Immune Cross-Opsonization Withinemm Clusters Following Group AStreptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity

Frost, Hannah R.; Laho, Delphine; Sanderson-Smith, Martina L.; Licciardi, Paul V.; Donath, Susan; Curtis, Nigel; Kado, Joseph; Dale, James B.; Steer, Andrew C.; Smeesters, Pierre

doi:10.1093/cid/cix599

Cited by 45 publications

(36 citation statements)

References 40 publications

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“…Indeed, in the latter populations D4 strains, which all encode the trio of M, Mrp, and Enn proteins, are considered endemic and have been linked to the development of rheumatic fever following skin infection (32,33). M proteins from D4 strains are relatively small and have been shown to not induce a high M-type-specific antibody response (34). In these cases, it is conceivable that the M-like proteins perform roles otherwise performed by M proteins.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Global Collection of Group A Streptococcus Genomes Reveals that the Majority Encode a Trio of M and M-Like Proteins

Frost

Davies

Delforge

et al. 2020

mSphere

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The core Mga (multiple gene activator) regulon of group A Streptococcus (GAS) contains genes encoding proteins involved in adhesion and immune evasion. While all GAS genomes contain genes for Mga and C5a peptidase, the intervening genes encoding M and M-like proteins vary between strains. The genetic make-up of the Mga regulon of GAS was characterized by utilizing a collection of 1,688 GAS genomes that are representative of the global GAS population. Sequence variations were examined with multiple alignments, and the expression of all core Mga regulon genes was examined by quantitative reverse transcription-PCR in a representative strain collection. In 85.2% of the sampled genomes, the Mga locus contained genes encoding Mga, Mrp, M, Enn, and C5a peptidase proteins. These isolates account for 53% of global infections. Only 9.1% of genomes did not contain either an mrp or an enn gene. The pairwise identity within Enn (68.6%) and Mrp (83.2%) protein sequences was higher than within M proteins (44.7%). Gene expression varied between strains tested, but high expression was recorded for all genes in at least one strain. Previous nomenclature issues were clarified with molecular gene definitions. Our findings support a shift in focus in the GAS research field to further consider the role of Mrp and Enn in virulence and vaccine development. IMPORTANCE While the GAS M protein has been the leading vaccine target for decades, the bacteria encode many other virulence factors of interest for vaccine development. In this work, we show that emm-like genes are encoded in a remarkable majority of GAS genomes and expressed at a level similar to that for the emm gene. In collaboration with the U.S. Centers for Disease Control, we developed molecular definitions of the different emm and emm-like gene families. This clarification should abrogate mistyping of strains, especially in the area of whole-genome typing. We have also updated the emm-typing collection by removing emm-like gene sequences and provided in-depth analysis of Mrp and Enn protein sequence structure and diversity.

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Section: Discussionmentioning

confidence: 99%

Analysis of Global Collection of Group A Streptococcus Genomes Reveals that the Majority Encode a Trio of M and M-Like Proteins

Frost

Davies

Delforge

et al. 2020

mSphere

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“…Study-specific exclusion criteria are: a personal or family history of severe GAS infection or post-infectious sequelae (ARF, RHD, APSGN); history of tonsillectomy; intolerance of throat swab procedure (exaggerated gag reflex); known hypersensitivity or other contraindication to beta-lactam, rifamycin, macrolide, or lincosamide antibiotics, or soya protein (the bacterial culture medium is soya based); and echocardiographic evidence of subclinical RHD [39]. Participants with evidence of pre-existing immunity to the challenge strain will also be excluded, defined for this study as a high serum IgG to a peptide comprising the first fifty amino acids of the M75 protein (N-terminal hypervariable region) measured by ELISA [40,41].…”

Section: Recruitment and Eligibility Criteriamentioning

confidence: 99%

Controlled human infection for vaccination against Streptococcus pyogenes (CHIVAS): Establishing a group A Streptococcus pharyngitis human infection study

