Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate for epidemiological typing is both a virulence factor and a vaccine antigen. Over 220 variants of this protein have been described, making comparisons between proteins difficult, and hindering M protein-based vaccine development. A functional classification based on 48 emm-clusters containing closely related M proteins that share binding and structural properties is proposed. The need for a paradigm shift from type-specific immunity against S. pyogenes to emm-cluster based immunity for this bacterium should be further investigated. Implementation of this emm-cluster-based system as a standard typing scheme for S. pyogenes will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development.

Group A Streptococcus (GAS; Streptococcus pyogenes) is a bacterial pathogen for which a commercial vaccine for humans is not available. Employing the advantages of high-throughput DNA sequencing technology to vaccine design, we have analyzed 2,083 globally sampled GAS genomes. The global GAS population structure reveals extensive genomic heterogeneity driven by homologous recombination and overlaid with high levels of accessory gene plasticity. We identified the existence of more than 290 clinically associated genomic phylogroups across 22 countries, highlighting challenges in designing vaccines of global utility. To determine vaccine candidate coverage, we investigated all of the previously described GAS candidate antigens for gene carriage and gene sequence heterogeneity. Only 15 of 28 vaccine antigen candidates were found to have both low naturally occurring sequence variation and high (>99%) coverage across this diverse GAS population. This technological platform for vaccine coverage determination is equally applicable to prospective GAS vaccine antigens identified in future studies.

In resource-limited tropical settings, both impetigo and rheumatic disease are endemic. The major cause of impetigo in these regions is the group A streptococcus and there is a growing body of opinion implicating impetigo in the pathogenesis of rheumatic fever and rheumatic heart disease (RHD). This potentially has major implications for control of these neglected diseases, which account for at least 350 000 deaths worldwide, annually. In this review, we summarize recent advances in the epidemiology of group A streptococcal skin disease and examine evidence for the relationship between group A streptococcal skin disease and rheumatic fever. Detailed epidemiologic studies of impetigo, particularly among indigenous communities in the Pacific among whom rheumatic fever is endemic, find the disease remarkably prevalent. In contrast, group A streptococcal pharyngitis occurs no more frequently than in regions wherein rheumatic fever is now rare. Studies of molecular epidemiology reveal that overall there is a greater diversity of group A streptococcal strains in tropical regions, and skin-associated strains appear predominant. These skin strains may move between skin and throat, and there is increasing evidence of skin-associated strains being linked to cases of rheumatic fever. The available data support the hypothesis that group A streptococcal impetigo plays a role in the pathogenesis of RHD. There is considerable scope to investigate this question through studies of pathogenesis, employing advances in both human and bacterial genetics, molecular immunology, and carefully designed trials aimed at control of impetigo.

Group A Streptococcus (GAS) infections result in a considerable underappreciated burden of acute and chronic disease globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important World Health Organization (WHO) activity, influencing prioritization of investments. Here, the role, status, and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision making, availability, and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitutes a key near-term strategic goal. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed.