Exacerbation history and blood eosinophil count prior to diagnosis of COPD and risk of subsequent exacerbations.

BACKGROUND: Prior exacerbation history is used to guide initial maintenance therapy in chronic obstructive pulmonary disease (COPD); however, the recommendations were derived from patients already diagnosed and treated. METHOD: We assessed the rates of moderate (i.e. treated with antibiotics and/or systemic corticosteroids) and severe (i.e. hospitalised) exacerbations in the year following diagnosis in patients newly diagnosed with COPD according to their prior history of exacerbations, blood eosinophil counts (BEC) and whether maintenance therapy was started. Data were extracted from the Optimum Patient Care Research Database. RESULTS: 73 189 patients were included. 61.9% had no exacerbations prior to diagnosis, 21.5% had 1 moderate, 16.5% had ≥2 moderate, and 0.3% had ≥1 severe. 50% were started on maintenance therapy. In patients not started on maintenance therapy the rates (95% confidence intervals) of moderate exacerbations in the year after diagnosis in patients with 0, 1 moderate, ≥2 moderate, ≥1 severe prior exacerbations were 0.34 (0.33-0.35), 0.59 (0.56-0.61), 1.18 (1.14-1.23) and 1.21 (0.73-1.69) respectively. Similar results were seen in patients started on maintenance therapy. BEC did not add significantly to the prediction of future exacerbation risk. CONCLUSION: A single moderate exacerbation in the year prior to diagnosis increases the risk of subsequent exacerbations and more frequent or severe exacerbations prior to diagnosis are associated with a higher risk.

Differential COVID-19 case ascertainment by age and vaccination status in Victoria, Australia: a serosurveillance and record linkage study.

Objectives: To compare serological evidence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with linked coronavirus disease 2019 (COVID-19) case notification data in Victoria, Australia, and to determine in vitro SARS-CoV-2 neutralisation activity based on prior infection and vaccination history. Design, setting, participants: Four cross-sectional serological surveys were conducted between 30 June and 31 October 2022 (a period of Omicron BA.4/BA.5 dominance) using 1,974 residual serum samples obtained from the Victorian Infectious Diseases Reference Laboratory. Serological results were linked to COVID-19 case notification and vaccination data. Surrogate virus neutralisation testing was performed to obtain in vitro inhibition estimates by anti-nucleocapsid serostatus and COVID-19 vaccination history. Main outcome measures: Adjusted anti-SARS-CoV-2 spike and nucleocapsid seropositivity by sex, age and region of residence; adjusted proportion of cases notified by anti-nucleocapsid serostatus, age and number of COVID-19 vaccination doses received; adjusted percentage in vitro inhibition against wildtype and Omicron BA.4/BA.5 SARS-CoV-2 variants by anti-nucleocapsid serostatus and COVID-19 vaccination history. Results: The prevalence of anti-SARS-CoV-2 nucleocapsid antibodies was inversely proportional to age. In October 2022, prevalence was 84% (95% confidence interval [95% CI]: 75-93%) among 18-29-year-olds, compared to 39% (95% CI: 27-52%) among ≥ 80-year-olds. In most age groups, approximately 40% of COVID-19 cases appear to have been notified via existing surveillance mechanisms. Case notification was highest among individuals older than 80 years and people who had received COVID-19 vaccine booster doses. In vitro neutralisation of Omicron BA.4/BA.5 sub-variants was highest for individuals with evidence of both prior infection and booster vaccination. Conclusions: Under-notification of SARS-CoV-2 infections in the Victorian population is not uniform across age and vaccination strata. Seroprevalence data that give insights into case notification behaviour provide additional context for the interpretation of existing COVID-19 surveillance information.

Patients report high information coordination between rostered primary care physicians and specialists: A cross-sectional study.

Our study aimed to describe patient experience of information coordination between their primary care physician and specialists and to examine the associations between their experience and their personal and primary care characteristics. We conducted a cross-sectional study of Ontario residents rostered to a primary care physician and visited a specialist physician in the previous 12 months by linking population-based health administrative data to the Health Care Experience Survey collected between 2013 and 2020. We described respondents' sociodemographic and health care utilization characteristics and their experience of information coordination between their primary care physician and specialists. We measured the adjusted association between patient-reported measures of information coordination before and after respondents received care from a specialist physician and their type of primary care model. 1,460 out 20,422 (weighted 7.5%) of the respondents reported that their specialist physician did not have basic medical information about their visit from their primary care physician in the previous 12 months. 2,298 out of 16,442 (weighted 14.9%) of the respondents reported that their primary care physician seemed uninformed about the care they received from the specialist. Females, younger individuals, those with a college or undergraduate level of education, and users of walk-in clinics had a higher likelihood of reporting a lack of information coordination between the primary care and specialist physicians. Only respondents rostered to an enhanced fee-for-service model had a higher odds of reporting that the specialist physician did not have basic medical information about their visit compared to those rostered to a Family Health Team (OR 1.22, 95% Cl 1.12-1.40). We found no significant association between respondent's type of primary care model and that their primary care physician was uninformed about the care received from the specialist physician. In this population-based health study, respondents reported high information coordination between their primary care physician and specialists. Except for respondents rostered to an enhanced fee-for-service model of care, we did not find any difference in information coordination across other primary care models.

Clonal succession after prolonged antiretroviral therapy rejuvenates CD8+ T cell responses against HIV-1.

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8+ T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8+ T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8+ T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8+ T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.

Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs.

The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic-pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite-time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite-time profiles for a Phase 2 study of a new antimalarial drug, cipargamin. We simulated cipargamin concentration- and malaria parasite-profiles based on a Phase 2 study of eight volunteers who received cipargamin 7 days after inoculation with malaria parasites. The cipargamin profiles were generated from a two-compartment PK model and parasite profiles from a previously published biologically informed PD model. One thousand PK-PD data sets of eight patients were simulated, following the sampling intervals of the Phase 2 study. The mechanistic PK-PD model was incorporated in a Bayesian hierarchical framework, and the parameters were estimated. Population PK model parameters describing absorption, distribution, and clearance were estimated with minimal bias (mean relative bias ranged from 1.7% to 8.4%). The PD model was fitted to the parasitaemia profiles in each simulated data set using the estimated PK parameters. Posterior predictive checks demonstrate that our PK-PD model adequately captures the simulated PD profiles. The bias of the estimated population average PD parameters was low-moderate in magnitude. This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose-effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials.

Attenuated effector T cells are linked to control of chronic HBV infection.

Hepatitis B virus (HBV)-specific CD8+ T cells play a dominant role during acute-resolving HBV infection but are functionally impaired during chronic HBV infection in humans. These functional deficits have been linked with metabolic and phenotypic heterogeneity, but it has remained unclear to what extent different subsets of HBV-specific CD8+ T cells still suppress viral replication. We addressed this issue by deep profiling, functional testing and perturbation of HBV-specific CD8+ T cells during different phases of chronic HBV infection. Our data revealed a mechanism of effector CD8+ T cell attenuation that emerges alongside classical CD8+ T cell exhaustion. Attenuated HBV-specific CD8+ T cells were characterized by cytotoxic properties and a dampened effector differentiation program, determined by antigen recognition and TGFß signaling, and were associated with viral control during chronic HBV infection. These observations identify a distinct subset of CD8+ T cells linked with immune efficacy in the context of a chronic human viral infection with immunotherapeutic potential.

Structural basis for mouse LAG3 interactions with the MHC class II molecule I-Ab.

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-Ab, revealing that domain 1 (D1) of LAG3 binds a conserved, membrane-proximal region of MHC-II spanning both the α2 and ß2 subdomains. LAG3 dimerization restricts the intermolecular spacing of MHC-II molecules, which may attenuate T cell activation by enforcing suboptimal signaling geometry. The LAG3-MHC-II interface overlaps with the MHC-II-binding site of the T cell coreceptor CD4, implicating disruption of CD4-MHC-II interactions as a mechanism for LAG3 immunosuppressive function. Lastly, antibody epitope analysis indicates that multiple LAG3 inhibitors do not recognize the MHC-II-binding interface of LAG3, suggesting a role for functionally distinct mechanisms of LAG3 antagonism in therapeutic development.

