|Year : 2017 | Volume
| Issue : 2 | Page : 176-183
Molecular biology of Group A Streptococcus and its implications in vaccine strategies
Director, Research and Training, Microbiological Laboratory, R. S. Puram, Coimbatore, Tamil Nadu, India
|Date of Web Publication||5-Jul-2017|
N K Brahmadathan
Microbiological Laboratory, 12A Cowley Brown Road, R.S. Puram, Coimbatore - 641 002, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Infections due to Streptococcus pyogenes and their complications are a problem of major concern in many countries, including India. Primary prophylaxis with benzathine penicillin is the key to control and prevent sequelae such as acute rheumatic fever and rheumatic heart disease (RF/RHD) or post-streptococcal glomerulonephritis (PSGN). Non-compliance to prophylaxis due to fear of injection and anaphylaxis is major issues in RF/RHD control in India and leads to continued high prevalence of infection and post-streptococcal sequelae. Differing reports on the efficacy of two weekly, three weekly or monthly injections raise questions on the actual dosages to be administered. Availability of more effective antibiotics with better dosages has replaced the use of penicillin; hence, companies are reluctant to manufacture penicillin preparations in India. It is in this context that a concept of a Group A streptococci vaccine is looked at and whether or not a globally designed vaccine will be useful in the Indian context. Modern molecular techniques and genomic analysis of S. pyogenes have identified many molecules as vaccine candidates among which the M-protein has attracted the most attention. High diversity of M (emm) types in endemic regions raises questions about the efficacy of such a vaccine. A recent 30-valent M-protein-based vaccine that elicits antibodies to homologous as well as non-vaccine M types looks promising. This review will discuss the genomics of S. pyogenes, the various candidate vaccine molecules and highlight their efficacy in the Indian context where control of post-streptococcal sequelae remains a challenge.
Keywords: Emm types, Group A streptococci, Group A streptococci vaccines, multilocus sequence typing types, rheumatic fever/rheumatic heart disease
|How to cite this article:|
Brahmadathan N K. Molecular biology of Group A Streptococcus and its implications in vaccine strategies. Indian J Med Microbiol 2017;35:176-83
|How to cite this URL:|
Brahmadathan N K. Molecular biology of Group A Streptococcus and its implications in vaccine strategies. Indian J Med Microbiol [serial online] 2017 [cited 2017 Sep 26];35:176-83. Available from: http://www.ijmm.org/text.asp?2017/35/2/176/209593
| ~ Introduction|| |
Infections due to Streptococcus pyogenes (Group A streptococci, GAS) and their complications, especially rheumatic fever/rheumatic heart disease (RF/RHD) continue to be a problem of major concern in India. This disease affects more than 34 million people, causing >500,000 deaths and 10 million disability-adjusted life years (DALYs) lost per year, almost all mostly in low- and middle-income countries. Many epidemiological studies were carried out in the past to document the magnitude of the problem in different parts of India.,,,,, Multicentric studies were initiated during the last three decades to include different geographical regions of the country so as to define the epidemiology under diverse conditions. Intervention strategies were implemented to control both primary infections and their sequelae as well as to design a national control programme for RF/RHD in India. One important component of these studies was to generate data on the distribution of GAS genotypes (emm types) to determine their distribution patterns across the country. This was aimed at determining if a multivalent vaccine employing predominant emm types would be suitable for India. The ultimate objective was to control and prevent GAS infections and their sequelae by appropriate strategies, including the possible use of a locally designed GAS vaccine.
| ~ Epidemiology of Group a Streptococcal Infections and Their Complications in India|| |
Due to their self-limiting nature, both GAS pharyngitis and impetigo are often clinically neglected. Two-thirds of pharyngitis cases are of viral etiology and differentiating them from those of GAS etiology is important to initiate treatment and prevent the development of complications., In endemic regions, asymptomatic carriage of GAS is high and differentiating them from 'bonafide' pathogenic strains complicates the epidemiology of pharyngitis. Several studies from India and other countries have also shown the predominance of Group G/C streptococci (GGS/GCS) in asymptomatic carriage which many believe may even contribute towards the pathogenesis of RF/RHD.,, This concept is supported by the demonstration of certain virulence factors among GGS/GCS strains that are similar to those found among GAS strains with rheumatogenic potential. Thus, epidemiology of GAS infections in endemic regions is more complex which makes their control and prevention all the more difficult.
