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Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%–30%. Despite this

A new variant of Streptococcus pyogenes serotype M1 (designated ‘M1UK’) has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor S. pyogenes ‘M1global’ and M1UK clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for speA upregulation is unknown. Here we investigate the previously unappreciated expansion of M1UK in Australia, now isolated from the majority of serious infections caused by serotype M1 S. pyogenes. M1UK sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing S. pyogenes in Asia. A single SNP in the 5’ transcriptional leader sequence of the transfer-messenger RNA gene ssrA drives enhanced SpeA superantigen expression as a result of ssrA terminator read-through in the M1UK lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance.

Background For decades, the research community has called for participant information sheets/consent forms (PICFs) to be improved. Recommendations include simplifying content, reducing length, presenting information in layers and using multimedia. However, there are relatively few studies that have evaluated health consumers’ (patients/carers) perspectives on the type and organisation of information, and the level of detail to be included in a PICF to optimise an informed decision to enter a trial. We aimed to elicit consumers’ views on a layered approach to consent that provides the key information for decision-making in a short PICF (layer 1) with additional optional information that is accessed separately (layer 2). We also elicited consumers’ views on the optimal content and layout of the layered consent materials for a large and complex Bayesian adaptive platform trial (the SNAP trial). Methods We conducted a qualitative multicentre study (4 focus groups and 2 semi-structured interviews) involving adolescent and adult survivors of Staphylococcus aureus bloodstream infection (22) and their carers (2). Interview transcripts were examined using inductive thematic analysis. Results Consumers supported a layered approach to consent. The primary theme that emerged was the value of agency; the ability to exert some control over the amount of information read before the consent form is signed. Three other themes emerged; the need to prioritise participants’ information needs; the importance of health literacy; the importance of information about a trial’s benefits (over its risks) for decision-making and the interplay between the two. Conclusions Our findings suggest that consumers may challenge the one-size-fits-all approach currently applied to the development of PICFs in countries like Australia. Consumers supported a layered approach to consent that offers choice in the amount of information to be read before deciding whether to enter a trial. A 3-page PICF was considered sufficient for decision-making for the SNAP trial, provided that further information was available and accessible.

Background We aimed to describe attitudes toward treatment of herpes simplex virus type 2 (HSV-2) meningitis and prioritize future trials. Methods This was a self-administered online survey of HSV-2 meningitis treatment among infectious diseases (ID) specialists in France, Sweden, Australia, and Denmark. Results A total of 223 ID specialists (45% female) from France (36%), Denmark (24%), Sweden (21%), and Australia (19%) participated in the survey, primarily from university hospitals (64%). The estimated overall response rate was 11% and ranged from 6% (Australia) to 64% (Denmark). Intravenous (IV) acyclovir followed by oral valacyclovir was the favored treatment in 110 of 179 (61%), whereas monotherapy with either IV acyclovir or oral valacyclovir was used by 35 of 179 (20%) and 34 of 179 (19%), respectively. The median total duration was reported to be 7 days (interquartile range, 7–10 days) regardless of antiviral regimen. Immunocompromise influenced decisions on antiviral treatment in 110 of 189 (58%) of respondents, mainly by prolonged total duration of treatment (36/110 [33%]), prolonged IV administration (31/110 [28%]), and mandatory antiviral treatment (25/110 [23%]). Treatment with acyclovir/valacyclovir versus placebo and comparison of acyclovir versus valacyclovir were assigned the highest prioritization scores for future randomized controlled trials on HSV-2 meningitis. Conclusions Perceptions of indications for as well as type and duration of antiviral treatment varied substantially among ID specialists.

Community-associated, methicillin-resistant Staphylococcus aureus (MRSA) lineages have emerged in many geographically distinct regions around the world during the past 30 y. Here, we apply consistent phylodynamic methods across multiple community-associated MRSA lineages to describe and contrast their patterns of emergence and dissemination. We generated whole-genome sequencing data for the Australian sequence type (ST) ST93-MRSA-IV from remote communities in Far North Queensland and Papua New Guinea, and the Bengal Bay ST772-MRSA-V clone from metropolitan communities in Pakistan. Increases in the effective reproduction number (R e ) and sustained transmission (R e > 1) coincided with spread of progenitor methicillin-susceptible S. aureus (MSSA) in remote northern Australian populations, dissemination of the ST93-MRSA-IV genotype into population centers on the Australian East Coast, and subsequent importation into the highlands of Papua New Guinea and Far North Queensland. Applying the same phylodynamic methods to existing lineage datasets, we identified common signatures of epidemic growth in the emergence and epidemiological trajectory of community-associated S. aureus lineages from America, Asia, Australasia, and Europe. Surges in R e were observed at the divergence of antibiotic-resistant strains, coinciding with their establishment in regional population centers. Epidemic growth was also observed among drug-resistant MSSA clades in Africa and northern Australia. Our data suggest that the emergence of community-associated MRSA in the late 20th century was driven by a combination of antibiotic-resistant genotypes and host epidemiology, leading to abrupt changes in lineage-wide transmission dynamics and sustained transmission in regional population centers.

Background Based primarily on in vitro and animal models, with little data directly addressing patient outcomes, current guidelines recommend treating staphylococcal prosthetic valve endocarditis (PVE) with antibiotic combinations including gentamicin and rifampin. Here, we synthesize the clinical data on adjunctive rifampin and gentamicin in staphylococcal PVE. Methods We conducted a systematic review and meta-analysis of PubMed- and Cochrane-indexed studies reporting outcomes of staphylococcal PVE treated with adjunctive rifampin, gentamicin, both agents, or neither (ie, glycopeptide or β-lactam monotherapy). We recorded outcomes including mortality, relapsed infection, length of stay, nephrotoxicity, hepatotoxicity, and important drug–drug interactions (DDIs). Results Four relevant studies were identified. Two studies (n = 117) suggested that adding gentamicin to rifampin-containing regimens did not reduce clinical failure (odds ratio [OR], 0.98 [95% confidence interval {CI}, .39–2.46]), and 2 studies (n = 201) suggested that adding rifampin to gentamicin-containing regimens did not reduce clinical failure (OR, 1.29 [95% CI, .71–2.33]). Neither gentamicin nor rifampin was associated with reduced infection relapse; 1 study found that rifampin treatment was associated with longer hospitalizations (mean, 31.3 vs 42.3 days; P < .001). Comparative safety outcomes were rarely reported, but 1 study found rifampin to be associated with hepatoxicity, nephrotoxicity, and DDIs, leading to treatment discontinuation in 31% of patients. Conclusions The existing clinical data do not suggest a benefit of either adjunctive gentamicin or rifampin in staphylococcal PVE. Given that other studies also suggest these agents add nephrotoxicity, hepatoxicity, and risk of DDIs without benefit in staphylococcal endovascular infections, we suggest that recommendations for gentamicin and rifampin in PVE be downgraded and primarily be used within the context of clinical trials.

BACKGROUND: The COVID-19 pandemic has had a profound effect on the presentation and management of trauma at the Royal Melbourne Hospital, a level 1 adult major trauma service and a designated COVID-19 hospital. This study compares the changes in epidemiology and trauma patient access to emergency imaging and surgery during the pandemic response. METHODS: The population of interest was all trauma patients captured in the hospital's trauma registry from 16 March 2016 to 10 September 2020. Regression modelling assessed changes in mechanism and severity of the injury, and mortality during two lockdowns compared with the proceeding 4 years. Cases were matched with hospital administrative databases to assess median time from admission to emergency computed tomography (CT) scan, operating theatre, length of stay (LOS) and immediate surgery (OPSTAT). RESULTS: Throughout 2020, the hospital treated 525 COVID-19 patients. Compared with previous years, there was up to 34% reduction in major trauma and a 28% reduction in minor trauma admissions during the pandemic (p < 0.05). Intensive care unit admissions were almost half of predicted. Some of the largest reductions were seen in motor vehicle crashes (49%) and falls (28%) (p < 0.05). Time to CT, surgery and immediate surgery (OPSTAT) showed no change and having a suspected COVID-19 diagnosis did not prolong any of these times except for the LOS. Mortality was similar to previous years. CONCLUSION: The COVID-19 pandemic has had widespread societal changes, resulting in a substantial decrease in trauma presentations. Despite COVID's immense impact on the hospital's trauma service, the quality of care was not impaired.

Background Inappropriate antimicrobial prescribing contributes to the emergence of antimicrobial resistance. Gaps exist in the understanding of antimicrobial prescribing in the remote setting. We aimed to assess adherence to guidelines and appropriateness of antimicrobial prescribing in Central Australia. Methods A retrospective study assessing antimicrobial prescriptions in ten Aboriginal clinics (three in remote communities and seven in regional centre) using a validated evaluation tool. Antimicrobials prescribed between 1 January—31 December 2018 were randomly selected for inclusion into the study. The main outcome measures were the rates of guideline adherence and inappropriate prescribing. Results A total of 180 prescriptions were included (96.1% Aboriginal, 32.2% male). Ninety-nine (55.0%) prescriptions were written by general practitioners (GPs), 57 (31.7%) by nurses and 24 (13.3%) by others. Forty-three (25.7%) assessable prescriptions were deemed inappropriate and 75 (44.4%) did not adhere to guidelines. Prescriptions written by GPs were less likely to adhere to guidelines, particularly GPs located in remote communities. The most common reasons for inappropriate prescribing were incorrect dosage/frequency and antimicrobial not indicated. Skin and soft-tissue infection was the commonest indication, with 29 of 41 (70.7%) prescriptions deemed appropriate. Prescriptions for lower respiratory-tract infection had the lowest rate of appropriateness, with one of seven prescriptions deemed appropriate (14.3%). Antimicrobials with the lowest rate of appropriateness were ciprofloxacin, amoxicillin-clavulanate and cefalexin, at 50%, 56%, and 62%, respectively. Conclusion A quarter of antimicrobial prescriptions written in select remote central Australian Aboriginal primary healthcare clinics were deemed inappropriate. The implementation of a comprehensive antimicrobial stewardship program is recommended.

Clinical risk factors for nephrotoxicity in Staphylococcus aureus bacteraemia remain largely undetermined, despite its common occurrence and clinical significance. In an international, multicentre, prospective clinical trial (CAMERA2), which compared standard therapy (vancomycin monotherapy) to combination therapy (adding an anti-staphylococcal beta-lactam) for methicillin-resistant S. aureus bacteraemia, significantly more people in the combination therapy arm experienced acute kidney injury compared with those in the monotherapy arm (23% vs 6%).The aim of this post hoc analysis was to explore in greater depth the risk factors for acute kidney injury from the CAMERA2 trial.Among participants of the CAMERA2 trial, demographic-related, infection-related and treatment-related risk factors were assessed for their relationship with acute kidney injury by univariable and multivariable logistic regression. Acute kidney injury was defined by a modified-KDIGO (Kidney Disease: Improving Global Outcomes) criteria (not including urinary output).Of the 266 participants included, age (p = 0.04), randomisation to combination therapy (p = 0.002), vancomycin area under the concentration-time curve (p = 0.03) and receipt of (flu)cloxacillin as the companion beta-lactam (p0.001) were significantly associated with acute kidney injury. On a multivariable analysis, concurrent use of (flu)cloxacillin increased the risk of acute kidney injury over four times compared with the use of cefazolin or no beta-lactam. The association of vancomycin area under the concentration-time curve with acute kidney injury also persisted in the multivariable model.For participants receiving vancomycin for S. aureus bacteraemia, use of (flu)cloxacillin and increased vancomycin area under the concentration-time curve were risk factors for acute kidney injury. These represent potentially modifiable risk factors for nephrotoxicity and highlight the importance of avoiding the use of concurrent nephrotoxins.