Opportunities to strengthen respiratory virus surveillance systems in Australia: lessons learned from the COVID-19 response.

Abstract: Disease surveillance data was critical in supporting public health decisions throughout the coronavirus disease 2019 (COVID-19) pandemic. At the same time, the unprecedented circumstances of the pandemic revealed many shortcomings of surveillance systems for viral respiratory pathogens. Strengthening of surveillance systems was identified as a priority for the recently established Australian Centre for Disease Control, which represents a critical opportunity to review pre-pandemic and pandemic surveillance practices, and to decide on future priorities, during both pandemic and inter-pandemic periods. On 20 October 2022, we ran a workshop with experts from the academic and government sectors who had contributed to the COVID-19 response in Australia on 'The role of surveillance in epidemic response', at the University of New South Wales, Sydney, Australia. Following the workshop, we developed five recommendations to strengthen respiratory virus surveillance systems in Australia, which we present here. Our recommendations are not intended to be exhaustive. We instead chose to focus on data types that are highly valuable yet typically overlooked by surveillance planners. Three of the recommendations focus on data collection activities that support the monitoring and prediction of disease impact and the effectiveness of interventions (what to measure) and two focus on surveillance methods and capabilities (how to measure). Implementation of our recommendations would enable more robust, timely, and impactful epidemic analysis.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner.

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.

The Asymptomatic Proportion of SARS-CoV-2 Omicron Variant Infections in Households: A Systematic Review.

Understanding the clinical spectrum of SARS-CoV-2 infection, including the asymptomatic fraction, is important as asymptomatic individuals are still able to infect other individuals and contribute to ongoing transmission. The WHO Unity Household transmission investigation (HHTI) protocol provides a platform for the prospective and systematic collection of high-quality clinical, epidemiological, serological and virological data from SARS-CoV-2 confirmed cases and their household contacts. These data can be used to understand key severity and transmissibility parameters-including the asymptomatic proportion-in relation to local epidemic context and help inform public health response. We aimed to estimate the asymptomatic proportion of SARS-CoV-2 Omicron variant infections in Unity-aligned HHTIs. We conducted a systematic review and meta-analysis in alignment with the PRISMA 2020 guidelines and registered our systematic review on PROSPERO (CRD42022378648). We searched EMBASE, Web of Science, MEDLINE and bioRxiv and medRxiv from 1 November 2021 to 22 August 2023. We identified 8368 records, of which 98 underwent full text review. We identified only three studies for data extraction, with substantial variation in study design and corresponding estimates of the asymptomatic proportion. As a result, we did not generate a pooled estimate or I2 metric. The limited number of quality studies that we identified highlights the need for improved preparedness and response capabilities to facilitate robust HHTI implementation, analysis and reporting, to better inform national, regional and global risk assessments and policymaking.

Characterising HIV-1 transmission in Victoria, Australia: a molecular epidemiological study.

Background: In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia. Methods: A comprehensive collection of HIV-1 pol sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale. Findings: Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 pol sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers (R e ) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low R e values. Interpretation: This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia. Funding: National Health and Medical Research Council, Australian Research Council.

Complex Hospital-Based Electronic Prescribing-Based Intervention to Support Antimicrobial Stewardship: Qualitative Study.

