Global emm type distribution of group A streptococci: systematic review and implications for vaccine development

doi:10.1016/S1473-3099(09)70178-1

The Lancet Infectious Diseases

Volume 9, Issue 10, October 2009, Pages 611-616

https://doi.org/10.1016/S1473-3099(09)70178-1 Get rights and content

Summary

emm sequence typing is the most widely used method for defining group A streptococcal (GAS) strains, and has been applied to isolates in all regions of the world. We did a systematic review of the global distribution of GAS emm types. 102 articles and reports were included (38 081 isolates). Epidemiological data from high-income countries were predominant, with sparse data from low-income countries. The epidemiology of GAS disease in Africa and the Pacific region seems to be different from that in other regions, particularly high-income countries. In Africa and the Pacific, there were no dominant emm types, a higher diversity of emm types, and many of the common emm types in other parts of the world were less common (including emm 1, 4, 6, and 12). Our data have implications for the development of GAS vaccines. On the basis of the available data, the current formulation of the experimental multivalent emm vaccine would provide good coverage in high-income countries, particularly USA, Canada, and Europe, but poor coverage in Africa and the Pacific, and only average coverage in Asia and the Middle East.

Introduction

Group A streptococcal (GAS) infections are a major cause of morbidity and mortality worldwide.¹ Streptococcus pyogenes causes a wide range of clinical disease. In high-income countries, pharyngitis and invasive disease are the GAS diseases of greatest public health importance, whereas in low-income countries, acute rheumatic fever, rheumatic heart disease, invasive disease, and acute post-streptococcal glomerulonephritis are the major severe diseases, with endemic streptococcal impetigo also leading to very high morbidity. On a global scale, the overwhelming burden of GAS disease is found in low-income countries, where more than 95% of the estimated 663 000 cases of invasive GAS disease and more than 95% of the estimated 294 000 deaths due to rheumatic heart disease occur. However, accurate data are not available from most low-income countries, and published summary data are likely to be underestimates.¹

Due to the size and severity of the burden of GAS disease, epidemiological surveillance has been crucial to detect changes in disease distribution in various populations. An important part of epidemiological surveillance for GAS disease has been the typing of collected bacterial isolates. Several different methods are available to type GAS.² Typing based on the M protein, a cell-surface protein that is the major virulence and immunological determinant of GAS, has been the most widely used method.3, 4, 5 Classic M-protein serological typing was largely replaced by sequence typing of the 5′ end of the M protein (emm) gene in the late 1990s.⁶ Large epidemiological studies of pharyngitis and invasive disease have been done using emm sequence typing, particularly in the USA, Canada, and Europe.7, 8, 9, 10 Population-based studies using emm typing have also been done in many other countries.

Available molecular epidemiological data have informed the development of GAS vaccine candidates. Several vaccine candidates have shown promise; however, only one vaccine, a 26-valent M-protein-based vaccine, has recently reached clinical trials.11, 12 Serotypes for this vaccine were chosen if they were known to be common causes of invasive GAS disease or uncomplicated pharyngitis in the USA, or if they were associated with rheumatic fever in classic studies from the USA in the mid-20th century.¹³ Recent studies of GAS disease in North America found that emm types in the 26-valent vaccine accounted for 79% of all invasive isolates from ten sites in the USA between 2000 and 2004, and 85% of pharyngitis isolates from 13 sites in the USA and Canada between 2000 and 2007.7, 14

Differences in the distribution of emm sequence types between global regions have been noted previously,7, 15 but a thorough review of the available global data has not been undertaken, as it has for other bacteria, including Streptococcus pneumoniae.16, 17 In addition, a review of the coverage and potential impact of the experimental multivalent GAS vaccine on a global scale, particularly in low-income countries where the burden of disease is greatest, has not been undertaken. Therefore, we did a global review of the distribution of emm types of GAS and assessed the implications of our findings for the development of GAS vaccines.

Section snippets

Data sources

We searched for studies that described the epidemiology of GAS based on emm or M typing by use of a systematic approach that complied with the QUORUM guidelines.¹⁸ Figure 1 summarises our approach. Searches were done in Medline and EmBase from the start of 1990 to the end of March, 2009, by use of the search term “Streptococcus pyogenes” combined with the search terms “epidemiology”, “emm”, and “streptococcal M protein”. Relevant abstracts from the Lancefield Symposia on Streptococci and

Results

The final database contained 102 datasets, contributing 38 081 isolates (webappendix). These isolates were not equally distributed between regions, with high-income countries contributing 32 143 isolates (84·4%), Asia contributing 2248 isolates (5·9%), Pacific Island countries and Indigenous Australians contributing 1383 isolates (3·6%), the Middle East contributing 1219 isolates (3·2%), Latin America contributing 757 isolates (2·0%), and Africa contributing 331 isolates (0·9%). 31 334 isolates

Discussion

Our study has revealed differences in the emm type distribution of GAS across global regions, and in particular has revealed marked differences in the molecular epidemiology in Africa and the Pacific region compared with high-income countries. A distinct profile of emm types exists in Africa and the Pacific, with an apparent lack of dominant emm types and a greater molecular diversity.

The reasons for the contrasting molecular epidemiology in Africa and the Pacific are not clear. It might be

Search strategy and selection criteria

These are described in detail in the Methods section.

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ReviewGlobal emm type distribution of group A streptococci: systematic review and implications for vaccine development

Summary

Introduction

Section snippets

Data sources

Results

Discussion

Search strategy and selection criteria

Lancet Infect Dis

Lancet

J Pediatr

Laboratory diagnosis of group A streptococcal infections

The antigenic complex of Streptococcus hemolyticus, I: demonstration of a type-specific substance in extracts of Streptococcus hemolyticus

J Exp Med

Current knowledge of the type specific M antigens of group A streptococci

J Immunol

Sequencing emm-specific PCR products for routine and accurate typing of group A streptococci

J Clin Microbiol

emm typing and validation of provisional M types for group A streptococci

Emerg Infect Dis

The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000–2004

Clin Infect Dis

The epidemiology of severe Streptococcus pyogenes associated disease in Europe

Eurosurveillance

Group A streptococcal pharyngitis serotype surveillance in North America, 2000–2002

Clin Infect Dis

Progress in group A streptococcal vaccine development

Pediatr Infect Dis J

Safety and immunogenicity of 26-valent group A streptococcus vaccine in healthy adult volunteers

Clin Infect Dis

Immunogenicity of a 26-valent group A streptococcal vaccine

Infect Immun

Contrasting molecular epidemiology of group A streptococci causing tropical and nontropical infections of the skin and throat

J Infect Dis

The contribution of specific pneumococcal serogroups to different disease manifestations: implications for conjugate vaccine formulation and use, part II

Clin Infect Dis

Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I

Clin Infect Dis

Streptococcus Laboratory. Protocol for emm typing

Review
Global emm type distribution of group A streptococci: systematic review and implications for vaccine development