Background Chronic hepatitis B is a public health concern in Aboriginal communities in the Northern Territory of Australia with prevalence almost four times the non-Aboriginal population. Infection is suspected to mainly occur in early life, however, the mode of transmission and vaccine effectiveness is not known in this population. WHO has set a target for hepatitis B elimination by 2030; elimination in this disproportionately affected population in Australia will require understanding of the modes of transmission and vaccine effectiveness. Methods We conducted the study at four very remote Aboriginal communities. We approached mothers who had chronic hepatitis B and had given birth between 1988 and 2013 for consent. We obtained hepatitis B serology, immunisation and birth details from the medical record. If both mother and child had hepatitis B viral DNA detected, we performed viral whole genome sequencing. Results We approached 45 women for consent, of whom 23 agreed to participate. We included 20 mothers and 38 of their children. Of the 20 included mothers, 5 (25%) had children who were hepatitis B immune by exposure and 3 (15%) had children with evidence of chronic hepatitis B infection at the time of assessment. Hepatitis B immunoglobulin (HBIg) had been given at birth in 29/38 (76.3, 95% CI 59.8–88.6) children, and 26 children (68.4, 95% CI 51.3–82.5) were fully vaccinated. Of the 3 children who had chronic hepatitis B, all had received HBIg at birth and two were fully vaccinated. Of the 5 who were immune by exposure, 4 had received HBIg at birth and one was fully vaccinated. Whole genome sequencing revealed one episode of definite mother to child transmission. There was also one definite case of horizontal transmission. Conclusions Chronic hepatitis B in this context is a sensitive issue, with a high proportion of women refusing consent. Although uncommon, there is ongoing transmission of hepatitis B to Aboriginal children in remote northern Australia despite vaccination, and this is likely occurring by both vertical and horizontal routes. Prevention will require ongoing investment to overcome the many barriers experienced by this population in accessing care.

The search for clinically effective antivirals against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is ongoing. Repurposing of drugs licensed for non-coronavirus disease 2019 (COVID-19) indications has been extensively investigated in laboratory models and in clinical studies with mixed results. Nafamostat mesylate (nafamostat) is a drug licensed in Japan and Korea for indications including acute pancreatitis and disseminated intravascular coagulation. It is available only for continuous intravenous infusion. In vitro human lung cell line studies with nafamostat demonstrate high antiviral potency against SARS-CoV-2 (half maximal inhibitory concentration [IC50] of 0.0022 µM [compared to remdesivir 1.3 µM]), ostensibly via inhibition of the cellular enzyme transmembrane protease serine 2 (TMPRSS2) preventing viral entry into human cells. In addition, the established antithrombotic activity is hypothesised to be advantageous given thrombosis-associated sequelae of COVID-19. Clinical reports to date are limited, but indicate a potential benefit of nafamostat in patients with moderate to severe COVID-19. In this review, we will explore the pre-clinical, pharmacokinetic and clinical outcome data presently available for nafamostat as a treatment for COVID-19. The recruitment to ongoing clinical trials is a priority to provide more robust data on the safety and efficacy of nafamostat as a treatment for COVID-19.

Background The incidence of Gram-negative bacteraemia is rising globally and remains a major cause of morbidity and mortality. The majority of patients with Gram-negative bacteraemia initially receive intravenous (IV) antibiotic therapy. However, it remains unclear whether patients can step down to oral antibiotics after appropriate clinical response has been observed without compromising outcomes. Compared with IV therapy, oral therapy eliminates the risk of catheter-associated adverse events, enhances patient quality of life and reduces healthcare costs. As current management of Gram-negative bacteraemia entails a duration of IV therapy with limited evidence to guide oral conversion, we aim to evaluate the clinical efficacy and economic impact of early stepdown to oral antibiotics. Methods This is an international, multicentre, randomised controlled, open-label, phase III, non-inferiority trial. To be eligible, adult participants must be clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia. Randomisation to the intervention or standard arms will be performed with 1:1 allocation ratio. Participants randomised to the intervention arm (within 72 h from index blood culture collection) will be immediately switched to an oral fluoroquinolone or trimethoprim-sulfamethoxazole. Participants randomised to the standard arm will continue to receive IV therapy for at least 24 h post-randomisation before clinical re-assessment and decision-making by the treating doctor. The recommended treatment duration is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Primary outcome is 30-day all-cause mortality, and the key secondary outcome is health economic evaluation, including estimation of total healthcare cost as well as assessment of patient quality of life and number of quality-adjusted life years saved. Assuming a 30-day mortality of 8% in the standard and intervention arms, with 6% non-inferiority margin, the target sample size is 720 participants which provides 80% power with a one-sided 0.025 α-level after adjustment for 5% drop-out. Discussion A finding of non-inferiority in efficacy of oral fluoroquinolones or trimethoprim-sulfamethoxazole versus IV standard of care antibiotics may hypothetically translate to wider adoption of a more cost-effective treatment strategy with better quality of life outcomes. Trial registration ClinicalTrials.govNCT05199324. Registered 20 January 2022.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Background Infectious diseases (ID) physicians perform a pivotal role in directing the response to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Aim To assess the impact of SARS‐CoV‐2 on workload and the perceptions of ID physicians regarding the national response in Australia and New Zealand in the pre‐pandemic. Methods A survey of ID physicians in Australia and New Zealand was undertaken from 3 to 10 March 2020. Respondents were asked to estimate time spent on SARS‐CoV‐2‐related activities in February and report their agreement with statements on a 5‐point Likert scale ranging from ‘strongly agree’ to ‘strongly disagree’. We also asked about the intended use of investigational agents. Results There were 214 respondents (36% of 600 eligible participants). The median workload due to SARS‐CoV‐2‐related activities was 34% of one full‐time equivalent (interquartile range 18–68%). Less than a quarter (50, 23%) of respondents had experience managing cases, while 33% (70) had experience preparing during similar pandemics. Nevertheless, 88% (188/213) believed they were well informed when giving testing and management advice, and 45% (95/212) believed their national response was well coordinated. Additionally, 41% (88/214) were worried about becoming infected through occupational exposure. Over half (116, 54%) the respondents intended to use lopinavir/ritonavir in confirmed cases of COVID‐19 with severe disease. Conclusions ID physicians spent a large proportion of time on SARS‐CoV‐2‐related activities. Increased staffing is required to avoid burnout. Importantly, ID physicians feel well informed when giving advice. A national body should be established to co‐ordinate response. Treatment efficacy trials are needed to clarify the utility of unproven treatments.

Background The Northern Territory (NT) of Australia has a mix of climates, sparsely distributed population and a large proportion of the populace are Indigenous Australians, and influenza is known to have a disproportionate impact upon this group. Understanding the epidemiology of influenza in this region would inform public health strategies. Objectives To assess if there are consistent patterns in characteristics of influenza outbreaks in the NT. Methods Laboratory confirmed influenza cases in the NT are notified to the NT Centre for Disease Control. We conducted analyses on notified cases from 2007‐2016 to determine incidence rates (by age group, Indigenous status and area), seasonality of cases and spatial distribution of influenza types. Notified cases were linked to laboratory datasets to update information on influenza type or subtype Results The disparity in Indigenous and non‐Indigenous notification rates varied by age group, with rate ratios for Indigenous versus non‐Indigenous ranging from 1.58 (95% CI:1.39, 1.80) for ages 15‐24 to 5.56 (95% CI: 4.71, 6.57) for ages 55‐64. The disparity between Indigenous and non‐Indigenous notification rates appeared higher in the Central Australia region. Indigenous versus non‐Indigenous hospitalisation and mortality rate ratios were 6.51 (95% CI: 5.91, 7.18) and 5.46 (95% CI: 2.40, 12.71) respectively. Inter‐seasonal peaks during February and March occurred in 2011, 2013 and 2014, and were due to influenza activity in the tropical north of the NT. Conclusions Our results highlight the importance of influenza vaccination across all age groups for Indigenous Australians. An early vaccination campaign targeted against outbreaks in February‐March would be best focused on the tropical north.

Nanopore sequencing and phylodynamic modeling have been used to reconstruct the transmission dynamics of viral epidemics, but their application to bacterial pathogens has remained challenging. Cost-effective bacterial genome sequencing and variant calling on nanopore platforms would greatly enhance surveillance and outbreak response in communities without access to sequencing infrastructure. Here, we adapt random forest models for single nucleotide polymorphism (SNP) polishing developed by Sanderson and colleagues (2020. High precision Neisseria gonorrhoeae variant and antimicrobial resistance calling from metagenomic nanopore sequencing. Genome Res. 30(9):1354–1363) to estimate divergence and effective reproduction numbers (Re) of two methicillin-resistant Staphylococcus aureus (MRSA) outbreaks from remote communities in Far North Queensland and Papua New Guinea (PNG; n = 159). Successive barcoded panels of S. aureus isolates (2 × 12 per MinION) sequenced at low coverage (>5× to 10×) provided sufficient data to accurately infer genotypes with high recall when compared with Illumina references. Random forest models achieved high resolution on ST93 outbreak sequence types (>90% accuracy and precision) and enabled phylodynamic inference of epidemiological parameters using birth–death skyline models. Our method reproduced phylogenetic topology, origin of the outbreaks, and indications of epidemic growth (Re > 1). Nextflow pipelines implement SNP polisher training, evaluation, and outbreak alignments, enabling reconstruction of within-lineage transmission dynamics for infection control of bacterial disease outbreaks on portable nanopore platforms. Our study shows that nanopore technology can be used for bacterial outbreak reconstruction at competitive costs, providing opportunities for infection control in hospitals and communities without access to sequencing infrastructure, such as in remote northern Australia and PNG.

