A 2-dose regimen of the vaccine modified vaccinia Ankara-Bavarian Nordic (MVA-BN) can generate neutralizing antibodies for monkeypox virus clades Ib and IIb. We observed higher response to clade IIb; that result provides evidence that MVA-BN vaccination can induce cross-neutralizing antibodies for monkeypox virus clade Ib as well as for clade IIb.

To date, no vaccine has been approved against Zika virus (ZIKV). Any such vaccine must be safe to use during pregnancy and needs to consider immune interactions from prior flavivirus exposure given these viruses co-circulate and share the same mosquito vector. To address these issues, we have developed a vaccine using a modified vaccinia Ankara (MVA) virus. Here, we describe the development of this MVA vectored Zika vaccine that encodes structural proteins, premembrane and envelope, and non-structural (NS) proteins, NS3 and NS5 (MVA-ZIKA-B). A two-dose vaccination regimen with MVA-ZIKA-B resulted in significant serum neutralizing activity and induced polyfunctional T cell responses that protected in a mouse model of Zika, rendering virus undetectable across multiple tissues after virus challenge. Vaccine-associated protection was also characterised by high IgG antibodies against the ZIKV envelope and potent interferon-gamma (IFNγ)-positive T cell responses when stimulated ex vivo with ZIKV peptides. Further stability studies showed that the vaccine antigens were stably expressed, and the vaccine progressed to GMP manufacturing. A phase I human trial with MVA-ZIKA-B is ongoing.

Herpes simplex virus (HSV) encephalitis is the most frequent cause of sporadic encephalitis globally. Despite the emergence of the antiviral drug aciclovir curtailing mortality, this disease remains a clinical challenge due to its rapid progression and associated neurological sequelae; indicating the urgent requirement for adjunctive neuroprotective treatment options. Recent studies using both human samples and murine models have highlighted how cell mediated immune cells including CD8+, CD4+ and brain tissue-resident memory T cells have the capacity to act as a ‘double-edged sword’; both serving to protect the host against HSV encephalitis, but also increasing neuroglial injury by inflammation. Factors which impair cell-mediated immunity may predispose individuals to herpes simplex encephalitis, including defects in viral immune evasion strategies (infected cell protein 47, UL13 kinase), host genetic pre-disposition (toll-like receptor 3 deficiency, lymphotoxin-α deficiency, Rel mutations) and external factors such as stress. Additionally, there is a particular need for clinical vigilance for patients on immunosuppressive treatments which impair cell-mediated immunity, including azathioprine, hydroxychloroquine and methotrexate. Conversely, understanding these molecular mechanisms may provide new insights into the use of immunomodulatory strategies including anakinra, tocilizumab, and the implementation of targeted vaccination. This review summarises the current state of knowledge of how an impaired cell-mediated immune response could promote herpes simplex virus encephalitis, followed by an exploration of the clinical applications and therapeutic interventions which could viably be implemented to ameliorate immune-mediated tissue injury.

Japanese encephalitis (JE) virus (JEV) is a leading cause of neurological infection in the Asia-Pacific region with devastating socioeconomic consequences. We aimed to develop a target product profile (TPP) for JE diagnostics in endemic areas in the context of other flaviviruses, to better define improvements needed for patient management and public health. Thematic experts were identified from a scoping review, World Health Organization and Encephalitis International databases, as well as author networks. Initial interviews were performed with selected experts to inform a draft TPP document and start a Delphi process, aiming for consensus of ≥75% on each characteristic. A one-day meeting facilitated in-depth discussion, with breakout groups and electronic voting to develop the final TPP document. In total, 460 participants were invited. Five interviews enabled drafting a TPP. Two iterative surveys were completed by 44 respondents, including clinicians, scientists, and public health experts from 15 countries. A hybrid meeting was attended by 42 participants. Seven priority characteristics were discussed, and consensus was achieved for six; no clear consensus was reached for the preferred test sensitivity and specificity, with 73% agreement. Discussion points and expert consensus were consolidated into a roadmap for development and implementation to guide future work. A diverse group of health professionals agreed that improved diagnostics for JE are needed, and that a priority is a test for patient management that detects JE alongside other relevant flavivirus infections. There was a mandate for a rapid diagnostic test (RDT), and it was suggested that this could be implemented in a two-tiered diagnostic algorithm. The final TPP is presented in the paper; this aims to help define the updates needed to better support patient management and public health interventions, to provide a strategic reference document to drive innovation and improve clarity for JE diagnostic test developers.

We describe the burden of severe influenza in England overall, and in risk groups (as defined by age, immunocompromise, and other comorbidities) and those with recent COVID-19. The INFORM (INvestigation oF cOvid-19 Risk among iMmunocompromised populations) cohort uses pseudonymised, routinely collected electronic health records of individuals aged ≥ 12 years from a random 25

Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8+ T-cells directed against HLA-B*15:01-restricted Spike-derived S919-927 peptide (B15/S919+CD8+ T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8+ T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S919+CD8+ T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S919+CD8+ T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S919+CD8+ T-cell responses lacking a highly expanded key public B15/S919+CD8+ T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S919+CD8+ T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S919+CD8+ T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S919+CD8+ T-cells did not differ across disease severity. Moreover, B15/S919+CD8+ T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.

Recently, a novel subclade of mpox virus (MPXV), clade Ib, has emerged in Eastern Democratic Republic of the Congo (DRC). Modified vaccinia Ankara-Bavarian Nordic (MVA-BN) is a third-generation smallpox vaccine that is authorised and in use as a vaccine against mpox. MVA-BN provides approximately 78% protection against disease to Clade IIb MPXV, but there are no data for Clade Ib. We used a plaque reduction neutralisation assay (PRNT) with MPXV clinical isolates from Clade Ib and IIb to investigate immunity in vaccinated health care workers. Here we show that a two-dose regimen of MVA-BN can induce MPXV-neutralising antibodies against both clades, with higher responses to Clade IIb than Clade Ib. KEY POINTS 1. Vaccination with MVA-BN generates antibodies that can neutralise MPXV Clade Ib and IIb. 2. Despite the small sample size paired analysis across the vaccine recipients demonstrate higher neutralisation to Clade IIb than Ib. ### Competing Interest Statement LT has received consulting fees from MHRA and Bavarian Nordic. ### Funding Statement This work was funded by the DECIPHER MPOX consortium (HORIZON-JU-GH-EDCTP3, Grant number 101194676) and The Pandemic Institute (Liverpool). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Research Ethics Committee of University of Liverpool gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Immunomodulatory therapy is a key tool to prevent aggressive host-pathogen reactions and associated mortality in severe COVID-19. Secondary infection was detected in 0.6% of COVID-19 patients with immunomodulators versus 0.2% of those with no therapy. However, the impact of this therapy on organisms causing secondary infection in COVID-19 patients is unknown. We aimed to describe the distribution of bacteria and fungi causing secondary infections of COVID-19 patients with and without immunomodulatory therapy. COVID-19 episodes from UKHSA’s hospitalized COVID-19 patient dataset (SARS-CoV-2 positive specimen date within 14 days of, or during, hospital admission, 1 January 2020–31 August 2023), bacterial and fungal data from UKHSA’s microbiological datasets (5 December 2019–27 September 2023) and prescribing data from 22 trusts in England which contributed to Electronic Prescribing and Medicines Administrations data (1 January 2020–31 August 2023) were extracted. Medications included were immunomodulators used for COVID-19 therapy administered between 7 days before SARS-CoV-2 positivity to 27 days afterwards or censored to one day before a secondary infection positive specimen collection. Secondary infections were defined as hospitalized COVID-19 patients with a bacterial/fungal infection occurring 2–27 days after SARS-CoV-2 positive specimen date. COVID-19 patients with a bacterial/fungal infection occurring 27 days before to 1 day after SARS-CoV-2 positivity were excluded. The dataset included 482 COVID-19 episodes with secondary infection, 64.3% of which had no immunomodulators (n=310) and 35.7% with immunomodulatory therapy (n=172). Within these COVID-19 episodes, 800 bacterial/fungal organism-specific infection episodes were identified during 27 day follow up, the maximum present in one COVID-19 episode was four. There were few demographic differences between those receiving therapy and those without; however, those with immunomodulators tended to have a greater Charlson comorbidity index (CCI) than those without (CCI≥3: 25.0% versus 16.5%, P=0.023). Of patients with secondary infection and immunomodulatory therapy, 61.1% had multiple organisms detected versus 48.7% in those receiving no therapy (median: 2 versus 1, P=0.0192). Pattern of polymicrobial infection differed by immunomodulator status, for example COVID-19 episodes associated with immunomodulatory therapy were more likely to have a Gram-negative and fungal combination than those without therapy (10.5% versus 4.6%, P=0.072). Enterococcus spp., Klebsiella spp. and Escherichia spp. were the most common organisms in all secondary infections (23.0%, 20.7% and 19.3%, respectively) and in the no immunomodulatory therapy group (24.5%, 19.7% and 20.6%, respectively). Whereas the top three in the therapy group were Klebsiella spp., Staphylococcus spp. and Pseudomonas spp. (22.7%, 22.1% and 20.9%, respectively). COVID-19 patients who receive immunomodulatory therapy have a greater percentage of polymicrobial infections and different genus distribution than those without therapy. Therefore, empirical therapy guidance may need to differ based on immunomodulatory therapy usage for COVID-19 treatment. However, given that patients received immunomodulatory therapy for severe COVID-19, the increased comorbidities and incidence of Pseudomonas species may be indicative of patient location (ICU versus non-ICU) confounding the relationship between immunomodulatory therapy and species distribution. At present patients’ ward location is unavailable in the datasets utilized so further work is required to investigate this fully.