Osowicki

Azzopardi

Baker

et al. 2019

Vaccine

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Group A Streptococcus (GAS) is a highly-adapted and human-restricted pathogen responsible for a high global burden of disease across a diverse clinical spectrum. Vaccine development has been impeded by scientific, regulatory, and commercial obstacles. Human infection studies (HIS) are increasingly contributing to drug, diagnostics, and vaccine development, reducing uncertainty at early stages, especially for pathogens with animal models that incompletely reproduce key elements of human disease. We review the small number of historical GAS HIS and present the study protocol for a dose-ranging inpatient study in healthy adults. The primary objective of the study is to establish a new GAS pharyngitis HIS with an attack rate of at least 60% as a safe and reliable platform for vaccine evaluation and pathogenesis research. According to an adaptive dose-ranging study design, emm75 GAS doses manufactured in keeping with principles of Good Manufacturing Practice will be directly applied by swab to the pharynx of carefully screened healthy adult volunteers at low risk of severe complicated GAS disease. Participants will remain as closely monitored inpatients for up to six days, observed for development of the primary outcome of acute symptomatic pharyngitis, as defined by clinical and microbiological criteria. All participants will be treated with antibiotics and followed as outpatients for six months. An intensive sampling schedule will facilitate extensive studies of host and organism dynamics during experimental pharyngitis. Ethics approval has been obtained and the study has been registered at ClinicalTrials.gov (NCT03361163).

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“…In a third study by Chiang-Ni et al in Taiwan, an analysis of both invasive and noninvasive strains revealed that cluster E6 was associated with both types of infections, while clusters D4, E2, and E3 were responsible for causing invasive isolates in their population ( 16 ). Recently, Frost et al demonstrated that M type-specific and cross-reactive immune responses frequently align with emm clusters, raising new opportunities to design multivalent vaccines with broad coverage ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Systematic Review and Meta-analysis of the Prevalence of Group A Streptococcal emm Clusters in Africa To Inform Vaccine Development

Salie

Engel

Moloi

et al. 2020

mSphere

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An emm-cluster based system was proposed as a standard typing scheme to facilitate and enhance future studies of group A Streptococcus (GAS) epidemiological surveillance, M protein function, and vaccine development strategies. We provide an evidence-based distribution of GAS emm clusters in Africa and assess the potential coverage of the new 30-valent vaccine in terms of an emm cluster-based approach. Two reviewers independently assessed studies retrieved from a comprehensive search and extracted relevant data. Meta-analyses were performed (random-effects model) to aggregate emm cluster prevalence estimates. Eight studies (n = 1,595 isolates) revealed the predominant emm clusters as E6 (18%; 95% confidence interval [CI], 12.6% to 24.0%), followed by E3 (14%; 95% CI, 11.2% to 17.4%) and E4 (13%; 95% CI, 9.5% to 16.0%). There was negligible variation in emm clusters with regard to regions, age, and socioeconomic status across the continent. Considering an emm cluster-based vaccine strategy, which assumes cross-protection within clusters, the 30-valent vaccine currently in clinical development would provide hypothetical coverage to 80.3% of isolates in Africa. This systematic review indicates the most predominant GAS emm cluster in Africa is E6 followed by E3, E4, and D4. The current 30-valent vaccine would provide considerable coverage across the diversity of emm cluster types in Africa. Future efforts could be directed toward estimating the overall potential coverage of the new 30-valent vaccine based on cross-opsonization studies with representative panels of GAS isolates from populations at highest risk for GAS diseases. IMPORTANCE Low vaccine coverage is of grave public health concern, particularly in developing countries where epidemiological data are often absent. To inform vaccine development for group A Streptococcus (GAS), we report on the epidemiology of the M protein emm clusters from GAS infections in Africa, where GAS-related illnesses and their sequelae, including rheumatic fever and rheumatic heart disease, are of a high burden. This first report of emm clusters across the continent indicates a high probably of coverage by the M protein-based vaccine currently undergoing testing were an emm-cluster based approach to be used.

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Immune Cross-Opsonization Withinemm Clusters Following Group AStreptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity

Abstract: These data demonstrate that M type-specific and cross-reactive immune responses occur following skin infection. The cross-reactive immune responses frequently align with emm clusters, raising new opportunities to design multivalent vaccines with broad coverage.

Cited by 45 publications

References 40 publications

Analysis of Global Collection of Group A Streptococcus Genomes Reveals that the Majority Encode a Trio of M and M-Like Proteins

Analysis of Global Collection of Group A Streptococcus Genomes Reveals that the Majority Encode a Trio of M and M-Like Proteins

Controlled human infection for vaccination against Streptococcus pyogenes (CHIVAS): Establishing a group A Streptococcus pharyngitis human infection study

Systematic Review and Meta-analysis of the Prevalence of Group A Streptococcal emm Clusters in Africa To Inform Vaccine Development

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