Geers D, Aguilar-Bretones M, Zaeck LM
… +23 more, Gill PA, Gonzalez-Lopez C, Handrejk K, Tan NH, den Hartog Y, Gommers L, Bogers S, Mykytyn AZ, Sablerolles RSG, Goorhuis A, Postma DF, Visser LG, Dalm VASH, Lafeber M, Kootstra NA, van Baarle D, Haagmans BL, Koopmans MPG, GeurtsvanKessel CH, van der Kuy PHM, van Nierop GP, van Zelm MC, de Vries RD
OBJECTIVES: Ongoing escape from pre-existing antibodies by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) necessitates yearly coronavirus disease 2019 (COVID-19) vaccine updates. Monovalent variant...OBJECTIVES: Ongoing escape from pre-existing antibodies by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) necessitates yearly coronavirus disease 2019 (COVID-19) vaccine updates. Monovalent variant-specific booster vaccines for at-risk populations aim to re-direct antibody responses towards antigenically distinct variants. However, multiple past exposures to the ancestral SARS-CoV-2 spike (S) protein through vaccination and infection could hinder the de novo induction of variant-specific immune responses. METHODS: Here, we profiled SARS-CoV-2-specific antibody, T- and B-cell responses in healthcare workers up to 6 months after monovalent XBB.1.5 vaccination. RESULTS: Neutralizing antibodies targeting Omicron subvariants circulating at the time of vaccination were preferentially boosted by vaccination but remained lower than those neutralizing the ancestral strain. Similar responses were observed for antibodies that mediate functionality through antibody-dependent cellular cytotoxicity, although these responses were more promiscuous. Broadly S-reactive B-cells were recalled by vaccination, with limited de novo induction of XBB.1.5-specific B-cell clones. B-cells targeting the receptor binding domain of circulating Omicron subvariants were favored, and T-cell responses cross-reacted with all SARS-CoV-2 variants that were assessed. CONCLUSIONS: Combined, this comprehensive immune profiling demonstrates that despite evidence of imprinted antibody responses targeting ancestral S, monovalent booster vaccination skews the immune response to Omicron lineage recognition.
BACKGROUND: The World Health Organization (WHO) 2024 Hepatitis B virus (HBV) treatment guidelines expand eligibility for nucleos(t)ide analogue treatment in individuals with chronic HBV infection. For countries to implem...BACKGROUND: The World Health Organization (WHO) 2024 Hepatitis B virus (HBV) treatment guidelines expand eligibility for nucleos(t)ide analogue treatment in individuals with chronic HBV infection. For countries to implement these guidelines, there is a critical need to understand the population who are treatment eligible. While HBV drug resistance (HBVDR) is uncommon, monitoring for any potential resistance is a relevant public health consideration. METHODS: We studied a population in rural Uganda to describe the proportion of individuals eligible for treatment based on the 2024 WHO treatment guidelines. We determined how this proportion varies according to the eligibility criteria used, comparing the performance of different assessment tools. We calculated Aspartate Aminotransferase-to-Platelet Ratio Index; APRI, Gamma-Glutamyl Transpeptidase-to-Platelet Ratio; GPR and transient elastography; TE and performed HBV sequencing using Oxford Nanopore Technology to determine the prevalence of HBVDR in treatment naive and treatment experienced individuals. RESULTS: In this cohort, 24/63 (38%) individuals with CHB were eligible for treatment. This fell to 14/63 (22%) in a hypothetical scenario where TE was not available for the assessment of liver fibrosis. We demonstrate a lack of concordance between non-invasive tests (NIT) of liver disease in treatment-naive HBV mono-infected individuals. An APRI cut-off of 0.5 had a sensitivity of 23.0% for predicting a TE score of >7 kPa (F2 fibrosis). Sensitivity for detecting F2 fibrosis was increased to 38.5% using an APRI cut off of 0.36, and to 46.2% using the GPR. We did not identify any HBVDR in the HBV mono-infected treatment-naive population (n=58). 24/210 individuals were living with HIV/HBV coinfection; HBV was sequenced in 5 of these of whom 2 had genomic evidence of nucleos(t)ide analogue resistance (rt180M/204V). CONCLUSIONS: While the WHO 2024 treatment criteria offer an opportunity to expand access to care, there is a need to determine how assessment tools differ in determination of eligibility in different settings. HBVDR remains uncommon but more research is needed to understand its prevalence and clinical impact in African populations.