Background:Scrub typhus and other doxycycline-treatable infections are significant contributors of acute encephalitis syndrome (AES) in India. Limited surveillance in South India has hindered their recognition and the inclusion of doxycycline in treatment protocols. We aimed to systematically investigate infectious aetiologies of AES in children from Karnataka, India, and develop clinical prediction models for diagnosing scrub typhus and guiding clinical decisions for doxycycline therapy. Methods:This multicentre, prospective study enrolled children aged >28 days to 18 years with AES presenting to three tertiary care hospitals in Bengaluru, India. Primary outcomes were microbiological diagnosis of AES and clinical prediction models for diagnosing scrub typhus and identifying patients with doxycycline-treatable causes. Models were developed using multivariable logistic regression, internally validated, and simplified into point-scoring systems. Model performance was evaluated using c-statistics, calibration slopes, and calibration-in-the-large, adhering to TRIPOD guidelines. Findings:Between February 2020 and February 2023, 714 children were screened, of whom 587 were included. Of these, 315 (54%) had a microbiological diagnosis. Scrub typhus accounted for 138/315 (44%), and doxycycline-treatable causes were diagnosed in 193/315 (61%) of these cases. Key predictors associated with both scrub typhus and doxycycline-treatable causes were age, illness duration, lymphadenopathy, oedema, hepatomegaly, lymphocyte count, platelet count, and serum albumin levels. Adjusted c-statistics were 0.83 (95% CI: 0.78-0.87) for the scrub typhus model and 0.75 (95% CI: 0.7-0.81) for the doxycycline model, with calibration slopes of 0.85 (0.82-0.88) and 0.83 (0.78-0.87), respectively. CITL values were -0.03 (-0.06-0) and 0.05 (0.02-0.09). Points-based scores predicted probabilities ranging from 5% to 99.8% (scrub typhus model) and 20%-99% (doxycycline-treatable model). Interpretation:Scrub typhus was the most common microbiological diagnosis, and most patients had a doxycycline-treatable cause, underscoring the need to prioritise doxycycline in empirical treatment protocols in South India. The models demonstrated strong performance; however external validation is necessary for broader applicability. Funding:DBT/Wellcome Trust India Alliance FellowshipIA/CPHE/18/1/503960.

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3–6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors. Walmsley and colleagues report that systemic hypoxia induces persistent loss of histone H3K4me3 marks and epigenetic reprogramming in neutrophil progenitors, resulting in long-term impairment of subsequent neutrophil effector functions.

The circulating enteroviruses (EVs) serotypes in hand, foot and mouth disease (HFMD) inpatients remained unclear. This study aimed to investigate the serotype-specific associations between clinical characteristics and severity of HFMD inpatients. The study utilised a prospective, hospital-based cohort design and a tiered diagnostic algorithm incorporating real-time RT-PCR and nested RT-PCR for serotyping. Clinical data were prospectively collected throughout hospitalization. Clinical severity was measured using diagnoses of central nervous system (CNS) complications and three other outcomes. A total of 1768 inpatients were enrolled consecutively between February 2017 and February 2018. The proportions of CNS complications varied by serotype (p < 0.001), with the highest for EV-A71 (40%), followed by CV-A4 (17%), CV-A2 (13%), CV-A10 (10%), CV-A6 (7%), and CV-A16 (4%). Children with CV-A2 and CV-A4 were less likely to have rashes on hands, feet, or buttocks and more likely to develop high fever, while those with EV-A71 had fewer mouth lesions. Of 230 lab-confirmed HFMD inpatients with CNS complications, EV-A71 accounted for 45% while CV-A6, CV-A16, CV-A4, CV-A10 and CV-A2 accounted for 35%. The logistic regression analysis revealed that non-CNS-specific symptoms such as cold limbs and vomiting, and clinical testing indicators including blood globulin, platelet, serum chloride and neutrophil counts, were associated with CNS complications. Non-EV-A71 EVs can also cause severe diseases, but those with EV-A71 infection are more likely to suffer CNS complications and other severe manifestations. The study highlighted the emergence of enterovirus serotypes, suggesting the need for future research on virus changes and associated disease burden.

Objectives: We aimed to characterise coronavirus disease 2019 (COVID-19) severity, mortality and healthcare utilisation in immunocompromised individuals in England during 2023, using INFORM (INvestigation oF cOvid-19 Risk among iMmunocompromised populations) study data. Methods: Retrospective cohort study (ISRCTN53375662) using pseudonymised electronic health records of individuals aged >= 12 years from a random 25% sample of England's population. Over 1 January-31 December 2023, adjusted incidence rate ratios (aIRRs; adjusted for age, sex, non-immunocompromising comorbidities) between immunocompromised and non-immunocompromised individuals for COVID-19related hospitalisation, death, and healthcare utilisation were estimated. Results: Immunocompromised individuals represented 4.0% of 12,056,685 individuals studied but accounted for 21.7% and 21.9% of COVID-19 hospitalisations and deaths, respectively. Risk of severe COVID-19 was elevated for immunocompromised vs. non-immunocompromised; aIRRs: 2.04, 95% CI 1.95-2.14 (COVID-19 hospitalisation); 1.69, 95% CI 1.53-1.87 (COVID-19 death). COVID-19 vaccination was more likely in immunocompromised vs. non-immunocompromised (>= 4 doses 72.6% vs. 29.8%). The aIRRs for COVID-19-related general practitioner consultations and accident and emergency/day case visits were 2.26 (95% CI 2.22-2.29) and 3.02 (95% CI 2.84-3.20), respectively, for immunocompromised vs. non-immunocompromised. Conclusions: Beyond three years since the start of the COVID-19 pandemic, immunocompromised individuals remain disproportionately impacted from COVID-19 despite increased vaccination. These findings highlight a persistent need for additional COVID-19 interventions for immunocompromised populations. (c) 2025 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

COVID-19 vaccines were updated to address immune escape from variants of concern (VOC). We explored the impact of ancestral/BA.1 bivalent mRNA booster vaccination (Autumn 2022) on peripheral and nasal antibody and T-cell responses to SARS-CoV-2 in an observational cohort of 133 healthcare workers, building on previous longitudinal vaccination studies. We demonstrate that maintenance of antibody and T-cell responses up to eighteen months following the third vaccine is at least partially driven by intercurrent infection. Boosting with the bivalent vaccine increases the breadth of circulating and nasal antibodies to spike, which waned over time but was still detectable six months post-dose. T-cell responses are well maintained and highly cross-reactive to VOCs irrespective of booster vaccination. Vaccination strongly boosted nasal IgG, but this was short-lived compared to circulating antibodies. Overall, ongoing COVID-19 vaccination provides benefit, boosting immunity in individuals who have not been recently infected, but new strategies may be needed to provide longer-term nasal immunity.