Several studies have been carried out in India that indicates high prevalence and incidence of RF/RHD among children and young adolescents.,,,,, Due to their chronic nature and near fatal complications, RF and RHD need to be better managed with adequate and continuous prophylactic measures. Certain school-based surveys have indicated that adequate primary prophylaxis with benzathine penicillin G can successfully prevent the pathogenesis of RF/RHD in the future years., Although clinical algorithms were proposed earlier, a microbiological diagnosis is an important component, especially to differentiate 'bonafide' GAS pharyngitis from that of viral origin., Failure to establish a GAS etiology can lead to inadequate or unnecessary antibiotic prophylaxis. Supervised primary penicillin prophylaxis is the key to control and prevent later complications; indeed non-compliance to prophylaxis lead to endemicity of infection and a high prevalence of post-streptococcal sequelae.
Long-acting (benzathine) penicillin G has been the cornerstone of both primary and secondary prophylaxis for many decades. Intramuscular nature of administration and fear of anaphylaxis increases non-compliance, an important issue in the control of RF/RHD in India. The four-weekly regimen of secondary prophylaxis of yesteryears was changed to a three-weekly schedule in India because some studies found that the serum levels of the antibiotic were negligible at 21 days. Some studies have even questioned the efficacy of a three weekly schedule and suggested that it be changed to a fortnightly schedule. This may also be related to the quality of the penicillin being marketed. The use of oral penicillin is recommended by the American Pediatric Association for primary prophylaxis while amikacin or even clindamycin have been recommended as alternate drugs of choice. Due to the availability of more powerful and better dosage antibiotics, most pharmaceutical companies in India have stopped manufacturing benzathine penicillin which makes prophylaxis more expensive and therefore less compliant. It is in this context that a concept of a GAS vaccine is looked at and whether or not a globally designed vaccine will be useful in the Indian context.
| ~ Contrasting Epdeimiology of Group a Streptococcal Infection|| |
The contrasting epidemiology of GAS infections and their complications in tropics and temperate climates has for many years led to the belief that GAS strains with specific 'rheumatogenic' and 'nephritogenic' potential exist among them. In temperate climates, cases of pharyngitis occur more commonly in winter months while less common impetigo cases are seen during the warmer seasons., In tropical regions, impetigo is more common than pharyngitis and has hardly any seasonal distribution. Systematic studies done among Australian aboriginal population in the Northern Territory have shown very high incidence of RF/RHD with hardly any case of GAS pharyngitis in this population. Although there has been a reported resurgence of RF/RHD in some parts of the USA, much of the Western literature confirms a high incidence of invasive GAS disease., On the contrary, there is scanty literature on this subject from tropical countries. Based on studies on emm gene family patterns of GAS strains (which are markers for tissue preferences), Bessen et al., showed that among rural aboriginal Australians family pattern A-C were more often associated with throat infection while pattern D was found among skin strains from Australian aboriginal population. In contrast, a study conducted in South India showed a predominance of pattern E among both pharyngitis-associated throat strains and colonising strains indicating that most south Indian GAS strains are capable of causing both throat and skin infections. Thus, in warmer tropical countries where GAS pharyngitis, impetigo and post-streptococcal complications are endemic, the concept of rheumatogenic and nephritogenic strains is very tenuous and is not supported by epidemiological and molecular studies.
| ~ Genetic Structure of Group a Streptococci|| |
The complete genome sequence of GAS was first reported by Ferretti  based on the sequencing of M type 1. A set of 1852, 442–bp sequence containing 1752 protein-coding genes were identified [Figure 1]. Approximately one-third of the genes had no identifiable function while >40 putative virulence-associated genes were reported. In addition, genes coding for proteins probably associated with molecular mimicry were also identified. Present in the genome were four different bacteriophage genomes coding for superantigen-like proteins. The latter is believed to include at least six potential virulence factors. The presence of the phage genomes also led to conclude that horizontal transfer of genes may be responsible for the emergence of new strains with increased pathogenic potential. Sequencing and studies on genetic diversity of M types such as 3 and 18 by DNA-DNA microarray and polymerase chain reaction tiling showed that the core content of genes in all strains was identical. Further, differences in gene content were shown to be due to variation in phage content.