During severe infections,The bacterium

HLA-A*11:01 is one of the most prevalent human leukocyte antigens (HLAs), especially in East Asian and Oceanian populations. It is also highly expressed in Indigenous people who are at high risk of severe influenza disease. As CD8+T cells can provide broadly cross-reactive immunity to distinct influenza strains and subtypes, including influenza A, B and C viruses, understanding CD8+T cell immunity to influenza viruses across prominent HLA types is needed to rationally design a universal influenza vaccine and generate protective immunity especially for high-risk populations. As only a handful of HLA-A*11:01-restricted CD8+T cell epitopes have been described for influenza A viruses (IAVs) and epitopes for influenza B viruses (IBVs) were still unknown, we embarked on an epitope discovery study to define a CD8+T cell landscape for HLA-A*11:01-expressing Indigenous and non-Indigenous Australian people. Using mass-spectrometry, we identified IAV- and IBV-derived peptides presented by HLA-A*11:01 during infection. 79 IAV and 57 IBV peptides were subsequently screened for immunogenicityin vitrowith peripheral blood mononuclear cells from HLA-A*11:01-expressing Indigenous and non-Indigenous Australian donors. CD8+T cell immunogenicity screening revealed two immunogenic IAV epitopes (A11/PB2320-331and A11/PB2323-331) and the first HLA-A*11:01-restricted IBV epitopes (A11/M41-49, A11/NS1186-195and A11/NP511-520). The immunogenic IAV- and IBV-derived peptides were >90% conserved among their respective influenza viruses. Identification of novel immunogenic HLA-A*11:01-restricted CD8+T cell epitopes has implications for understanding how CD8+T cell immunity is generated towards IAVs and IBVs. These findings can inform the development of rationally designed, broadly cross-reactive influenza vaccines to ensure protection from severe influenza disease in HLA-A*11:01-expressing individuals.

Registry randomised clinical trials (RRCTs) have the potential to provide pragmatic answers to important clinical questions. RRCTs can be embedded into large population-based registries or smaller single site registries to provide timely answers at a reduced cost compared with traditional randomised controlled trials. RRCTs can take a number of forms in addition to the traditional individual-level randomised trial, including parallel group trials, platform or adaptive trials, cluster randomised trials and cluster randomised stepped-wedge trials. From an implementation perspective, initially it is advantageous to embed RRCT into well-established registries as these have typically already overcome any issues with end point validation and adjudication. With advances in data linkage and data quality, RRCTs can play an important role in answering clinical questions in a pragmatic, cost-effective way.

Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

IntroductionThere has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.Methods and analysisWe propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia’s Therapeutic Goods Administration Special Access Scheme. A phage product with highin vitroactivity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50–100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics.Ethics and disseminationParticipant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/).Trial registration numberRegistered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000).

BACKGROUND Respiratory syncytial virus (RSV) is understood to be a cause of significant disease in older adults and children. Further analysis of RSV in younger adults may reveal further insight into its role as an important pathogen in all age groups. METHODS We identified, through laboratory data, adults who tested positive for either influenza or RSV between January 2017 and June 2019 at a single Australian hospital. We compared baseline demographics, testing patterns, hospitalisations and outcomes between these groups. RESULTS Of 1128 influenza and 193 RSV patients, the RSV cohort was older (mean age 54.7 vs. 64.9, p

Background: Respiratory syncytial virus (RSV) is understood to be a cause of significant disease in older adults and children. Further analysis of RSV in younger adults may reveal further insight into its role as an important pathogen in all age groups. Methods: We identified, through laboratory data, adults who tested positive for either influenza or RSV between January 2017 and June 2019 at a single Australian hospital. We compared baseline demographics, testing patterns, hospitalisations and outcomes between these groups. Results: Of 1128 influenza and 193 RSV patients, the RSV cohort was older (mean age 54.7 vs. 64.9, p

BackgroundVancomycin is a first line antibiotic for many common infectious diseases and is the most commonly prescribed antibiotic in the United States hospital setting. Vancomycin is also well known to cause kidney injury; two recent prospective studies have identified that increasing vancomycin area under the concentration curve predicts vancomycin induced kidney injury (VIKI). However, outside of clinical trials, it is unclear if pre-clinical data can quantitatively describe VIKI in patients.MethodsData were simultaneously analyzed from a pre-clinical rat model and two prospective clinical studies. Logged vancomycin area under the concentration curve (AUC) data for rats (n=48) and patients from PROVIDE (n=263) and CAMERA2 (n=291) were included. VIKI was defined as urinary KIM-1 concentrations ≥9.42 ng/mL in the rat and according to KDIGO stage 1 kidney injury for all human patients. Multiple generalized linear models were explored, and the order of magnitude was calculated between the probability of acute kidney injury (AKI) from the average obtained in the clinical studies (i.e. CAMERA2 and PROVIDE) and the rat for 0.1 increments in Log10AUC bounded common concentrations obtained in the therapeutic range (i.e. ~200 −800 mg*24h/L).ResultsA logit link model best fit the data. When calculating the multiplicative factors between the studies therapeutic range AUCs, the rat was an average 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 (i.e. log 10 AUC=2.3) and 794.3 mg*h/L (i.e. log 10 AUC=2.9), respectively.ConclusionsA pre-clinical rat model was quantitatively linked to toxicity data from two large human studies. The rat is an attractive pre-clinical model to explore exposure toxicity relationships with vancomycin. External validation is required.

Background Urinary tract infections are common and are increasingly resistant to antibiotic therapy. Northern Australia is a sparsely populated region with limited access to healthcare, a relatively high burden of disease, a substantial regional and remote population, and high rates of antibiotic resistance in skin pathogens. Objectives To explore trends in antibiotic resistance for common uropathogens Escherichia coli and Klebsiella pneumoniae in northern Australia, and how these relate to current treatment guidelines in the community and hospital settings. Methods We used data from an antibiotic resistance surveillance system. We calculated the monthly and yearly percentage of isolates that were resistant in each antibiotic class, by bacterium. We analysed resistance proportions geographically and temporally, stratifying by healthcare setting. Using simple linear regression, we investigated longitudinal trends in monthly resistance proportions and correlation between community and hospital isolates. Results Our analysis included 177 223 urinary isolates from four pathology providers between 2007 and 2020. Resistance to most studied antibiotics remained Conclusions Antibiotic resistance in uropathogens is increasing in northern Australia, but treatment guidelines generally remain appropriate for empirical therapy of patients with suspected infection (except trimethoprim in some settings). Our findings demonstrate the importance of local surveillance data (HOTspots) to inform clinical decision making and guidelines.

