Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis.

Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.

Antibiotics to eradicate Streptococcus pyogenes pharyngeal carriage in asymptomatic children and adults: A systematic review.

Streptococcus pyogenes (S. pyogenes) is a Gram-positive bacteria which causes a spectrum of diseases ranging from asymptomatic infection to life-threatening sepsis. Studies report up to 2000 times greater risk of invasive S. pyogenes disease in close contacts of index cases within 30-days of symptom onset. Despite this, there is variability in the management of asymptomatic carriage of S. pyogenes and those at risk of secondary cases of invasive S. pyogenes infection. OBJECTIVE: Our systematic review assessed the efficacy of different antibiotic regimens used for eradication of S. pyogenes from the pharynx in asymptomatic individuals. METHODS: We searched Pubmed, EMBASE (1974-), OVID Medline (1948-) and the Cochrane CENTRAL registry. We included randomised controlled trials (RCTs) with asymptomatic participants with >50% with pharyngeal cultures positive with S. pyogenes at baseline. Only studies with microbiological methods including culture (+/- polymerase chain reaction, PCR) were included. We included studies published in English. Each included study was assessed by two independent reviewers for data extraction and risk of bias. RESULTS: Of 1166 unique records identified, three RCTs were included in the review. Two of the three included RCTs found oral clindamycin for 10-days was the most efficacious regimen, compared to intramuscular benzathine penicillin G followed by 4 days of oral rifampicin, or monotherapy using benzathine penicillin, phenoxymethylpenicillin or erythromycin. Two RCTs were assessed as being at high risk of bias, with the third study demonstrating low/some risk of bias. CONCLUSIONS: Current available evidence for the optimal antibiotic in eradicating pharyngeal S. pyogenes carriage is limited. Future RCTs should include penicillin, first-generation cephalosporins, rifampicin, macrolides (such as azithromycin) and clindamycin.

Global Streptococcus pyogenes strain diversity, disease associations, and implications for vaccine development: a systematic review.

The high strain diversity of Streptococcus pyogenes serves as a major obstacle to vaccine development against this leading global pathogen. We did a systematic review of studies in PubMed, MEDLINE, and Embase that reported the global distribution of S pyogenes emm-types and emm-clusters from Jan 1, 1990, to Feb 23, 2023. 212 datasets were included from 55 countries, encompassing 74 468 bacterial isolates belonging to 211 emm-types. Globally, an inverse correlation was observed between strain diversity and the UNDP Human Development Index (HDI; r=-0·72; p<0·0001), which remained consistent upon subanalysis by global region and site of infection. Greater strain diversity was associated with a lower HDI, suggesting the role of social determinants in diseases caused by S pyogenes. We used a population-weighted analysis to adjust for the disproportionate number of epidemiological studies from high-income countries and identified 15 key representative isolates as vaccine targets. Strong strain type associations were observed between the site of infection (invasive, skin, and throat) and several streptococcal lineages. In conclusion, the development of a truly global vaccine to reduce the immense burden of diseases caused by S pyogenes should consider the multidimensional diversity of the pathogen, including its social and environmental context, and not merely its geographical distribution.

Naturally acquired functional antibody responses to group A Streptococcus differ between major strain types.

