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Controlled human infection (CHI) models can provide insights into transmission of pathogens such as Streptococcus pyogenes (Strep A). As part of the Controlled Human Infection with Penicillin for Streptococcus pyogenes (CHIPS) trial, we explored the potential for transmission among participants deliberately infected with the Strep A emm75 strain. Three approaches to understanding transmission were employed: the use of agar settle plates to capture possible droplet or airborne spread of Strep A; measurement of distance droplets could spread during conversation; and environmental swabbing of high-touch items to detect Strep A on surfaces. Of the 60 (27%) CHIPS trial participants across five cohorts, 16 were enrolled in this sub-study; availability of study staff was the primary reason for selection. In total, 189 plates and 260 swabs were collected. Strep A was grown on one settle plate from a participant on the second day, using plates placed 30 cm away. This participant received the placebo dose of penicillin and had met the primary endpoint of pharyngitis. Whole-genome sequencing identified this to be the challenge strain. Strep A was not detected on any swabs. In this small sample of CHI participants, we did not find evidence of Strep A transmission by the airborne route or fomites, and just one instance of droplet spread while acutely symptomatic with streptococcal pharyngitis. Although these experiments provide evidence of minimal transmission within controlled clinical settings, greater efforts are required to explore Strep A transmission in naturalistic settings.IMPORTANCE Streptococcus pyogenes remains a significant driver of morbidity and mortality, particularly in under-resourced settings. Understanding the transmission modalities of this pathogen is essential to ensuring the success of prevention methods. This proposed paper presents a nascent attempt to determine the transmission potential of Streptococcus pyogenes nested within a larger controlled human infection model., Competing Interests: The authors declare no conflict of interest.

Background: Antibiotic consumption can lead to antimicrobial resistance and microbiome imbalance. We sought to estimate global antibiotic consumption for sore throat, and the potential reduction in consumption due to effective vaccination against group A Streptococcus (Strep A)., Methods: We reviewed and analysed articles published between January 2000 and February 2022, identified though Clarivate Analytics' Web of Science search platform, with reference to antibiotic prescribing or consumption, sore throat, pharyngitis, or tonsillitis. We then used those analyses, combined with assumptions for the effectiveness, duration of protection, and coverage of a vaccine, to calculate the estimated reduction in antibiotic prescribing due to the introduction of Strep A vaccines., Findings: We identified 101 studies covering 38 countries. The mean prescribing rate for sore throat was approximately 5 courses per 100 population per year, accounting for approximately 5% of all antibiotic consumption. Based on 2020 population estimates for countries with empiric prescribing rates, antibiotic consumption for sore throat was estimated to exceed 37 million courses annually, of which half could be attributable to treatment for Strep A. A vaccine that reduces rates of Strep A infection by 80%, with 80% coverage and 10 year's duration of protection, could avert 2.8 million courses of antibiotics prescribed for sore throat treatment among 5-14 year-olds in countries with observed prescribing rates, increasing to an estimated 7.5 million averted if an effective vaccination program also reduced precautionary prescribing., Interpretation: A vaccine that prevents Strep A throat infections in children may reduce antibiotic prescribing for sore throat by 32-87% depending on changes to prescribing and consumption behaviours., Funding: The Wellcome Trust, grant agreement number 215490/Z/19/Z., Competing Interests: Declaration of interests The authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Group A Streptococcus (GAS) causes pharyngitis (sore throat) and impetigo (skin sores) GAS pharyngitis triggers rheumatic fever (RF) with epidemiological evidence supporting that GAS impetigo may also trigger RF in Australian Aboriginal children. Understanding the concurrent burden of these superficial GAS infections is critical to RF prevention. This pilot study aimed to trial tools for concurrent surveillance of sore throats and skins sore for contemporary studies of RF pathogenesis including development of a sore throat checklist for Aboriginal families and pharynx photography., Methods: Yarning circle conversations and semi-structured interviews were performed with Aboriginal caregivers and used to develop the language and composition of a sore throat checklist. The sore throat story checklist was combined with established methods of GAS pharyngitis and impetigo surveillance (examination, bacteriological culture, rapid antigen detection and serological tests) and new technologies (photography) and used for a pilot cross-sectional surveillance study of Aboriginal children attending their health clinic for a routine appointment. Feasibility, acceptability, and study costs were compiled., Results: Ten Aboriginal caregivers participated in the sore-throat yarning circles; a checklist was derived from predominant symptoms and their common descriptors. Over two days, 21 Aboriginal children were approached for the pilot surveillance study, of whom 17 were recruited; median age was 9 years [IQR 5.5-13.5], 65% were female. One child declined throat swabbing and three declined finger pricks; all other surveillance elements were completed by each child indicating high acceptability of surveillance assessments. Mean time for screening assessment was 19 minutes per child. Transport of clinical specimens enabled gold standard microbiological and serological testing for GAS. Retrospective examination of sore throat photography concorded with assessments performed on the day., Conclusion: Yarning circle conversations were effective in deriving culturally appropriate sore throat questionnaires for GAS pharyngitis surveillance. New and established tools were feasible, practical and acceptable to participants and enable surveillance to determine the burden of superficial GAS infections in communities at high risk of RF. Surveillance of GAS pharyngitis and impetgio in remote Australia informs primary RF prevention with potential global translation., Competing Interests: The authors declare there are no competing interests., (©2023 Pickering et al.)

