasive diseases in the United States was tested in 30 healthy adults and was found to be immunogenic and safe [20, 21]. In this issue of Clinical Infectious Diseases, O'Loughlin et al. [22] report an average annual rate of invasive GAS disease in the United States of 3.5 cases per 100,000 population, with a case-fatality rate of 13.7%. These rates were stable over the surveillance years (2000–2004) and are comparable to the rates in a previous surveillance report by the ABCs for the period 1995–1999 [2]. M serotypes in the proposed 26-valent vaccine accounted for 79% of isolates; for 85% and 88% of the isolates responsible for NF and STSS isolates, respectively; and for 79% of deaths. The authors calculated that the 26-valent vaccine could prevent 49%–63% of invasive GAS infections among children and 43%–50% of such infections among the elderly population, with a similar decrease in the number of deaths. These percentages may be overestimated, because they are based on a vaccine efficacy rate of 84% found in clinical trials involving healthy adults. On the other hand, herd immunity or indirect effects of vaccination, as observed in H. influenzae type b and pneumococcal vaccines, may increase the calculated efficacy among children and elderly individuals. Although the stability of the emm types of GAS, which cause invasive disease in the United States, is promising in terms of use of the 26-valent vaccine in this population, there may be limitations with regard to global administration of this vaccine. In the >150 M protein genotypes identified by emm typing, geographical and temporal differences have been observed. Epidemiologic information indicates lower vaccine coverage in Asia [23], and little is known regarding the circulation of M types in the developing world. Increased diversity and different emm types are suggested in the few studies available; for example, a study from Ethiopia found that 46% of the prevalent emm types are not included in the 26-valent vaccine [24]. Another concern related to multivalent M protein vaccines is serotype replacement, resulting in increased carriage and disease associated with serotypes not included in these vaccines. Although this phenomenon has not been detected since the introduction of the conjugate H. influenzae type b vaccine [25], it did occur during the clinical trials of the pneumococcal conjugate vaccine [26]. More recently, the pneumococcal conjugate vaccine was associated with increased rate of invasive disease caused by nonvaccine serotypes among the subpopulation of highly vaccinated Alaskan native children [27]. This potential lesson from a previous multivalent vaccine emphasizes the need for ongoing M serotype surveillance when a GAS multivalent vaccine is introduced into a population. The geographic and temporal variability of the M protein, a possible serotype switch after vaccine introduction, and the ability of a single invasive strain to spread rapidly through a community may limit the efficacy of an M serotype–specific vaccine. Thus, other (non–M protein) vaccine candidates that are expressed by many or all serotypes also must be considered [28]. C5a peptidase [29,30–31] and surface markers, such as fibronectin-binding protein [32, 33], group A carbohydrate [34], and the conserved C-terminal region of the M protein [35, 36], have been associated with reduced colonization and, in some cases, evoked protective immune response when tested in animal models. There is a need for a GAS vaccine in both the developing and the developed world, but the needs for these regions differ. Understanding these needs and differences in epidemiology, as well as the molecular basis of GAS virulence, should promote further vaccine development. Potential conflicts of interest. R.C.P. and D.L.K.: no conflicts.