BACKGROUND: Antimicrobial resistance (AMR) represents a growing concern for public health. OBJECTIVE: We sought to explore the challenges associated with development and implementation of a complex intervention designed to improve AMS in hospitals. METHODS: We conducted a qualitative evaluation of a complex AMS intervention with educational, behavioral, and technological components in 5 wards of an English hospital. At 2 weeks and 7 weeks after initiating the intervention, we interviewed 25 users of the intervention, including senior and junior prescribers, a senior nurse, a pharmacist, and a microbiologist. Topics discussed included perceived impacts of different elements of the intervention and facilitators and barriers to effective use. Interviews were supplemented by 2 observations of ward rounds to gain insights into AMS practices. Data were audio-recorded, transcribed, and inductively and deductively analyzed thematically using NVivo12. RESULTS: Tracing the adoption and impact of the various components of the intervention was difficult, as it had been introduced into a setting with competing pressures. These particularly affected behavioral and educational components (eg, training, awareness-building activities), which were often delivered ad hoc. We found that the participatory intervention design had addressed typical use cases but had not catered for edge cases that only became visible when the intervention was delivered in real-world settings (eg, variations in prescribing workflows across different specialties and conditions). CONCLUSIONS: Effective user-focused design of complex interventions to promote AMS can support acceptance and use. However, not all requirements and potential barriers to use can be fully anticipated or tested in advance of full implementation in real-world settings.

Healthcare Resource Utilization Associated with Intermittent Oral Corticosteroid Prescribing Patterns in Asthma.

Purpose: Oral corticosteroid (OCS) use for asthma is associated with considerable healthcare resource utilization (HCRU) and costs. However, no study has investigated this in relation to patterns of intermittent OCS prescription. Methods: This historical UK cohort study used primary care medical records, linked to Hospital Episode Statistics, from 2008 to 2019, of patients (≥4 years old) with asthma prescribed intermittent OCS. Patients were categorized by OCS prescribing pattern (one-off [single], less frequent [≥90-day gap] and frequent [<90-day gap]) and matched 1:1 (by sex, age and index date) with people never prescribed OCS with/without asthma. HCRU (reported as episodes, except for length of hospital stay [days] and any prescription [records]) and associated costs were compared between intermittent OCS and non-OCS cohorts, and among intermittent OCS prescribing patterns. Results: Of 149,191 eligible patients, 50.3% had one-off, 27.4% less frequent, and 22.3% frequent intermittent OCS prescribing patterns. Annualized non-respiratory HCRU rates were greater in the intermittent OCS versus non-OCS cohorts for GP visits (5.93 vs 4.70 episodes, p < 0.0001), hospital admissions (0.24 vs 0.16 episodes, p < 0.0001), and length of stay (1.87 vs 1.58 days, p < 0.0001). In the intermittent OCS cohort, rates were highest in the frequent prescribing group for GP visits (7.49 episodes; p < 0.0001 vs one-off), length of stay (2.15 days; p < 0.0001) and any prescription including OCS (25.22 prescriptions; p < 0.0001). Mean per-patient non-respiratory related and all-cause HCRU-related costs were higher with intermittent OCS than no OCS (£3902 vs £2722 and £8623 vs £4929, respectively), as were mean annualized costs (£565 vs £313 and £1526 vs £634, respectively). A dose-response relationship existed; HCRU-related costs were highest in the frequent prescribing cohort (p < 0.0001). Conclusion: Intermittent OCS use and more frequent intermittent OCS prescription patterns were associated with increased HCRU and associated costs. Improved asthma management is needed to reduce reliance on intermittent OCS in primary care.

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a real-life setting: the NOVEL observational longiTudinal studY.

BACKGROUND: The relationships between spirometric assessment of lung function and symptoms (including exacerbations) in patients with asthma and/or chronic obstructive pulmonary disease (COPD) in a real-life setting are uncertain. OBJECTIVES: To assess the relationships between baseline post-bronchodilator (post-BD) spirometry measures of lung function and symptoms and exacerbations in patients with a physician-assigned diagnosis of asthma and/or COPD. DESIGN: The NOVEL observational longiTudinal studY (NOVELTY) is a global, prospective, 3-year observational study. METHODS: Logistic regression analysis was used to evaluate relationships. Spirometry measures were assessed as percent predicted (%pred). Symptoms were assessed at baseline, and exacerbations were assessed at baseline and Year 1. RESULTS: A total of 11,181 patients in NOVELTY had spirometry data (asthma, n = 5903; COPD, n = 3881; asthma + COPD, n = 1397). A 10% lower post-BD %pred forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) - adjusted for age and sex - were significantly associated with dyspnea (modified Medical Research Council ⩾ grade 2), frequent breathlessness [St George's Respiratory Questionnaire (SGRQ)], frequent wheeze attacks (SGRQ), nocturnal awakening (Respiratory Symptoms Questionnaire; ⩾1 night/week), and frequent productive cough (SGRQ). Lower post-BD %pred FEV1 and, to a lesser extent, lower post-BD %pred FVC were significantly associated with ⩾1 physician-reported exacerbation at baseline or Year 1. This association was stronger in patients with COPD than in those with asthma. CONCLUSION: In a real-life setting, reduced lung function is consistently associated with symptoms in patients with asthma, COPD, or asthma + COPD. The relationship with exacerbations is stronger in COPD only than in asthma. TRAIL REGISTRATION: clinicaltrials.gov identifier: NCT02760329 (www.clinicaltrials.gov).