Background: Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab., Methods: This observational, dose-finding study was done in a clinical trials facility in Melbourne (VIC, Australia). Groups of healthy volunteers aged 18-40 years, at low risk of complicated S pyogenes disease, and without high type-specific anti-emm75 IgG antibodies against the challenge strain were challenged and closely monitored as inpatients for up to 6 days, and then as outpatients for 6 months. Antibiotics were started upon diagnosis (clinical signs and symptoms of pharyngitis and a positive rapid molecular test) or after 5 days in those without pharyngitis. Rapid test results were confirmed by standard bacterial culture. After a sentinel participant, cohorts of five and then ten participants were challenged, with protocol-directed dose-escalation or de-escalation for subsequent cohorts. The primary outcome was the proportion of participants at each dose level with pharyngitis by day 5 after challenge. The study is registered with ClinicalTrials.gov, NCT03361163., Findings: Between July 10, 2018, and Sept 23, 2019, 25 healthy adults were challenged with emm75 S pyogenes and included in analyses. Pharyngitis was diagnosed in 17 (85%; 95% CI 62-97) of 20 participants at the starting dose level (1-3 × 10 5 colony-forming units [CFU]/mL). This high proportion prompted dose de-escalation. At the lower dose level (1-3 × 10 4 CFU/mL), pharyngitis was diagnosed in one of five participants. Immunological, biochemical, and microbiological results supported the clinical picture, with acute symptomatic pharyngitis characterised by pharyngeal colonisation by S pyogenes accompanied by significantly elevated C-reactive protein and inflammatory cytokines (eg, interferon-γ and interleukin-6), and modest serological responses to streptolysin O and deoxyribonuclease B. There were no severe (grade 3) or serious adverse events related to challenge., Interpretation: We have established a reliable pharyngitis human infection model with reassuring early safety findings to accelerate development of vaccines and other interventions to control disease due to S pyogenes., Funding: Australian National Health and Medical Research Council., Competing Interests: Declaration of interests JBD is the inventor of technologies related to the development of S pyogenes vaccines; the University of Tennessee Research Foundation has licensed these technologies to Vaxent, of which JBD is the chief scientific officer and a member. MP and MFG are inventors on patents related to S pyogenes vaccines, and Griffith University (Gold Coast, QLD, Australia) has licensed some of these technologies to Olymvax Pharmaceuticals (China). NJM is an inventor on a patent related to S pyogenes analytical methods and compositions. MJW has a patent pending related to S pyogenes vaccines. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Acute rheumatic fever and rheumatic heart disease cause a high burden of disease in Fiji and surrounding Pacific Island countries, but little is known about the epidemiology of group A streptococcal (GAS) pharyngitis in the region. We designed a study to estimate the prevalence of carriage of beta-hemolytic streptococci (BHS) and the incidence of BHS culture-positive sore throat in school aged children in Fiji., Methods: We conducted twice-weekly prospective surveillance of school children aged 5 to 14 years in 4 schools in Fiji during a 9-month period in 2006, after an initial phase of pharyngeal swabbing to determine the prevalence of BHS carriage., Results: We enrolled 685 children. The prevalence of GAS carriage was 6.0%, while the prevalence of group C streptococcal (GCS) and group G streptococcal (GGS) carriage was 6.9% and 12%, respectively. There were 61 episodes of GAS culture-positive sore throat during the study period equating to an incidence of 14.7 cases per 100 child-years (95% CI, 11.2-18.8). The incidence of GCS/GGS culture-positive sore throat was 28.8 cases per 100 child-years (95% CI, 23.9-34.5). The clinical nature of GAS culture-positive sore throat was more severe than culture-negative sore throat, but overall was mild compared with that found in previous studies. Of the 101 GAS isolates that emm sequence typed there were 45 emm types with no dominant types. There were very few emm types commonly encountered in industrialized nations and only 9 of the 45 emm types found in this study are emm types included in the 26-valent GAS vaccine undergoing clinical trials., Conclusions: GAS culture-positive sore throat was more common than expected. Group C and group G streptococci were frequently isolated in throat cultures, although their contribution to pharyngeal infection is not clear. The molecular epidemiology of pharyngeal GAS in our study differed greatly from that in industrialized nations and this has implications for GAS vaccine clinical research in Fiji and other tropical developing countries.