Background The recent development of vaccines for respiratory syncytial virus (RSV) has created a pressing need to better quantify the morbidity and mortality of RSV infection in haematological malignancies (HM). The present study investigated RSV morbidity and mortality in a large, unselected HM population as part of the UNCOVER health data research programme using secondary care data routinely collected by the National Health Service (NHS) in England. Methods Cancer registry and linked hospital attendance, treatment and survival data were obtained from the NHS England National Cancer Registration Service for all adults with HM diagnosed between 2014 and 2021, alongside a control cohort of patients with non-melanoma skin cancer (NMSC) aged ≥75. Primary outcomes were RSV-related death, hospital admission with RSV as the primary cause, and hospital admission with RSV as a contributory cause. Secondary outcomes included duration of RSV-related hospital admissions, readmission rates, overall survival (OS) and cause-specific survival (CSS) following RSV-related hospitalisation. Baseline variables included comorbidity measured by the Charlson Comorbidity Index and socioeconomic deprivation measured as index of multiple deprivation (IMD) quintiles. Crude incidence rates were reported with incidence rate ratio and P-values calculated using Poisson regression. Within the HM population, propensity score matching (1:4 nearest neighbour) was used to compare outcomes following RSV-related vs matched RSV-unrelated hospitalisations. Admission length was compared using Mann-Whitney U test, while readmission rates were analysed using Anderson-Gill recurrent event models. OS and CSS were analysed using Kaplan-Meier estimates and log-rank tests. Risk factors for severe RSV disease, defined as RSV-related death or hospital admission with RSV as the primary cause, were identified using uni- and multivariable Cox proportional hazards (coxph) models, with cause-specific competing risks regression used to account for RSV-unrelated deaths. Findings The HM population included 260,029 patients [median age 71 years (IQR 61-80); 56.9% male]. The most common diagnoses were mature B-cell neoplasms (40.7%), plasma cell neoplasms (PCN; 15.1%), myeloproliferative neoplasms (12.9%), myelodysplastic syndrome (MDS; 8.0%), and acute myeloid leukaemia (AML; 6.7%). Over a median follow-up of 39.7 months,131,575 (50.6%) received systemic anti-cancer therapy (SACT) and 10,662 (4.1%) underwent haematopoietic stem cell transplantation (HSCT). Incidence rates for RSV-related death (3.3/100,000 person-years), hospitalisation with RSV as a primary cause (11.7/100,000 person-years) or as a contributory cause (75.2/100,000 person-years) were 2.7- (P=0.017), 5.2- (P<0.001), and 11.4-fold (P<0.001) higher, respectively, than in the control population [n=134,489, median age 82 (IQR 78-86) years]. Compared to matched RSV-unrelated admissions, RSV-related hospitalisations in HM patients were associated with longer admissions (median 7 vs 5 days, P<0.001), higher readmission rates [1.6-fold for first readmission (P<0.001), 1.2-fold for second (P=0.009)]; shorter OS (median 27.4 vs 52.7 months, P=0.003); a 1.7-fold increased risk of infection-related death (P<0.001); and a 1.2-fold increased risk of HM-related death (P=0.005). Multivariable and cause-specific coxph analyses identified acute lymphoblastic leukaemia, AML, MDS, PCN, SACT within 6 months and HSCT within 12 months as independent risk factors for severe RSV. Notably, neither age nor comorbidity were significant predictors of severe RSV, whereas there was a non-linear relationship between severe RSV risk and deprivation. Compared to IMD5 (least deprived), severe RSV risk increased with greater deprivation, reaching significance in IMD2 (P=0.017). However, IMD1 (most deprived) was associated with high RSV-related mortality but low hospitalisation rates with RSV as the primary cause. Conclusion Given that advanced age is an established risk factor for adverse RSV outcomes, our findings clearly identify HM as an even greater risk factor, providing a strong rationale for prioritising individuals with HM in unfolding RSV vaccination programmes. Among patients with HM, diagnoses including acute leukaemia, MDS and PCN, as well as recent therapy (SACT or HSCT), were associated with a higher risk of severe RSV infections. Such infections may be under-diagnosed and under-treated in patients living in the most deprived areas.