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a study performed in a real-life setting: the NOVELTY studyBackground: Asthma and chronic obstructive pulmonary disease (COPD) have many symptoms in common. To confirm diagnosis, doctors use spirometry, a test to measure the amount of air that can be breathed out from the lungs and how fast it can be blown out. The relationship between these measurements and symptoms in asthma and COPD is not well understood.Objectives: The aim of this research is to describe the characteristics, treatment, and impact of asthma and/or COPD in patients who are receiving their usual medical care.Methods: NOVELTY is a large study of around 12,000 patients across 19 countries. This analysis of NOVELTY looked at the relationships between two spirometry measurements and the symptoms of asthma and/or COPD experienced by patients. The spirometry measurements were: - forced expiratory volume in 1 second (FEV₁) ­ the amount of air that can be blown out of the lungs in 1 second- forced vital capacity (FVC) ­ the amount of air that can be forcibly breathed out from the lungs after taking the deepest breath possibleResults: The lower the FEV₁ and FVC, the more common the symptoms of breathlessness, wheeze attacks, night-time awakening, and coughing up of phlegm or mucus. These relationships were similar for FEV₁ and FVC. Lower FEV₁ was more strongly associated with worse symptoms in COPD than in asthma.Conclusion: These findings help to improve our understanding of the relationships between spirometry measures and symptoms in patients with asthma and/or COPD.

Immunotoxin-mediated depletion of Gag-specific CD8+ T cells undermines natural control of SIV.

Antibody-mediated depletion studies have demonstrated that CD8+ T cells are required for effective immune control of SIV. However, this approach is potentially confounded by several factors, including reactive CD4+ T cell proliferation, and provides no information on epitope specificity, a likely determinant of CD8+ T cell efficacy. We circumvented these limitations by selectively depleting CD8+ T cells specific for the Gag epitope CTPYDINQM (CM9) via the administration of immunotoxin-conjugated tetrameric complexes of CM9/Mamu-A*01. Immunotoxin administration effectively depleted circulating but not tissue-localized CM9-specific CD8+ T cells, akin to the bulk depletion pattern observed with antibodies directed against CD8. However, we found no evidence to indicate that circulating CM9-specific CD8+ T cells suppressed viral replication in Mamu-A*01+ rhesus macaques during acute or chronic progressive infection with a pathogenic strain of SIV. This observation extended to macaques with established infection during and after continuous antiretroviral therapy. In contrast, natural controller macaques experienced dramatic increases in plasma viremia after immunotoxin administration, highlighting the importance of CD8+ T cell-mediated immunity against CM9. Collectively, these data showed that CM9-specific CD8+ T cells were necessary but not sufficient for robust immune control of SIV in a nonhuman primate model and, more generally, validated an approach that could inform the design of next-generation vaccines against HIV-1.

Immune imprinting in early life shapes cross-reactivity to influenza B virus haemagglutinin.

Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that affect cross-reactivity to future influenza viruses. However, direct serological evidence linked to susceptibility is limited. Here we analysed haemagglutination-inhibition titres in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against influenza B virus (IBV) isolates from 1940 to 2021. We included testing of 'future' isolates that circulated after sample collection. We show that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the B/Yamagata and B/Victoria lineages, predicting lineage-specific birth-cohort distributions of observed medically attended IBV infections. Our data suggest that immunological measurements of imprinting could be important in modelling and predicting virus epidemiology.