Objective: The objective of this study was to determine the incidence, transmission, carriage, and risk factors for group A streptococcal pharyngitis in school-aged children and their families., Methods: A 16-month, prospective, family-based cohort study was undertaken from August 2001 through December 2002 in Melbourne, Australia. A total of 202 families (853 people) with at least 1 child aged 3 to 12 years were randomly selected from 3 primary care practices across suburban Melbourne to collect surveillance data for acute group A streptococcal pharyngitis, including serology for index and secondary cases and intermittent carriage data. Cohort retention was 97% for 16 months., Results: The incidence of acute sore throat, group A streptococcal swab-positive pharyngitis, and serologically confirmed group A streptococcal pharyngitis was 33, 13, and 8 per 100 child-years, respectively, for school-aged children (5-12 years) and 60, 20, and 15 per 100 family-years, respectively. Sore throat was less common in adults than children, but adults with sore throat were as likely as children to have group A streptococcal culture-positive or serologically proven pharyngitis. In families who had a primary case, 43% had at least 1 secondary case, and in family members who were at risk, 13% contracted a secondary case. The spring, summer, and winter carriage rates for children were 13%, 8%, and 16%, respectively, and for adults the rate was 2% across all seasons., Conclusions: Group A streptococcal pharyngitis is still common, and the peak incidence occurs in school-aged children. However, the incidence in adults is higher than expected, and the number of secondary cases in families may be an important factor when considering the potential benefits of treatment.

Background: The aim of the study was to describe the epidemiology of pharyngitis and pyoderma in a Central Australian Aboriginal community with a high prevalence of rheumatic heart disease (RHD) and compare it to communities in the Top End of the Northern Territory., Methods: Following ethics approval and community consultation, selected households were enrolled and visited over a 13-month period. People were asked if they had a sore throat and/or skin sores and asked about current or recent use of antibiotics; all throats and any pyoderma lesions were swabbed for bacterial culture. Beta-haemolytic streptococci (BHS), including group A streptococcus (GAS), were identified in the central laboratory using standard methods. Household crowding was also assessed. Results were then compared to those from the Top End study., Results: Sore throat was relatively common (480 episodes per 100 person years), although there was only one case of GAS pharyngitis in 326 consultations. Only 5.5% of children <15 years had pyoderma during the course of the study. This is the opposite picture to that reported in the Top End where symptomatic pharyngitis is rare and pyoderma is common., Conclusions: Although the data are limited, the epidemiology of pharyngitis and pyoderma in this Central Australian Aboriginal community appears to be more akin to that seen in temperate climates rather than tropical Top End communities. In this community, RHD preventative measure should continue to include aggressive treatment of pharyngitis according to recommendations.