Group A Streptococcus (GAS) is a leading human pathogen for which there is no licensed vaccine. Infections are most common in young children and the elderly suggesting immunity accumulates with exposure until immune senescence in older age. Though protection has been postulated to be strain type specific, based on the M-protein (emm-type), the antigenic basis of population-level immunity remains poorly understood. Naturally acquired GAS antibody responses were investigated using intravenous immunoglobulin (IVIG), which contains pooled immunoglobulins from thousands of healthy human donors, as a surrogate for population immunity. Functional opsonophagocytic killing assays were conducted with GAS strains (n = 6) representing the three major emm-pattern types (emm12, A-C pattern; emm53, D-pattern; and emm75, E-pattern). While IVIG induced opsonophagocytic killing of all GAS strains tested, specificity assays showed the profile of protective antibodies differed considerably between emm-types. Antibodies targeting the M-protein were a major component of the functional IVIG antibody response for emm12 and emm53 strains but not for emm75 strains. The striking differences in the contribution of M-protein specific antibodies to killing suggest naturally acquired immunity differs between strains from the major emm-patterns. This challenges the dogma that M-protein is the primary protective antigen across all GAS straintypes. IMPORTANCE Group A Streptococcus (GAS) is a globally important pathogen. With the surge of invasive GAS infections that have occurred in multiple countries, contemporaneous with the relaxation of COVID-19 pandemic restrictions, there is increased interest in the mechanisms underpinning GAS immunity. We utilized intravenous immunoglobulin (IVIG), pooled immunoglobulins from thousands of healthy donors, as a surrogate for population-level immunity to GAS, and explored the contribution of strain-specific (M-type specific) antibodies to GAS immunity using functional killing assays. This revealed striking differences between major strain types as to the contribution of strain specific antibodies to killing. For GAS strains belonging to the E pattern group, M-type specific antibodies do not mediate killing and immunity, which contrasts with strains belonging to pattern A-C and D groups. This challenges the historical dogma, originally proposed by Rebecca Lancefield in the 1950-1960s, that the M-protein is the major protective antigen across all GAS strain types.

Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy.

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proof-of-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.

Scabies prevalence after ivermectin-based mass drug administration for lymphatic filariasis, Samoa 2018-2019.

BACKGROUND: Scabies is a common skin infestation caused by the Sarcoptes scabei mite. Ivermectin, one of three drugs used in mass drug administration (MDA) for lymphatic filariasis, is also effective for treating scabies. Ivermectin-based MDA was first conducted in Samoa in August 2018, with ivermectin being offered to those aged ≥5 years. Here, we report scabies prevalence in Samoa after MDA. METHODS: We conducted household surveys 1.5-3.5 months (Survey 1) and 6-8 months (Survey 2) after the 2018 MDA in 35 primary sampling units. We conducted clinical examination for scabies-like rash and used International Alliance for the Control of Scabies classification criteria. We estimated scabies prevalence by age, gender and region. Multivariable logistic regression was used to assess factors associated with prevalence. RESULTS: We surveyed 2868 people (499 households) and 2796 people (544 households) aged 0-75 years in Surveys 1 and 2, respectively. Scabies prevalence increased from 2.4% (95% CI 2.1-2.7%) to 4.4% (95% CI 4.0-4.9%) between surveys. Scabies was associated with younger age (0-4 years: aOR 3.5 [2.9-4.2]; 5-15 years: aOR 1.6 [1.4-1.8] compared to ≥16 years), female gender (aOR 1.2 [95% CI 1.1-1.4]; region (aOR range from 1.4 [1.1-1.7] to 2.5 [2.1-3.1] between regions), large households (aOR 2.6 [2.0-3.4] households ≥13), and not taking MDA in 2018 (aOR 1.3 [95% CI 1.1-1.6]). CONCLUSIONS: We found moderate prevalence of scabies in two population-representative surveys conducted within 8 months of the 2018 MDA for lymphatic filariasis. Prevalence appeared to increase between the surveys, and ongoing surveillance is recommended, particularly in young children.

Safety of Streptococcus pyogenes Vaccines: Anticipating and Overcoming Challenges for Clinical Trials and Post-Marketing Monitoring.

Streptococcus pyogenes (Strep A) infections result in a vastly underestimated burden of acute and chronic disease globally. The Strep A Vaccine Global Consortium's (SAVAC's) mission is to accelerate the development of safe, effective, and affordable S. pyogenes vaccines. The safety of vaccine recipients is of paramount importance. A single S. pyogenes vaccine clinical trial conducted in the 1960s raised important safety concerns. A SAVAC Safety Working Group was established to review the safety assessment methodology and results of more recent early-phase clinical trials and to consider future challenges for vaccine safety assessments across all phases of vaccine development. No clinical or biological safety signals were detected in any of these early-phase trials in the modern era. Improvements in vaccine safety assessments need further consideration, particularly for pediatric clinical trials, large-scale efficacy trials, and preparation for post-marketing pharmacovigilance.

Population-based assessment of cardiovascular complications of rheumatic heart disease in Fiji: a record-linkage analysis.