The burden and consequences of skin infections for remote living indigenous people are high. While skin infections are recognised as an antecedent to conditions such as acute rheumatic fever in children, data are limited concerning skin infection complications such as cellulitis, abscesses and osteomyelitis in older children and adults. In a 1-year retrospective audit of 439 patients presenting to two remote health clinics, 330/439 (75%) patients presented with a skin infection and 18 (4%) developed a complication.

We report the kinetics of immune responses in relation to clinical and virological features of a patient with mild-to-moderate coronavirus disease-19 (COVID-19) requiring hospitalisation. Increased antibody-secreting cells, follicular T-helper cells, activated CD4+ and CD8+ T-cells and IgM/IgG SARS-CoV-2-binding antibodies were detected in blood, prior to symptomatic recovery. These immunological changes persisted for at least 7 days following full resolution of symptoms, indicating substantial anti-viral immunity in this non-severe COVID-19

In clinical practice, differing opinions exists regarding the optimal management of patients with penicillin-susceptible Staphylococcus aureus (PSSA) bloodstream infection (BSI). The aim of this study was to compare the 30-day mortality of patients treated with benzylpenicillin or flucloxacillin for PSSA BSI from a large prospectively collected data set from Australia and New Zealand. A logistic regression model and propensity score treatment analysis using inverse probability of treatment weighting were used. A total of 915 patients were included in the study, with an overall mortality rate of 12.9% (118/915) [benzylpenicillin 10.5% (33/315) and flucloxacillin 14.2% (85/600)]. Endocarditis was associated with benzylpenicillin treatment choice, whereas skin and soft-tissue infection was associated with flucloxacillin treatment choice. In the multivariate analysis, increased 30-day mortality was associated with flucloxacillin compared with benzylpenicillin [odds ratio (OR) = 1.6, 95% confidence interval (CI) 1.0–2.5; P = 0.05). When adjusted for treatment choice in the propensity score analysis, flucloxacillin was again associated with increased 30-day mortality (OR = 1.06, 95% CI 1.01–1.1; P = 0.03). An increase in 30-day mortality associated with flucloxacillin use suggests a potential benefit for benzylpenicillin therapy in patients with PSSA BSI.

BACKGROUND: Hospitalisation with skin infection in Western Australian (WA) Aboriginal children is common, with the highest rates in infants and children from remote WA. OBJECTIVE: We aimed to quantify infant, maternal, and sociodemographic risk factors for skin infection hospitalisation in WA children, focussing on Aboriginal children aged

Acute post-streptococcal glomerulonephritis (APSGN) is a postinfectious immune-mediated kidney disease associated with group A Streptococcus (GAS). The prevalence of APSGN varies within and between countries and is influenced by socioeconomic, host, and bacterial factors. The disease is more prevalent in developing countries and resource-poor settings of developed countries, such as the Indigenous populations residing in tropical Australia. The M-protein is a universally present GAS surface antigen that is the focus of molecular typing and vaccine research. Early reports suggested that some M-proteins (emm types) are more likely to cause APSGN than others. Here, we present the first systematic review of the global distribution of APSGN-associated GAS emm types. There were 46 emm types among the 676 cases described in 15 reviewed articles. Only 43% APSGN cases would have had theoretical coverage from the experimental M protein-based GAS vaccine. Vaccine coverage was higher in regions such as North America (97%) and the United Kingdom (98%) than Africa (67%) and Australia (38%). Variable vaccine coverage against APSGN- associated emm types highlights the need for further research into this disease, particularly in settings of poverty, where APSGN prevalence is higher. Three GAS emm types (emm49, emm60, and emm55) consistently occur in APSGN cases around the world. Future studies would therefore benefit from examining the genomic epidemiology of these emm types to unravel potential markers of APSGN.

Summary The aim of this study was to describe the burden and organism antibiotic resistance patterns of skin and soft tissue infections (SSTI) due to Staphylococcus aureus presenting in a remote Australian Northern Territory community in the Barkly region. We collated reported antibiograms of all skin and superficial soft tissue swab specimens obtained from the town's Indigenous medical clinic from 12 of the 13 months between November 2016 and December 2017. Clinician's notes for the consultation associated with each test request were examined to determine the nature of the clinical problem and to access other relevant data. Amongst 309 tissue swab specimens, S. aureus was cultured in 215 (70%), of which 202 isolations were from Indigenous Australians. Of the 215 S. aureus, 98 [46%, 95% confidence interval (CI) 31–52] were methicillin resistant S. aureus (MRSA) and 117 (54%, 95% CI 48–61) sensitive (MSSA). Significant numbers were also resistant to other frequently used oral antibiotics, with resistance to erythromycin in 52 (24%), clindamycin in 51 (24%), trimethoprim in 22 (10%) and fusidic acid in eight (4%). In the Barkly region of Australia's NT in 2017, community-acquired staphylococcal SSTI needing professional care is equally likely to be caused by MRSA as by MSSA.

The entry point and timing of ancient human migration into continental Sahul (the combined landmass of Australia, New Guinea, and Tasmania) are subject to debate. Unique strains of hepatitis B virus (HBV) are endemic among modern-day Australian Aboriginals (HBV/C4) and Indigenous Melanesians (HBV/C3). We postulated that HBV genomes could be used to infer human population movements because the main HBV transmission route in endemic populations is via mother-to-child for genotypes B and C infections. Phylogenetic and phylogeographic analyses of HBV genomes inferred the origin of HBV/C4 to be >59 thousand years ago (ka) (95% HPD: 34-85 ka), and most likely to have occurred on the Sunda Shelf (southeast extension of the continental shelf of Southeast Asia). Our analysis further suggested an age of >51 ka (95% Highest Posterior Density (HPD): 36-67 ka) for the most recent common ancestor of HBV/C4 in Australia, correlating with the arrival time of anatomically modern humans into Australia, with the entry point suggested along a southern route via Timor. While we also inferred the origin of HBC/C3 to be on the Sunda Shelf, our analyses suggested that it was carried into Melanesia by Indigenous Melanesians who migrated through New Guinea north of the highlands. These findings reveal that HBV genomes can be used to infer ancient human population movements.