BACKGROUND: People living with HIV (PLWH) who experience advanced immunosuppression are susceptible to severe COVID-19 and demonstrate compromised vaccine responses due to low CD4 counts and uncontrolled HIV viral load....BACKGROUND: People living with HIV (PLWH) who experience advanced immunosuppression are susceptible to severe COVID-19 and demonstrate compromised vaccine responses due to low CD4 counts and uncontrolled HIV viral load. Although vaccine boosters enhance immunity in the general population, their immunogenicity in individuals with advanced HIV remains inadequately characterised. METHODS: This study evaluated the humoral and cellular immunogenicity of COVID-19 vaccine boosters in 41 individuals with advanced HIV at baseline and 4 weeks post-vaccination. Binding antibodies, neutralising antibodies, antibody-dependent cellular cytotoxicity (ADCC), as well as spike-specific CD4+ and CD8+ T-cell responses were quantified and characterised. RESULTS: Booster vaccination was found to increase binding antibody titres (8.0-fold) and neutralising activity (3.9-fold), even among participants with CD4 counts <100 cells/mm³, although absolute responses remained lower than the controls. ADCC activity also modestly increased post-vaccination (2.1-fold). Spike-specific CD4+ T-cell responses increased in magnitude (0.001% to 0.160%, p=0.0001) and responder frequency (49% to 83%, p=0.0167) post-vaccination, while CD8+ T-cell responses remained low. Compared to the controls, PLWH had similar magnitudes of spike-specific CD4+ T-cell responses but significantly lower CD8+ T-cell responses. CONCLUSION: COVID-19 vaccine boosters enhance immunity in PLWH, however, the responses remain suboptimal compared to immunocompetent individuals, emphasising the need for tailored vaccination strategies.
OBJECTIVES: To examine the association between prenatal antibiotic exposure and Group B Streptococcus (GBS) disease within 4 weeks postpartum. METHODS: We conducted a population-based cohort study including all singleton...OBJECTIVES: To examine the association between prenatal antibiotic exposure and Group B Streptococcus (GBS) disease within 4 weeks postpartum. METHODS: We conducted a population-based cohort study including all singleton live births in Sweden from 2006 to 2016, using national registers. Neonates were classified by prenatal antibiotic exposure status, and GBS disease was ascertained within four weeks postpartum. Adjusted odds ratios (aOR) were estimated using multivariable logistic regression with a robust variance estimator. Effect heterogeneity by GBS risk factors was evaluated, and potential confounding by indication was assessed by additional adjustment for these risk factors. RESULTS: Among 1,095,644 liveborn singletons, 24.5% were exposed to antibiotics. GBS incidence was higher among exposed neonates than unexposed (0.86 vs. 0.66 per 1000 live births; aOR, 1.29; 95% CI, 1.10-1.50), particularly among neonates without GBS risk factors (aOR, 1.34; 95% CI, 1.12-1.60). The strongest association occurred with early third-trimester exposure (aOR, 1.67; 95% CI, 1.17-2.38). Associations for antibiotics given within four weeks of delivery attenuated after adjustment for GBS risk factors. CONCLUSIONS: Prenatal antibiotic exposure can raise GBS risk within 4 weeks postpartum, especially in neonates not covered by risk-based intrapartum prophylaxis, with the early third-trimester being a critical window of susceptibility.
Lange B, Brehm TT, Arend SM
… +34 more, Arias-Guillén M, Bakker M, Berastegui C, Babiker M, Charif R, Duarte R, Flick H, Hofland RW, Ismail J, Kniepeiss D, Krepel J, Krishnan N, Kuijpers DL, Kunst H, van Leth F, Lezaic V, Los-Arcos I, Machová J, Milburn H, Morais SA, Kon OM, Osoro-Suarez C, Pessegueiro Miranda H, Pesut D, Rahman A, Reischig T, Sánchez-Montalvá A, Spohn HE, Stegenga MT, de Vries APJ, Wagner D, Wobser R, Lange C, Sester M
BACKGROUND: Solid organ transplant (SOT) recipients face elevated tuberculosis risk, yet optimal prevention strategies in low- to medium-incidence regions remain unclear. METHODS: We conducted a multicenter retrospective...BACKGROUND: Solid organ transplant (SOT) recipients face elevated tuberculosis risk, yet optimal prevention strategies in low- to medium-incidence regions remain unclear. METHODS: We conducted a multicenter retrospective cohort study of adult SOT recipients transplanted between 2007 and 2012 at 15 European centers, with follow-up through 2018. The primary outcome was microbiologically confirmed post-transplant tuberculosis. Incidence rates were calculated per 100,000 person-years; standardized incidence ratios (SIRs) used World Health Organization country-specific background rates. Cox models assessed risk factors. RESULTS: Among 5805 patients (median age 51; 62.7% male; 73.9% renal transplants), 33.8% were tested for tuberculosis infection and 10.3% received tuberculosis preventive therapy (TPT). Over 33,785 person-years, 23 patients (0.4%) developed tuberculosis (68.0/100,000 person-years). Highest incidence occurred in patients with positive screening but no TPT (233.8/100,000). Incidence was higher in Southern vs. Central Europe (251.9 vs. 28.7/100,000), with pooled SIRs of 12.8 and 3.1, respectively. Tuberculosis risk was elevated among Southern European recipients (HR 22.9) and those with migration history (HR 2.7). CONCLUSION: Tuberculosis risk is increased in European SOT recipients. Regionally adapted prevention strategies, including targeted screening in low-incidence areas and universal screening in higher-incidence regions, are warranted.