BACKGROUND:Brain infections pose substantial challenges in diagnosis and management and carry high mortality and morbidity, especially in low-income and middle-income countries. We aimed to improve the diagnosis and early management of patients admitted to hospital (adults aged 16 years and older and children aged >28 days) with suspected acute brain infections at 13 hospitals in Brazil, India, and Malawi. METHODS:With hospital stakeholders, policy makers, and patient and public representatives, we co-designed a multifaceted clinical and laboratory intervention, informed by an evaluation of routine practice. The intervention, tailored for each setting, included a diagnostic and management algorithm, a lumbar puncture pack, a testing panel, and staff training. We used multivariable logistic regression and interrupted time series analysis to compare the coprimary outcomes-the percentage of patients achieving a syndromic diagnosis and the percentage achieving a microbiological diagnosis before and after the intervention. The study was registered at ClinicalTrials.gov (NCT04190303) and is complete. FINDINGS:Between Jan 5, 2021, and Nov 30, 2022, we screened 10 462 patients and enrolled a total of 2233 patients at 13 hospital sites connected to the four study centres in Brazil, India, and Malawi. 1376 (62%) were recruited before the intervention and 857 (38%) were recruited after the intervention. 2154 patients (96%) had assessment of the primary outcome (1330 [62%] patients recruited pre-intervention and 824 [38%] recruited post-intervention). The median age across centres was 23 years (IQR 6-44), with 1276 (59%) being adults aged 16 years or older and 888 (41%) children aged between 29 days and 15 years; 1264 (59%) patients were male and 890 (41%) were female. Data on race and ethnicity were not recorded. 1020 (77%) of 1320 patients received a syndromic diagnosis before the intervention, rising to 701 (86%) of 813 after the intervention (adjusted odds ratio [aOR] 1·81 [95% CI 1·40-2·34]; p<0·0001). A microbiological diagnosis was made in 294 (22%) of 1330 patients pre-intervention, increasing to 250 (30%) of 824 patients post-intervention (aOR 1·46 [95% CI 1·18-1·79]; p=0·00040). Interrupted time series analysis confirmed that these increases exceeded a modest underlying trend of improvement over time. The percentage receiving a lumbar puncture, time to appropriate therapy, and functional outcome also improved. INTERPRETATION:Diagnosis and management of patients with suspected acute brain infections improved following introduction of a simple intervention package across a diverse range of hospitals on three continents. The intervention is now being implemented in other settings as part of the WHO Meningitis Roadmap and encephalitis control initiatives. FUNDING:UK National Institute for Health and Care Research.