OBJECTIVE: To determine population-based rates of non-fatal complications of rheumatic heart disease (RHD). DESIGN: Retrospective cohort study based on multiple sources of routine clinical and administrative data amalgamated by probabilistic record-linkage. SETTING: Fiji, an upper-middle-income country, where most of the population has access to government-funded healthcare services. PARTICIPANTS: National cohort of 2116 patients with clinically apparent RHD aged 5-69 years during 2008 and 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was hospitalisation for any of heart failure, atrial fibrillation, ischaemic stroke and infective endocarditis. Secondary outcomes were first hospitalisation for each of the complications individually in the national cohort as well as in hospital (n=1300) and maternity (n=210) subsets. Information on outcomes was obtained from discharge diagnoses coded in the hospital patient information system. Population-based rates were obtained using relative survival methods with census data as the denominator. RESULTS: Among 2116 patients in the national cohort (median age, 23.3 years; 57.7% women), 546 (25.8%) were hospitalised for an RHD complication, a substantial proportion of all cardiovascular admissions in the country during this period in those aged 0-40 years (heart failure, 210/454, 46.3%; ischaemic stroke 31/134, 23.1%). Absolute numbers of RHD complications peaked during the third decade of life with higher population-based rates in women compared with men (incidence rate ratio 1.4, 95% CI 1.3 to 1.6, p<0.001). Hospitalisation for any RHD complication was associated with substantially increased risk of death (HR 5.4, 95% CI 3.4 to 8.8, p<0.001), especially after the onset of heart failure (HR 6.6, 95% CI 4.8 to 9.1, p<0.001). CONCLUSIONS: Our study defines the burden of RHD-attributable morbidity in the general population of Fiji, potentially reflecting the situation in low-income and middle-income countries worldwide. Hospitalisation for an RHD complication is associated with markedly increased risk of death, re-emphasising the importance of effective early prevention.

One versus two doses of ivermectin-based mass drug administration for the control of scabies: A cluster randomised non-inferiority trial.

BACKGROUND: Mass drug administration (MDA) based on two doses of ivermectin, one week apart, substantially reduces prevalence of both scabies and impetigo. The Regimens of Ivermectin for Scabies Elimination (RISE) trial assessed whether one-dose ivermectin-based MDA would be as effective. METHODS: RISE was a cluster-randomised trial in Solomon Islands. We assigned 20 villages in a 1:1 ratio to one- or two-dose ivermectin-based MDA. We planned to test whether the impact of one dose on scabies prevalence at 12 and 24 months was non-inferior to two, at a 5% non-inferiority margin. RESULTS: We deferred endpoint assessment to 21 months due to COVID-19. We enrolled 5239 participants in 20 villages at baseline and 3369 at 21 months from an estimated population of 5500. At baseline scabies prevalence was similar in the two arms (one-dose 17·2%; two-dose 13·2%). At 21 months, there was no reduction in scabies prevalence (one-dose 18·7%; two-dose 13·4%), and the confidence interval around the difference included values substantially greater than 5%. There was however a reduction in prevalence among those who had been present at the baseline assessment (one-dose 15·9%; two-dose 10·8%). Additionally, we found a reduction in both scabies severity and impetigo prevalence in both arms, to a similar degree. CONCLUSIONS: There was no indication of an overall decline in scabies prevalence in either arm. The reduction in scabies prevalence in those present at baseline suggests that the unexpectedly high influx of people into the trial villages, likely related to the COVID-19 pandemic, may have compromised the effectiveness of the MDA. Despite the lack of effect there are important lessons to be learnt from this trial about conducting MDA for scabies in high prevalence settings. TRIAL REGISTRATION: Registered with Australian New Zealand Clinical Trials Registry ACTRN12618001086257.

Paediatric admissions with SARS-CoV-2 during the Delta and Omicron waves: an Australian single-centre retrospective study.

