E D I T O R I A L C O M M E N TA R Y

Group A Streptococcus Epidemiology and Vaccine Implications

Ronit Cohen-Poradosu1 and Dennis L. Kasper1,2
1

Channing Laboratory, Brigham and Womens Hospital, and 2Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts

(See the article by OLoughlin et al. on pages 85362)

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 infectionspecifically, acute rheumatic fever and poststreptococcal glomerulonephritis. The global impact of disease has been estimated to be 1500,000 deaths per year, primarily due to rheumatic fever, rheumatic heart disease, and invasive GAS infection. These gures place GAS among the worlds 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 inuenzae type b infection, and hepatitis [1]. A previous report by the Centers for Disease Control and Prevention Active
Received 15 June 2007; accepted 16 June 2007; electronically published 29 August 2007. Reprints or correspondence: Dr. Dennis L. Kasper, Dept. of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115 (dennis_kasper@hms .harvard.edu). Clinical Infectious Diseases 2007; 45:8635 2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4507-0006$15.00 DOI: 10.1086/521263

Bacterial Core surveillance (ABCs) system estimated that the rate of invasive GAS disease in the United States during 1995 1999 was 3.13.8 cases per 100,000 population, resulting in 900011,000 cases and 10001700 deaths per year, with a casefatality 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 doctors 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 [510], 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 benecial 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 Lanceelds [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 puried 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 puried 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 puried vaccine [18]. The understanding that the type-specic N terminus of the M protein responsible for induction of bactericidal anti-

Downloaded from http://cid.oxfordjournals.org/ by guest on April 1, 2014

EDITORIAL COMMENTARY CID 2007:45 (1 October) 863

bodies 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, OLoughlin 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 (20002004) and are comparable to the rates in a previous surveillance report by the ABCs for the period 19951999 [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 efcacy 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. inuenzae type b and pneumococcal vaccines, may increase the calculated efcacy 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 1150 M protein genotypes identied 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. inuenzae 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 efcacy of an M serotypespecic vaccine. Thus, other (nonM protein) vaccine candidates that are expressed by many or all serotypes also must be considered [28]. C5a peptidase [2931] and surface markers, such as bronectin-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 dif-

fer. Understanding these needs and differences in epidemiology, as well as the molecular basis of GAS virulence, should promote further vaccine development.
Acknowledgments
Potential conicts of interest. R.C.P. and D.L.K.: no conicts.

References
1. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5:68594. 2. OBrien KL, Beall B, Barrett NL, et al. Epidemiology of invasive group a streptococcus disease in the United States, 19951999. Clin Infect Dis 2002; 35:26876. 3. Tyrrell GJ, Lovgren M, Kress B, Grimsrud K. Invasive group A streptococcal disease in Alberta, Canada (2000 to 2002). J Clin Microbiol 2005; 43:167883. 4. Lamagni TL, Efstratiou A, Vuopio-Varkila J, Jasir A, Schalen C. The epidemiology of severe Streptococcus pyogenes associated disease in Europe. Euro Surveill 2005; 10:17984. 5. Shulman ST, Stollerman G, Beall B, Dale JB, Tanz RR. Temporal changes in streptococcal M protein types and the near-disappearance of acute rheumatic fever in the United States. Clin Infect Dis 2006; 42:4417. 6. Martin JM, Barbadora KA. Continued high caseload of rheumatic fever in western Pennsylvania: possible rheumatogenic emm types of Streptococcus pyogenes. J Pediatr 2006; 149: 5863. 7. Wald ER, Dashefsky B, Feidt C, Chiponis D, Byers C. Acute rheumatic fever in western Pennsylvania and the tristate area. Pediatrics 1987; 80:3714. 8. Veasy LG, Wiedmeier SE, Orsmond GS, et al. Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med 1987; 316:4217. 9. Lee GM, Wessels MR. Changing epidemiology of acute rheumatic fever in the United States. Clin Infect Dis 2006; 42:44850. 10. Leads from the MMWR: acute rheumatic fever at a Navy training centerSan Diego, California. JAMA 1988; 259:1782, 1787. 11. Prevention of Invasive Group A Streptococcal Infections Workshop Participants. Prevention of invasive group A streptococcal disease among household contacts of case patients and among postpartum and postsurgical patients: recommendations from the Centers for Disease Control and Prevention. Clin Infect Dis 2002; 35:9509. 12. Collis WRF. Intravenous vaccines of hemolytic streptococci in rheumatism in childhood. Lancet 1932; 220:12614. 13. Lanceeld RC. Current knowledge of typespecic M antigens of group A streptococci. J Immunol 1962; 89:30713. 14. Polly SM, Waldman RH, High P, Wittner MK,

Downloaded from http://cid.oxfordjournals.org/ by guest on April 1, 2014

864 CID 2007:45 (1 October) EDITORIAL COMMENTARY

15.

16.

17.

18.

19.

20.

21.

22.