PT003 / #262 Topic: AS11 - Epidemiology and Public Health POSTER TOUR 01: CLINICAL OUTCOMES IN SLE 22-05-2025 10:00 AM - 10:40 AM Patients with systemic lupus erythematosus (SLE) are at increased risk of infection relative to the general population. A previous analysis from our cohort found a crude incidence rate of serious infections at 117.7 (95% CI 98.3–141.0) per 1000 person-years in the first 12 months from cohort entry. We aimed to establish the long-term risk of serious infections in patients with moderate-to-severe SLE in a large national observational cohort. The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. We included patients starting a new biological (rituximab or belimumab) within the previous 12 months or a new standard of care DMARD drug within the last month. Our primary outcome was the long-term incidence of infections, and infections of special interest including herpes zoster. Infections occurring within 28 days of the initial infection were classified as relapses, whereas after 28 days were considered reinfections. Infections involving distinct organ systems or resulting in systemic dissemination within 28 days were recorded separately, unless pathogen identification confirmed they were related to a single infection event. Serious infections were those requiring intravenous antimicrobial treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centers and the UK Office for National Statistics. Between July 2010, and January 2023, 1342 individuals contributed 7073.4 person-years of follow-up. This included 929 (69.2%) participants on rituximab, 209(15.6%) on belimumab, and 204 (15.2%) receiving standard of care. The median age at cohort entry was 45 years (IQR 35–55),1206 (89.9%) were women, 670/1172 (57.2%) were White, 207 (17.7%) were South Asian, 202 (17.2%) were Black, and 93 (7.9%) were of East Asian, mixed or other ethnic backgrounds. In total, 1471 infections occurred in 545 (40.6%) individuals. Of these, 303 infections in 186 (13.9%) were classified as serious (Table 1). The crude incidence rate of all infections and serious infections were 208.0 (95% CI 197.3 -218.6) and 42.8 (95% CI 38.0– 47.7) per 1000 person-years, respectively. In the 186 individuals with serious infection, 126 (67.7%) experienced 1 serious infection,42 (22.6%) had 2, and 18 (9.7%) had 3 or more (max 11) serious infections. Herpes zoster occurred in 4.7% of the 1,342 participants at risk (incidence rate 8.9 cases per 1000 person-years, (95% CI 6.96 – 11.4)). Two cases of tuberculosis were reported, both required hospitalization; 1 was a TB recurrence 153 days after the second rituximab cycle (cumulative dose 3 grams), the other was diagnosed during pretreatment screening. Bacterial pathogens were identified by culture in 54 cases (Figure 1A). Figure 1B shows the distribution of other infectious agents in the cohort. There were 22 infection-related deaths at a median of 2783 days (IQR 1343 – 3709) following initiation of therapy. There were no safety signals indicating an increased risk of atypical or opportunistic infections, as these occurrences were rare. Table 1: Distribution of 303 serious infections which occurred in 186 individuals. Figure 1. Pie charts showing A Proportion of causative bacterial infectious agents, B other infectious agents Our longer-term analysis shows a lower crude incidence rate of serious infections than in the first 12 months of follow-up suggesting potential adaptation or mitigation of risk over time. We also noted the occurrence of pathogens that are potentially vaccine-preventable and so further work is required to understand vaccine protocols as well as the quality and durability of vaccine responses in this high-risk cohort.

Chikungunya virus (CHIKV) is an emerging cause of acute encephalitis syndrome (AES) in India, with limited data on its role in childhood AES in southern India. We systematically evaluated children with AES in southern India during a non-epidemic period for CHIKV. Serum and cerebrospinal fluid (CSF) samples were tested for CHIKV using IgM ELISA and real-time reverse transcriptase PCR. Amplicon sequencing was performed on PCR-positive samples. Clinical and laboratory features were compared between children with and without CSF CHIKV positivity (PCR/IgM antibodies). Of 376 children with AES, 20 (5.3%) had positive CHIKV tests. Co-infections were common, particularly with scrub typhus. Children presented with diverse symptoms affecting various organ systems. Neurological manifestations included meningism, seizures, cerebellar signs, behavioral abnormalities, cranial nerve involvement, involuntary movements, and hemiparesis/hemiplegia. Children with CSF CHIKV positivity showed more focal neurological deficits and transaminitis, and less musculoskeletal symptoms. Sequencing confirmation of CHIKV was made in all patients with positive CHIKV PCR, revealing a close relationship with 2016 Kenyan and Indian strains, albeit in a different clade within the East/Central/South African genotype. Along with important mutations known to impact CHIKV infectivity, four novel amino acid substitutions were detected in envelope protein coding regions. Our findings underscore the importance of routine and comprehensive CHIKV testing for children with AES, irrespective of season/outbreak. The high rate of co-infections warrants further research. Continued genomic surveillance is essential to monitor emerging mutations with epidemic potential, increased severity and the risk of neurological disease.