|Figure 1: Circular representation of the Streptococcus pyogenes strain SF370 genome. Outer circle predict coding regions transcribed on the forward (clockwise) DNA strand. Second circle predicted coding regions transcribed on the reverse (counter clockwise) DNA strand. Third circle stable RNA molecules. Fourth circle mobile genetic elements: Fifth circle known and putative virulence factors (Ferritti JJ et al. Proc Natl Acad Sci USA 2001;98:4658-63).|
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| ~ Phages in the Pathogenesis of Group a Streptococcal Infection|| |
As noted above, majority of differences in the genetic makeup of various GAS M types and strains among them are due to prophages and other exogenous elements. The strains subjected to sequencing showed that they contain prophages each encoding for one or two putative virulence factors with few exceptions. These phage associated virulence factors are now believed to contribute significantly towards the diversification of the strains and their pathogenesis. It is noteworthy that the largest overall difference in the genetic diversity is only 3%. While only 10% of the GAS genome is composed of prophage-encoded genes, 74% of the variations in the gene content are in the open reading frames of the different GAS strains. This shows that phages have contributed significantly to the evolution of GAS pathogenicity.
| ~ Population Genetics of Group a Streptococci|| |
Population genetics is the study of structure, function and inheritance of genes in natural populations. The population structure of GAS was first determined by studying the hypervariability of emm gene that code for the M-protein. This variability has shown a non-congruent relationship among various emm types. Based on the phylogenetic divergence of the 3' ends of the emm and emm-like genes, five emm subfamilies (SF1 through SF5) have been identified. The pattern of distribution of five subfamilies was then used to identify five emm patterns, namely, A through E. Extensive studies on a large number of emm types of GAS strains revealed a definite relationship of the emm pattern with site of infections. Further, insights into strain variation can be determined by multilocus sequence typing (MLST) which identify subtle genetic variations in the seven housekeeping genes. These variations are complex and contribute significantly towards the understanding of evolutionary events leading to strain diversity and epidemiology of GAS diseases.
| ~ M-proteins and Emm (Gene) Family Patterns|| |
M-protein is a helical coiled-coil surface protein extending about 600 nm from the cell wall and is made up of 441 amino acid residues [Figure 2]. It is made up of three main regions: non-helical, helical and anchor regions. The non-helical amino terminal (N) is made up of 11 amino acid residue, is distal from the cell surface, hypervariable and therefore serotype specific. The helical central rod region is made up of four blocks of repeating seven amino acid residues (A, B, C and D) and extends about 500 nm from the cell wall. The anchor region consists of the proline-glycine rich region which stabilises the molecule and is anchored to the peptidoglycan while a 19 amino acid residue with a charged tail of 6 amino acid residue is anchored to the membrane. The charged tail projects into the cytoplasm. The C-terminus consists of D and C repeat regions while variable (repeat B region) and hypervariable (repeat A region) with the non-repeat N-terminus give the serological specificity. Conventional typing scheme for GAS involved identification by type-specific M antisera which are however too complex and costly to prepare. This hampered the laboratory differentiation of diverse strains of GAS for a long time. Complete sequencing of gene/s coding for M-protein (emm gene) and advances in sequencing technology helped to standardise an emm typing technique. By this method, >200 emm types of GAS have been identified globally. This molecular technique has also been extensively used to study the diversity and clonality of GAS strains in different regions of the world. The emm and emm- like genes share a high degree of sequence homology within the signal peptide and conserved C-terminal region. The emm-like genes mostly occur by gene duplication from an ancestral gene and are located in tandem in a single locus. The distribution of four subfamily emm genes (SF1–SF4) in the vir regulon is based on their content and chromosomal arrangement. As discussed earlier, the classification into five patterns, namely, A–E and their association to tissue specificity is now well documented.
|Figure 2: M-protein structure. A 600 nm protein molecule with a hypervariable N terminus, helical coiled-coil central rod region and anchor region. The cell-associated portion has a part of the proximal conserved region of the coiled coil, a proline-glycine rich region anchored to the peptidoglycan and hydrophobic 19-amino acid region embedded in the cell membrane. The latter is attached to a charged tail which lies freely in the cytoplasm (Fischetti VA. M-protein and other surface proteins on streptococci. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Oklahoma City: University of Oklahoma Health Sciences Center; 2016. p. 27-54).|
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| ~ Distribution of Emmtypes in India|| |
Knowledge of the distribution of GAS emm types helps to understand the nature of GAS strains circulating within a community. During infection, antibodies against the N-terminal region of the M-protein molecule are rapidly generated in the host leading to homologous protective immunity. Due to the resultant selective pressure, strains undergo frequent size variation which results in the development of a wide variety of genotypes in the community; this results in endemicity of infection. Most western literature confirms a clonality of emm types among GAS causing infections in temperate countries , while literature from tropical regions shows a highly heterogeneous distribution of emm types. Reported literature from different regions of India shows significant differences in the distribution of emm types ,,, A study reported from Northern India  identified 37 emm types among 94 GAS isolates, the most frequent being emm 49 (8.5%) and 112 (7.5%) followed by emm 1-2, emm 75, emm 77 and emm 81. Despite the diversity in emm type pattern of throat and skin isolates, no significant association between emm type and source of isolation was observed. In an earlier study, same centre reported 16 emm types among 71 GAS isolates with emm 77 (29.6%) 81 (25.4%) and 11 (14.1%) predominating. In a study reported from Southern India, 11 emm types were identified among 34 GAS isolates. Sindhulina  reported a prevalence of 10 emm types among 11 GAS isolates recovered in another South Indian hospital. In a larger series from Northern India, in a study reported by Menon et al., 22 emm types were identified among 34 GAS isolates. In what would be the largest series reported so far from India we identified 77 emm types among 698 GAS isolates recovered from strains causing pharyngitis, impetigo and throat colonisation [Table 1]. Type emm 28 was most predominant among pharyngitis and throat colonisers while emm 122 was most predominant among impetigo isolates. In another comparative study of community (n = 319) and invasive GAS isolates (n = 58), we identified 73 and 37 emm types, respectively, confirming high diversity even among invasive isolates. Despite the limited number of studies and relatively smaller sample sizes, a common feature in all these studies is the high diversity of GAS genotypes circulating in the community. This indicates a constant emergence of newer strains probably reflecting a high rate of transmission and highly susceptible population. Similar observations have also been made from other economically deprived regions where GAS infections are endemic.,
|Table 1: Distribution of emm types of South Indian Group A streptococcal isolates|
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| ~ Multilocus Sequence Typing Patterns and Lack of Clonality among South Indian Group a Streptococcal Strains|| |
One new approach to identify and track the global spread of any bacterial pathogen is by determining the variations among house-keeping genes. Genetic relatedness among same molecular type (emm type in case of GAS strains) can be determined with a high degree of discrimination through MLST. More than 400 sequence types have been identified among GAS strains across the globe. In a study conducted in our laboratory, 87 STs were identified among 55 emm types of 143 South Indian GAS isolates [Table 2]. In many instances, same emm types identified different MLST patterns while in others, same MLST pattern was identified among different emm types. Phylogenetic trees derived from emm types and MLST types showed close similarities indicating similar points of origin. Family clusters identified in both phylogenetic trees indicated much diversity and very little clonality. This was the first time ever such a high heterogeneity among Indian GAS strains was confirmed by both molecular and bioinformatic methods.
|Table 2: Distribution of multilocus sequence typing patterns among emm types of South Indian Group A streptococcal isolates|
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| ~ Vaccine Strategies and Their Implications in the Indian Context|| |
The global burden of RF/RHD is roughly estimated to be 15.6 million with 282,000 new patients and 233,000 deaths each year. Population-based studies from developing countries have shown prevalence to be high in Africa and Asia, including India., Studies conducted in India during the last few decades of 20th Century, show a high prevalence of RHD that vary from 1 to 11 per 1000 school-going children in the age group of 5–15 years.,, There are also reports from some centres in India showing a declining trend; however, this needs to interpreted with caution as methodological differences do exist in these studies.,
Although the economic burden of GAS disease is unknown in India, a recent study from Fiji found that the cost of RHD mortality over a 5-year period is around US $30 million. This works out to be 1% of the GDP and puts a heavy economic burden for the country. It was also found that a GAS vaccine would be the most cost-effective method to control/prevent RF/RHD which in endemic regions would cost about US $137–458 per DALY averted if the vaccine provides 80% efficacy and 60%–95% coverage. This is in comparison to 22000–23000 US $ for the treatment of all cases of sore throat. Similar numbers for wealthy countries where GAS infections are less endemic would be approximately US $500 million per year for the treatment of sore throat. Although such data are unavailable for impetigo, PSGN, or invasive GAS disease, it can be assumed that an equally significant economic burden can be expected for the treatment of these conditions.