Background: It is postulated that the surge in incidence and severity of group A streptococcus (GAS) infections since the 1980s is due to the emergence of strains of GAS with increased virulence. We used active, population-based surveillance of invasive GAS disease, serologically confirmed pharyngitis, and carriage to determine whether particular strains were associated with invasive disease., Methods: Two hundred twenty GAS isolates were collected--78 invasive, 34 pharyngitis, and 108 carriage. Isolates were characterized using emm typing, random amplification of polymorphic DNA (RAPD) profiling, and superantigen genotyping., Results: emm1, emm12, and emm28 predominated in invasive disease and accounted for 30.8%, 12.8%, and 12.8% of all isolates, respectively. emm1, emm75, emm28, and emm4 were the most frequently isolated emm types in pharyngitis, and emm12 and emm1 predominated in carriage. emm12 was significantly associated with carriage rather than disease. There were no other significant associations between emm type and disease or carriage. There were no associations between any RAPD profile or superantigen genotype and invasive disease, pharyngitis, or carriage. One RAPD profile accounted for most cases of necrotizing fasciitis, which suggests that this strain might have particular features promoting connective-tissue infection., Conclusions: These data suggest that the emergence of GAS strains with increased virulence is not the main factor responsible for the surge in GAS-related infections. The prevalence of particular emm types, RAPD profiles, or superantigen genes in invasive disease may simply indicate widespread transmission of these strains in the population, rather than a particular ability to cause disease.

Background: Acute rheumatic fever is a major cause of heart disease in Aboriginal Australians. The epidemiology differs from that observed in regions with temperate climates; streptococcal pharyngitis is reportedly rare, and pyoderma is highly prevalent. A link between pyoderma and acute rheumatic fever has been proposed but is yet to be proven. Group C beta-hemolytic streptococci and group G beta-hemolytic streptococci have also been also implicated in the pathogenesis., Methods: Monthly, prospective surveillance of selected households was conducted in 3 remote Aboriginal communities. People were questioned about sore throat and pyoderma; swab specimens were obtained from all throats and any pyoderma lesions. Household population density was determined., Results: From data collected during 531 household visits, the childhood incidence of sore throat was calculated to be 8 cases per 100 person-years, with no cases of symptomatic group A beta-hemolytic streptococci pharyngitis. The median point prevalence for throat carriage was 3.7% for group A beta-hemolytic streptococci, 0.7% for group C beta-hemolytic streptococci, and 5.1% for group G beta-hemolytic streptococci. Group A beta-hemolytic streptococci were recovered from the throats of 19.5% of children at some time during the study. There was no seasonal trend or correlation with overcrowding. Almost 40% of children had pyoderma at least once, and the prevalence was greatest during the dry season. In community 1, the prevalence of pyoderma correlated with household crowding. Group C and G beta-hemolytic streptococci were rarely recovered from pyoderma lesions., Conclusions: These data are consistent with the hypothesis that recurrent skin infections immunize against throat colonization and infection. High rates of acute rheumatic fever were not driven by symptomatic group A beta-hemolytic streptococci throat infection. Group G and C beta-hemolytic streptococci were found in the throat but rarely in pyoderma lesions.