BACKGROUND: The clinical course of Australian children admitted to hospital with COVID-19 infection is not well understood, particularly over the Omicron period. METHODS: This study describes paediatric admissions to a single tertiary paediatric institution through the Delta and Omicron variant waves. All children admitted from 1 June 2021 to 30 September 2022 with a diagnosis of COVID-19 infection were included for analysis. RESULTS: 117 patients were admitted during the Delta wave compared with 737 during the Omicron wave. The median length of stay was 3.3 days (IQR 1.7-6.75.1) during Delta, compared with 2.1 days (IQR 1.1-4.53.4) during Omicron (p<0.01). 83 patients (9.7%) required intensive care unit (ICU) admission, a greater proportion during Delta (20, 17.1%) than Omicron (63, 8.6%, p<0.01). Patients admitted to the ICU were less likely to have received a dose of COVID-19 vaccination prior to admission than patients admitted to the ward (8, 24.2% vs 154, 45.8%, p=0.028). CONCLUSION: The Omicron wave resulted in an absolute increase in the number of children compared with Delta, but cases had lower severity, demonstrated by shorter length of stay and a smaller proportion of patients requiring intensive care. This is consistent with US and UK data describing a similar pattern.

The Streptococcus pyogenes vaccine landscape.

Recent efforts have re-invigorated the Streptococcus pyogenes (Group A Streptococcus) vaccine development field, though scientific, regulatory and commercial barriers persist, and the vaccine pipeline remains sparse. There is an ongoing need to accelerate all aspects of development to address the large global burden of disease caused by the pathogen. Building on over 100 years of S. pyogenes vaccine development, there are currently eight candidates on a product development track, including four M protein-based candidates and four candidates designed around non-M protein antigens. These candidates have demonstrated proof of concept for protection against S. pyogenes in preclinical models, one has demonstrated safety and immunogenicity in a Phase 1 trial and at least four others are poised to soon enter clinical trials. To maintain momentum, the Strep A Vaccine Global Consortium (SAVAC) was established to bring together experts to accelerate global S. pyogenes vaccine development. This article highlights the past, present and future of S. pyogenes vaccine development and emphasizes key priorities, and the role of SAVAC, in advancing the field.

Promiscuous evolution of Group A Streptococcal M and M-like proteins.

Group A Streptococcus (GAS) M and M-like proteins are essential virulence factors and represent the primary epidemiological marker of this pathogen. Protein sequences encoding 1054 M, Mrp and Enn proteins, from 1668 GAS genomes, were analysed by SplitsTree4, partitioning around medoids and co-occurrence. The splits network and groups-based analysis of all M and M-like proteins revealed four large protein groupings, with multiple evolutionary histories as represented by multiple edges for most splits, leading to 'M-family-groups' (FG) of protein sequences: FG I, Mrp; FG II, M protein and Protein H; FG III, Enn; and FG IV, M protein. M and Enn proteins formed two groups with nine sub-groups and Mrp proteins formed four groups with ten sub-groups. Discrete co-occurrence of M and M-like proteins were identified suggesting that while dynamic, evolution may be constrained by a combination of functional and virulence attributes. At a granular level, four distinct family-groups of M, Enn and Mrp proteins are observable, with Mrp representing the most genetically distinct of the family-group of proteins. While M and Enn protein families generally group into three distinct family-groups, horizontal and vertical gene flow between distinct GAS strains is ongoing.

Correction: A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

[This corrects the article DOI: 10.1371/journal.pntd.0009144.].

Acute rheumatic fever and rheumatic heart disease in children and adolescents in Victoria, Australia.

AIM: To describe the epidemiology and clinical profile of children and adolescents with acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in Victoria, Australia. METHODS: A retrospective audit was undertaken of children and adolescents with ARF and RHD attending the Royal Children's and Monash Children's Hospitals in Victoria, Australia between 2010 and 2019. Potential cases were identified by searching multiple sources for relevant ICD-10-AM codes and keywords, then reviewed manually. For confirmed cases, we collected data on patient demographics, clinical features, comorbidities and management. RESULTS: Of 179 participants included, there were 108 Victorian residents and 71 non-Victorian residents. 126 had at least one episode of ARF during the study period and 128 were diagnosed with RHD. In the Victorian resident group, the overall incidence of ARF was 0.8 per 100 000 5-14 year olds. This incidence was higher in Victorian Aboriginal and/or Torres Strait Islander (3.8 per 100 000) and Pacific Islander (32.1 per 100 000) sub-populations. Of 83 Victorian residents who had an ARF episode, 11 (13%) had a recurrence. Most Victorian residents with RHD had mixed aortic and mitral valve pathology (69.4%) and moderate to severe disease (61.9%). Most non-Victorian residents were Aboriginal and/or Torres Strait Islander people (80.3%) and were commonly transferred for tertiary or surgical management of RHD (83.1%). CONCLUSIONS: ARF and RHD continue to affect the health of significant numbers of children and adolescents living in Victoria, including severe and recurrent disease. Specialised services and a register-based control program may help to prevent complications and premature death.

Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease-streptococcal vaccine development: a national heart, lung and blood institute workshop report.

Streptococcus pyogenes, also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.

Increase in invasive group A streptococcal disease among Australian children coinciding with northern hemisphere surges.

Background: Increases in invasive group A streptococcal disease (iGAS) have recently been reported in multiple countries in the northern hemisphere, occurring during, and outside of, typical spring peaks. We report the epidemiology of iGAS among children in Australia from 1 July 2018 to 31 December 2022. Methods: The Paediatric Active Enhanced Disease Surveillance (PAEDS) Network prospectively collected iGAS patient notifications for children and young people aged less than 18 years admitted to five major Australian paediatric hospitals in Victoria, Queensland, Western Australia and the Northern Territory. Patients were eligible for inclusion if they had GAS isolated from a normally sterile body site, or met clinical criteria for streptococcal toxic shock syndrome or necrotising fasciitis with GAS isolated from a non-sterile site. We report patients' clinical and demographic characteristics, and estimate minimum incidence rates. Findings: We identified 280 paediatric iGAS patients, median age 4.5 years (interquartile range 1.4-6.4). We observed a pre-pandemic peak annualised incidence of 3.7 per 100,000 (95% CI 3.1-4.4) in the 3rd quarter of 2018, followed by a decline to less than 1.0 per 100,000 per quarter from 2020 to mid-2021. The annualised incidence increased sharply from mid-2022, peaking at 5.2 per 100,000 (95% CI 4.4-6.0) in the 3rd quarter and persisting into the 4th quarter (4.9 per 100,000, 95% CI 4.2-5.7). There were 3 attributable deaths and 84 (32%) patients had severe disease (overall case fatality rate 1%, 95% CI 0.2-3.3). Respiratory virus co-infection, positive in 57 of 119 patients tested, was associated with severe disease (RR 1.9, 95% CI 1.2-3.0). The most common emm-type was emm-1 (60 of 163 isolates that underwent emm-typing, 37%), followed by emm-12 (18%). Interpretation: Australia experienced an increase in the incidence of iGAS among children and young people in 2022 compared to pandemic years 2020-2021. This is similar to northern hemisphere observations, despite differences in seasons and circulating respiratory viruses. Outbreaks of iGAS continue to occur widely. This emphasises the unmet need for a vaccine to prevent significant morbidity associated with iGAS disease. Funding: Murdoch Children's Research Institute funded open access publishing of this manuscript.

Comparison of antibody responses to SARS-CoV-2 variants in Australian children.

There is limited understanding of antibody responses in children across different SARS-CoV-2 variants. As part of an ongoing household cohort study, we assessed the antibody response among unvaccinated children infected with Wuhan, Delta, or Omicron variants, as well as vaccinated children with breakthrough Omicron infection, using a SARS-CoV-2 S1-specific IgG assay and surrogate virus neutralization test (% inhibition). Most children infected with Delta (100%, 35/35) or Omicron (81.3%, 13/16) variants seroconverted by one month following infection. In contrast, 37.5% (21/56) children infected with Wuhan seroconverted, as previously reported. However, Omicron-infected children (geometric mean concentration 46.4 binding antibody units/ml; % inhibition = 16.3%) mounted a significantly lower antibody response than Delta (435.5 binding antibody untis/mL, % inhibition = 76.9%) or Wuhan (359.0 binding antibody units/mL, % inhibition = 74.0%). Vaccinated children with breakthrough Omicron infection mounted the highest antibody response (2856 binding antibody units/mL, % inhibition = 96.5%). Our findings suggest that despite a high seropositivity rate, Omicron infection in children results in lower antibody levels and function compared with Wuhan or Delta infection or with vaccinated children with breakthrough Omicron infection. Our data have important implications for public health measures and vaccination strategies to protect children.