Dorfman A. Protective studies with a group A streptococcal M protein vaccine. II. Challenge of volunteers after local immunization in the upper respiratory tract. J Infect Dis 1975; 131:21724. Beachey EH, Stollerman GH, Johnson RH, Ofek I, Bisno AL. Human immune response to immunization with a structurally dened polypeptide fragment of streptococcal M protein. J Exp Med 1979; 150:86277. Bronze MS, Courtney HS, Dale JB. Epitopes of group A streptococcal M protein that evoke cross-protective local immune responses. J Immunol 1992; 148:88893. Bronze MS, Beachey EH, Seyer JM, Dale JB. Protective and heart-cross-reactive epitopes of type 19 streptococcal M protein. Trans Assoc Am Physicians 1987; 100:804. Massell BF, Honikman LH, Amezcua J. Rheumatic fever following streptococcal vaccination: report of three cases. JAMA 1969; 207: 11159. Kotloff KL, Corretti M, Palmer K, et al. Safety and immunogenicity of a recombinant multivalent group A streptococcal vaccine in healthy adults: phase 1 trial. JAMA 2004; 292: 70915. McNeil SA, Halperin SA, Langley JM, et al. Safety and immunogenicity of 26-valent group A streptococcus vaccine in healthy adult volunteers. Clin Infect Dis 2005; 41:111422. Hu MC, Walls MA, Stroop SD, Reddish MA, Beall B, Dale JB. Immunogenicity of a 26valent group A streptococcal vaccine. Infect Immun 2002; 70:21717. OLoughlin RE, Roberson A, Cieslak PR, et al. The epidemiology of invasive group A streptococcal infection and potential vaccine im-

23.

24.

25.

26.

27.

28.

29.

30.

plications: United States, 20002004. Clin Infect Dis 2007; 45:85362 (in this issue). Ikebe T, Hirasawa K, Suzuki R, et al. Distribution of emm genotypes among group A streptococcus isolates from patients with severe invasive streptococcal infections in Japan, 20012005. Epidemiol Infect 2007; 9 Feb:13. Abdissa A, Asrat D, Kronvall G, et al. High diversity of group A streptococcal emm types among healthy schoolchildren in Ethiopia. Clin Infect Dis 2006; 42:13627. Barbour ML, Mayon-White RT, Coles C, Crook DW, Moxon ER. The impact of conjugate vaccine on carriage of Haemophilus inuenzae type b. J Infect Dis 1995; 171:938. Obaro SK, Adegbola RA, Banya WA, Greenwood BM. Carriage of pneumococci after pneumococcal vaccination. Lancet 1996; 348: 2712. Singleton RJ, Hennessy TW, Bulkow LR, et al. Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA 2007; 297:178492. Bisno AL, Rubin FA, Cleary PP, Dale JB. Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstaclesreport of a National Institute of Allergy and Infectious Diseases workshop. Clin Infect Dis 2005; 41: 11506. Cleary PP, Matsuka YV, Huynh T, Lam H, Olmsted SB. Immunization with C5a peptidase from either group A or B streptococci enhances clearance of group A streptococci from intranasally infected mice. Vaccine 2004; 22:433241. Ji Y, Carlson B, Kondagunta A, Cleary PP.

31.

32.

33.

34.

35.

36.

Intranasal immunization with C5a peptidase prevents nasopharyngeal colonization of mice by the group A streptococcus. Infect Immun 1997; 65:20807. Park HS, Cleary PP. Active and passive intranasal immunizations with streptococcal surface protein C5a peptidase prevent infection of murine nasal mucosa-associated lymphoid tissue, a functional homologue of human tonsils. Infect Immun 2005; 73:787886. Kawabata S, Kunitomo E, Terao Y, et al. Systemic and mucosal immunizations with bronectin-binding protein FBP54 induce protective immune responses against Streptococcus pyogenes challenge in mice. Infect Immun 2001; 69:92430. Guzman CA, Talay SR, Molinari G, Medina E, Chhatwal GS. Protective immune response against Streptococcus pyogenes in mice after intranasal vaccination with the bronectinbinding protein SfbI. J Infect Dis 1999; 179: 9016. Sabharwal H, Michon F, Nelson D, et al. Group A streptococcus (GAS) carbohydrate as an immunogen for protection against GAS infection. J Infect Dis 2006; 193:12935. Vohra H, Dey N, Gupta S, et al. M protein conserved region antibodies opsonise multiple strains of Streptococcus pyogenes with sequence variations in C-repeats. Res Microbiol 2005; 156:57582. Batzloff MR, Hayman WA, Davies MR, et al. Protection against group A streptococcus by immunization with J8-diphtheria toxoid: contribution of J8- and diphtheria toxoid-specic antibodies to protection. J Infect Dis 2003; 187:1598608.

Downloaded from http://cid.oxfordjournals.org/ by guest on April 1, 2014

EDITORIAL COMMENTARY CID 2007:45 (1 October) 865