Background & Objectives: There are no recent data from industrialised countries documenting the incidence and costs of group A streptococcal (GAS) pharyngitis. Such data are important in developing policy regarding management (e.g., whether or not to use antibiotics to treat sore throat) and in planning preventive strategies, including preparing for the arrival of GAS vaccines. The present study was undertaken to estimate the incidence and costs of GAS pharyngitis in school aged children in Melbourne, Australia. We report here the results after initial 11 months of surveillance., Methods: A total of 202 families (852 individuals) with at least one child aged 3 to 12 yr were enrolled across Melbourne in a family-based cohort study, and are being followed prospectively for 24 months. Surveillance data for acute GAS pharyngitis (including serology), throat carriage, and costs of the disease were collected. Additional cases of GAS pharyngitis have been ascertained to improve the precision of costing estimates., Results: Cohort retention was 97 per cent. The spring, summer and winter carriage rates for children were 13.0, 8.0 and 16.0 per cent respectively. The incidence of GAS pharyngitis was 14 per 100 person-years for children. For every primary case there were 0.7 secondary cases and 24 per cent of families experienced at least one episode of GAS pharyngitis per year. Preliminary costing data suggest that 46 per cent of cases lead to school absenteeism and a high rate of antibiotic use., Interpretation & Conclusion: The present data suggest that GAS pharyngitis remains very common in childhood, and that it has further implications in terms of secondary cases and costs.

Acute rheumatic fever (ARF) remains a major problem in tropical regions, resource-poor countries, and minority indigenous communities. It has long been thought that group A streptococcal (GAS) pharyngitis alone was responsible for acute rheumatic fever; this belief has been supported by laboratory and epidemiological evidence gathered over more than 60 years, mainly in temperate climates where GAS skin infection is uncommon. GAS strains have been characterised as either rheumatogenic or nephritogenic based on phenotypic and genotypic properties. Primary prevention strategies and vaccine development have long been based on these concepts. The epidemiology of ARF in Aboriginal communities of central and northern Australia challenges this view with reported rates of ARF and rheumatic heart disease (RHD) that are among the highest in the world. GAS throat colonisation is uncommon, however, and symptomatic GAS pharyngitis is rare; pyoderma is the major manifestation of GAS infection. Typical rheumatogenic strains do not occur. Moreover, group C and G streptococci have been shown to exchange key virulence determinants with GAS and are more commonly isolated from the throats of Aboriginal children. We suggest that GAS pyoderma and/or non-GAS infections are driving forces behind ARF in these communities and other high-incidence settings. The question needs to be resolved as a matter of urgency because current approaches to controlling ARF/RHD in Aboriginal communities have clearly been ineffective. New understanding of the pathogenesis of ARF would have an immediate effect on primary prevention strategies and vaccine development.

There are few good-quality studies of the effectiveness of antibiotic treatment of proven group A streptococcal (GAS) pharyngitis in children; available data suggest that antibiotics may reduce symptom duration. While there is limited justification for antibiotic treatment of GAS pharyngitis to prevent acute rheumatic fever in non-Indigenous Australians, there is no justification for routine antibiotic treatment of all patients with sore throat. Two strategies are open to clinicians: not to treat GAS pharyngitis with antibiotics, in which case no investigations should be done; or to treat cases of sore throat with clinical features that suggest GAS, in which case diagnosis should be confirmed with a throat swab, and penicillin started while awaiting the result. Penicillin should be discontinued if the swab is negative, or continued for 10 days if it is positive for GAS. Surveillance of GAS infections and acute rheumatic fever is needed in Australia, as are further studies of effectiveness (including cost-effectiveness) of antibiotic treatment of proven GAS pharyngitis.

Disease caused by group A streptococci (GAS) in tropical regions often takes the form of impetigo, whereas pharyngitis tends to predominate in temperate zones. GAS derived from asymptomatic throat infections and pyoderma lesions of rural Aboriginal Australians were evaluated for phylogenetic distant emm genes, which represent ecological markers for tissue site preference. On the basis of the percentage of total isolates from a given tissue, emm pattern A-C organisms exhibited a stronger predilection for the throat, whereas pattern D organisms preferred the skin. Only 16% of isolates collected by active surveillance displayed pattern A-C, which reflects the low incidence of oropharyngeal infection. Importantly, most (70%) pattern A-C organisms were isolated from skin sores, despite their innate tendency to infect the throat. Combined with findings from nontropical populations, analysis of the data supports the hypothesis that GAS tissue preferences are genetically predetermined and that host risk factors for infection strongly influence the differential reproduction of individual clones.