Age differentially impacts adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19.

Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.

Intermittent preventive treatment with sulphadoxine-pyrimethamine but not dihydroartemisinin-piperaquine modulates the relationship between inflammatory markers and adverse pregnancy outcomes in Malawi.

Women in malaria-endemic areas receive sulphadoxine-pyrimethamine (SP) as Intermittent Preventive Treatment in Pregnancy (IPTp) to reduce malaria. While dihydroartemisinin-piperaquine (DP) has superior antimalarial properties as IPTp, SP is associated with superior fetal growth. As maternal inflammation influences fetal growth, we investigated whether SP alters the relationship between inflammation and birth outcomes. We measured C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP) at enrollment (16-28 gestation weeks (gw)), visit 3 (24-36 gw) and delivery in 1319 Malawian women randomized to receive monthly SP, DP, or DP and single-dose azithromycin (AZ) in the IMPROVE trial (NCT03208179). Logistic regression was used to assess the relationship between adverse outcomes, inflammation, and treatment arm. Elevated AGP at enrollment was associated with adverse birth outcome (aRR 1.40, 95% CI: 1.15, 1.70), with similar associations observed across treatment arms, exceptions being that elevated AGP was associated with low maternal weight gain in SP recipients (aRR 1.94, 95% CI: 1.36, 2.76) and with small for gestational age in DP+AZ recepients (aRR 1.49, 95% CI 1.02, 2.17). At visit 3 there were few associations between inflammation andoutcomes. At delivery, women with elevated AGP receiving either DP or DP+AZ had an increased risk of adverse birth outcomes (aRR 1.60, 95% CI: 1.28, 2.00), including low birth weight, pre-term birth and foetal loss, this was not seen in women receiving SP (aRR 0.82, 95% CI: 0.54, 1.26). The risk of an association between elevated AGP and adverse birth outcome was higher in those receiving DP or DP+AZ compared to those receiving SP (aRR 1.95, 95% CI: 1.21, 3.13). No clear associations between CRP and adverse outcomes were observed. AGP identified women at risk of adverse pregnancy outcomes. SP modifies the relationship between inflammatory biomarkers and adverse outcomes. Our findings provide insights into potential mechanisms by which SP may improve pregnancy outcomes.

Combination of Antistaphylococcal ß-Lactam With Standard Therapy Compared to Standard Therapy Alone for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia: A Post Hoc Analysis of the CAMERA2 Trial Using a Desirability of Outcome Ranking Approach.

Background: Desirability of outcome ranking (DOOR) is an emerging approach to clinical trial outcome measurement using an ordinal scale to incorporate efficacy and safety endpoints. Methods: We applied a previously validated DOOR endpoint to a cohort of CAMERA2 trial participants with methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). Participants were randomly assigned to standard therapy, or to standard therapy plus an antistaphylococcal ß-lactam (combination therapy). Each participant was assigned a DOOR category, within which they were further ranked according to their hospital length of stay (LOS) and duration of intravenous antibiotic treatment. We calculated the probability and the generalized odds ratio of participants receiving combination therapy having worse outcomes than those receiving standard therapy. Results: Participants assigned combination therapy had a 54.5% (95% confidence interval [CI], 48.9%-60.1%; P = .11) probability and a 1.2-fold odds (95% CI, .95-1.50; P = .12) of having a worse outcome than participants on standard therapy. When further ranked according to LOS and duration of antibiotic treatment, participants in the combination group had a 55.6% (95% CI, 49.5%-61.7%) and 55.3% (95% CI, 49.2%-61.4%) probability of having a worse outcome than participants in the standard treatment group, respectively. Conclusions: When considering both efficacy and safety, treatment of MRSAB with a combination of standard therapy and a ß-lactam likely results in a worse clinical outcome than standard therapy. However, a small benefit of combination therapy cannot be excluded. Most likely the toxicity of combination therapy outweighed any benefit from faster clearance of bacteremia.