Although an efficient and potent GAS vaccine is still in the experimental stage, a possibility for such a vaccine exists more than ever before., Type-specific protective immunity developed during natural infection is long lasting and often remains as long as 30 years. In addition, infection with multiple types at different times results in immunity to different types. Studies in mice have shown that animals challenged with virulent strains are protected against subsequent intranasal challenge with the homologous type indicating the development of type-specific immunity. This clearly shows that the latter is a key factor while designing an M-protein-based type-specific vaccine. One major point against such a vaccine is the existence of >200 emm types that can cause human infection. As described earlier, epidemiological studies have shown that high diversity of emm types in endemic regions; this indicates that type-specific vaccines would be less effective in such settings. It is also shown that only very few emm types identified in Asia and Africa are actually included in the 26-valent vaccine of Dale., Steer et al. reported that a 26-valent vaccine that would give ≥72% coverage will give only 24%–39% in low- or middle-income setting. This vaccine was then reformulated into a 30-valent vaccine which showed protection not only against all 30 emm types but also was shown to elicit opsonising antibodies to non-vaccine emm types. More recently, Dale et al. used the emm cluster typing system, in combination with computational structure-based peptide modelling, as a novel approach to the design of potentially broadly protective M-protein-based vaccines. If the above studies confirm the findings, then a broadly effective vaccine is feasible for use against a wide variety of GAS types, including those encountered in low-income countries.
| ~ Other Group a Streptococcal Vaccines|| |
Conserved M-protein vaccines contain antigens from the conserved C-repeat portion of the M-protein. One such type vaccine is the J8 or the J14 vaccine that contain single minimal B cell epitopes from the same C-repeat region [Table 3]., These antigens elicit opsonic antibodies in mice which protect them against subsequent intraperitoneal or intranasal challenge. Highly conserved nature of these antigens across multiple emm types and geographic regions is a distinct advantage of the J8 vaccine. The StreptInCor vaccine incorporates selected T- and B-cell epitopes from the C-repeat region in a synthetic 55 amino acid polypeptide and is expected to enter clinical trials soon., Cell wall and secreted virulence factors, such as streptococcal C5a peptidase, GAS carbohydrate, and streptococcal fibronectin-binding proteins have also been extensively studied as vaccine candidates for the last 20 years, but none of these has entered clinical trials. A number of other candidate molecules consisting of conserved GAS gene segments have recently been tried. Several new antigens were identified following immunisation of mice with GAS gene segments and challenge studies. Some of these antigens were combined into a single vaccine called the 'Combo' which was found to provide broad coverage against multiple GAS strains in mouse models. In the United States, few companies such as Merck, ID Biomedical Corporation, Novartis Vaccines and Diagnostics (GSK), support many of these vaccine researches. They together with NIAID and NIH, (both in the USA) support volunteer studies in some of Pacific and South American countries. These initiatives are aimed at identifying a set of GAS strains or their antigens that will protect predominant global emm types causing primary infections, invasive diseases and post-streptococcal sequelae. This will also look at their feasibility in low- and middle-income countries and the economic aspects of production so that pharmaceutical companies will take active interest to collaborate with international agencies for the development of a complete GAS vaccine.
| ~ Conclusion|| |
The objective of developing a GAS vaccine is to reduce the GAS disease burden, especially the non-suppurative sequelae and invasive diseases across the globe. Understanding the molecular biology of GAS and its antigenic repertoire has helped to identify possible vaccine candidates for diverse geographical regions. The challenge will be to develop vaccine (s) containing multiple antigens that will protect against highly diverse GAS types that initiate the pathogenesis of both primary infections and their complications. Although no single vaccine candidate has fulfilled this criterion, ongoing research gives hope to the development of an effective GAS vaccine in the near future.
Financial support for studies from DBT, NIH (USA) and Germany are acknowledged.,
Financial support and sponsorship
Financial support for studies from DBT, NIH (USA) and Germany.,
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]