Nanopore sequencing and phylodynamic modelling have been used to reconstruct the transmission dynamics of viral epidemics, but their application to bacterial pathogens has remained challenging. Here, we implement Random Forest models for single nucleotide polymorphism (SNP) polishing to estimate divergence and effective reproduction numbers (Re) of two community-associated, methicillin-resistant Staphylococcus aureus (MRSA) outbreaks in remote Far North Queensland and Papua New Guinea (n = 159). Successive bar-coded panels of S. aureus isolates (2 × 12 per MinION) sequenced at low-coverage (> 5x - 10x) provided sufficient data to accurately infer assembly genotypes with high recall when compared with Illumina references. De novo SNP calling with Clair was followed by SNP polishing using intra- and inter-species models trained on Snippy reference calls. Models achieved sufficient resolution on ST93 outbreak sequence types (> 70 - 90% accuracy and precision) for phylodynamic modelling from lineage-wide hybrid alignments and birth-death skyline models in BEAST2. Our method reproduced phylogenetic topology, geographical source of the outbreaks, and indications of sustained transmission (Re > 1). We provide Nextflow pipelines that implement SNP polisher training, evaluation, and outbreak alignments, enabling reconstruction of within-lineage transmission dynamics for infection control of bacterial disease outbreaks using nanopore sequencing.

Community-associated, methicillin-resistantStaphylococcus aureus(MRSA) lineages have emerged in many geographically distinct regions around the world during the past 30 years. Here, we apply consistent phylodynamic methods across multiple community-associated MRSA lineages to describe and contrast their patterns of emergence and dissemination. We generated whole genome sequencing data for the Australian sequence type (ST) 93-MRSA-IV from remote communities in Far North Queensland and Papua New Guinea, and the Bengal Bay ST772-MRSA-V clone from metropolitan communities in Pakistan. Increases in the effective reproduction number (Re) and sustained transmission (Re> 1) coincided with spread of progenitor methicillin-susceptibleS. aureus(MSSA) in remote northern Australia, dissemination of the ST93-MRSA-IV geno-type into population centers on the Australian East Coast, and sub-sequent importation into the highlands of Papua New Guinea and Far North Queensland. Analysis of a ST772-MRSA-V cluster in Pakistan suggests that sustained transmission in the community following importation of resistant genotypes may be more common than previously thought. Applying the same phylodynamic methods to existing lineage datasets, we identified common signatures of epidemic growth in the emergence and epidemiological trajectory of community-associatedS. aureuslineages from America, Asia, Australasia and Europe. Surges in Rewere observed at the divergence of antibiotic resistant strains, coinciding with their establishment in regional population centers. Epidemic growth was also observed amongst drug-resistant MSSA clades in Africa and northern Australia. Our data suggest that the emergence of community-associated MRSA and MSSA lineages in the late 20th century was driven by a combination of antibiotic resistant genotypes and host epidemiology, leading to abrupt changes in lineage-wide transmission dynamics and sustained transmission in regional population centers.

Recently, we identified a Staphylococcus aureus sequence type 5 (ST5) clone in northern Australia with discrepant trimethoprim-sulfamethoxazole (SXT) susceptibility results. We aimed to identify isolates of this clone using Vitek 2 SXT resistance as a proxy and to compare its epidemiology with those of other circulating S. aureus strains. We collated Vitek 2 susceptibility data for S. aureus isolates collected through our laboratory and conducted a prospective, case-control study comparing clinical, microbiological, epidemiological, and genomic data for subsets of isolates reported as SXT resistant (cases) and SXT susceptible (controls) by Vitek 2. While overall SXT resistance rates remained relatively stable from 2011 to 2018 among 27,721 S. aureus isolates, non-multidrug-resistant methicillin-resistant S. aureus (MRSA) strains almost completely replaced multidrug-resistant MRSA strains as the predominant SXT-resistant MRSA phenotype. Demographic and clinical features of 51 case-control pairs were similar, but genotyping revealed stark differences: clonal complex 5 (CC5) MRSA predominated among SXT-resistant cases (34/51 [67%]), while CC93 MRSA predominated among susceptible controls (26/51 [51%]). All CC5 isolates were an ST5 clonal lineage that possessed the trimethoprim resistance gene dfrG within SCCmec IVo; all were SXT susceptible by Etest. The replacement of Vitek 2 reported SXT-resistant multidrug-resistant MRSA by non-multidrug-resistant MRSA appears related to the emergence of an ST5-MRSA-SCCmec IVo clone that is SXT susceptible by Etest and causes clinical disease similar to that caused by ST93-MRSA-SCCmec IVa. Reliance on Vitek 2 SXT reporting may lead to unnecessary restriction of effective oral treatment options for S. aureus infections. Whether the presence of dfrG within SCCmec IVo provides a selective advantage at the population level is currently unclear. IMPORTANCE Staphylococcus aureus is an important human pathogen that causes a wide range of clinical infections. In the past 2 decades, an epidemic of community-associated skin and soft tissue infections has been driven by S. aureus strains with specific virulence factors and resistance to beta-lactam antibiotics. Recently, an S. aureus strain with discrepant antimicrobial susceptibility testing results has emerged in northern Australia. This ST5-MRSA-SCCmec IVo clone is reported as resistant to trimethoprim-sulfamethoxazole by Vitek 2 but susceptible by phenotypic methods. ST5-MRSA-SCCmec IVo is now the second most common community-associated MRSA clone in parts of Australia and causes a spectrum of clinical disease similar to that caused by the virulent ST93-MRSA lineage. Whole-genome sequence analysis demonstrates that ST5-MRSA-SCCmecIVo is causing a clonal outbreak across a large geographical region. Although phenotypic testing suggests in vitro susceptibility to trimethoprim-sulfamethoxazole, it is unclear at this stage whether the presence of dfrG within SCCmec IVo provides a selective advantage at the population level.

Whole exome sequencing (WES) is a popular and successful technology which is widely used in both research and clinical settings. However, there is a paucity of reference data for Aboriginal Australians to underpin the translation of health-based genomic research. Here we provide a catalogue of variants called after sequencing the exomes of 50 Aboriginal individuals from the Northern Territory (NT) of Australia and compare these to 72 previously published exomes from a Western Australian (WA) population of Martu origin. Sequence data for both NT and WA samples were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 289,829 variants were identified in at least one individual in the NT cohort and 248,374 variants in at least one individual in the WA cohort. Of these, 166,719 variants were present in both cohorts, whilst 123,110 variants were private to the NT cohort and 81,655 were private to the WA cohort. Our data set provides a useful reference point for genomic studies on Aboriginal Australians., Measurement(s)Aboriginal Australian • DNA • sequence feature annotationTechnology Type(s)Whole Exome Sequencing • DNA sequencing • sequence annotationFactor Type(s)ancestry • sex • ageSample Characteristic - OrganismHomo sapiensSample Characteristic - LocationNorthern Territory Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12040638

Background: Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. Methods: We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the LIFT-V cohort, and collected blood to define baseline, early (day 7) and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells and antibody profiles, and investigated host factors that could contribute to vaccine responses. Findings:We found robust antibody responses to influenza vaccination induced in Indigenous Australians, with activation profiles of circulating T follicular helper type-1 (cT FH 1) cells at the acute response strongly correlating with total change of antibody vaccine titres induced by vaccination. Formation of influenza-specific haemagglutinin (HA)-binding memory B cells was significantly higher in seroconverters compared to non-seroconverters. Back-boosting of antibodies towards previously circulating influenza strains was observed following influenza vaccination. In-depth antibody characterisation revealed a reduction in IgG3 pre- and post-vaccination in the Indigenous Australian population, potentially linked to the increased frequency of G3m21* allotype. Interpretation: Overall, our data provide the first evidence that Indigenous populations elicit robust, broad and prototypical immune responses following immunisation with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and its subsequent complications. Funding: This work was funded by the Australian National Health and Medical Research Council (NHMRC) Program Grant (#1071916) to KK, NHMRC Project Grant (#1122524) to KK, ST, AM, NHMRC Project Grant (#1141840) to MP, KLF, Clifford Craig Foundation Grant (#145) to KLF, and NHMRC Investigator Grant (#1173871) to KK supported this work. EBC is a NHMRC Peter Doherty Fellow. ST is a NHMRC Career Development Fellow (#1145033). This work is supported by the NHMRC program grant 111 #1149990 (SJK), NHMRC project grant #1162760 (AKW). KK is supported by a NHMRC Senior Research Fellowship (#1102792) and SJK by a NHMRC Senior Principal Research Fellowship (#1136322). LH is supported by the Melbourne International Research Scholarship the Melbourne International Fee Remission Scholarship from The University of Melbourne. CES has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 792532. The Melbourne WHO Collaborating Centre for Reference Research on Influenza is supported by the Australian Government Department of Health. Declaration of Interest: None to declare. Ethical Approval: All experiments were conducted according to the Declaration of Helsinki principles and NHMRC Code of practice and approved by the University of Melbourne Human Research Ethics Committee (#1955465 and #1441452), the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (#2012-1928), and the Tasmanian Human Research Ethics Committee (#H0015460).

Indigenous people worldwide are at high-risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. We defined CD8+ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identified immunodominant protective CD8+ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2550-558-specific CD8+ T-cells cells being cross-reactive between IAV and IBV. Memory CD8+ T-cells towards these specificities were present in blood (CD27+CD45RA- phenotype) and tissues (CD103+CD69+ phenotype) of healthy subjects, and effector CD27-CD45RA-PD-1+CD38+CD8+ T-cells in IAV/IBV patients. Our data present the first evidence of influenza-specific CD8+ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8+ T-cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.One Sentence SummaryInfluenza-specific CD8+ T-cell specificities restricted by HLA-A*24:02.

Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8+ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8+ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2550–558-specific CD8+ T cells being cross-reactive between IAV and IBV. Memory CD8+ T cells towards these specificities are present in blood (CD27+CD45RA− phenotype) and tissues (CD103+CD69+ phenotype) of healthy individuals, and effector CD27−CD45RA−PD-1+CD38+CD8+ T cells in IAV/IBV patients. Our data show influenza-specific CD8+ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8+ T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease., The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8+ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.

Staphylococcus argenteus infection was initially described in Aboriginal patients in the Northern Territories of Australia as a predominant cause of skin infections and is rare outside Southeast Asia. A first well-characterized case of S. argenteus infection has now been described in the United States, involving a recurrent hemodialysis catheter infection, in which unstable daptomycin resistance evolved during daptomycin therapy. The unique colonial pigmentation of S. argenteus isolates in strains otherwise identified as Staphylococcus aureus is noteworthy.