Situ J, Wong TC, Wu S
… +26 more, Li Z, Shun EHK, Ho SFS, Yip CCY, Lo KHY, Tsoi JYH, Ma W, Lo ATK, Yiu J, Ng EYT, Kwong MY, Ip CYL, Chung HL, Chew NFS, Liang Y, Mao W, Ma X, Hui DTY, Wong SCY, Chan KM, Cheung CY, Kwong TS, Lung DC, Cheng VCC, Yuen KY, Sridhar S
OBJECTIVES: Rocahepevirus ratti genotype 1 (rHEV), commonly known as rat hepatitis E virus, is a recently identified cause of viral hepatitis. We compared rHEV infections with conventional hepatitis E and measured rHEV s...OBJECTIVES: Rocahepevirus ratti genotype 1 (rHEV), commonly known as rat hepatitis E virus, is a recently identified cause of viral hepatitis. We compared rHEV infections with conventional hepatitis E and measured rHEV seroprevalence in a large diverse human serum cohort. METHODS: Patients with hepatitis (n=2018) were tested for rHEV RNA in the context of a real-world clinical service in Hong Kong. rHEV IgG seroprevalence in various risk groups was measured using a validated immunoassay. Commensal rats were tested for rHEV RNA and sequences were compared with human-derived strains. RESULTS: From 2017 to 2025, 22 human rHEV infections were identified. Of these, 14 (63·6%) were immunocompromised compared to 22/78 (28·2%) conventional HEV patients (p<0.01). Hepatitis was milder in rHEV patients, but most immunocompromised rHEV patients progressed to chronic infection. Rat-derived rHEV belonged to two subtypes, one of which infected humans. Of 8294 individuals, 57 (0·7%) tested positive for rHEV IgG compared to 551 (6·6%) for HEV IgG. Increasing age predicted rHEV seropositivity (OR:1·03; 95% CI:1·01-1·05); persons with bloodborne pathogens did not exhibit higher rHEV seroprevalence. CONCLUSIONS: rHEV is a sporadic cause of hepatitis in humans with disproportionate clinical significance for immunocompromised hosts. Although clearly linked to rat epizootics, routes of rHEV transmission remain enigmatic.
OBJECTIVES: A prospective multicenter study was conducted to elucidate the phenotypic and genotypic characteristics of carbapenem-resistant Enterobacteriaceae (CRE) colonization and infection strains. METHODS: Strains we...OBJECTIVES: A prospective multicenter study was conducted to elucidate the phenotypic and genotypic characteristics of carbapenem-resistant Enterobacteriaceae (CRE) colonization and infection strains. METHODS: Strains were collected within one year from ten intensive care units (ICUs) in Anhui Province, China. Antimicrobial susceptibility testing and whole-genome sequencing (WGS) were performed. RESULTS: Among 310 colonization and 108 infection strains, Klebsiella pneumoniae predominated (74.4%), followed by Escherichia coli (18.4%). Resistance rates were low to tigecycline (2.6%) and colistin (4.2%) and high (>97.9%) to carbapenems, cephalosporins, and β-lactam/β-lactamase inhibitor combinations. Both sequence types (STs) and capsular serotypes showed substantial geographic diversity. ST11 was the predominant ST, while ST15-KL19 (34.4%) was the most frequent combination in colonization and infection strains. Notably, the ST48-KL62 clone was significantly more prevalent in infection strains than in colonization strains. Moreover, 86.6% of strains produced carbapenemases, primarily bla (64.4%), and 1.9% co-produced KPC- and MBL-type enzymes. High-risk E. coli ST167 strains carrying bla were identified. All CRKp carried biosynthetic genes for the siderophore (e.g., fepABCDG, iutA, iroEN). Virulence factors, including iucABCD, irp1/2, ybtAEPQSTUX, and fyuA, were significantly more prevalent in CRKp infection strains. However, ST15-KL19 lacked classic high-virulence factors (e.g., iucABCD, rmpA, rmpA2). Closely related strains were found within and across hospitals, indicating regional spread and intra-hospital transmission. CONCLUSIONS: This study not only characterizes the distinct regional and genomic distribution patterns of CRE but also associates specific clones and virulence determinants with infection risk, thereby providing molecular markers to identify high-risk carriers and facilitate targeted treatment, prevention, and control measures.
OBJECTIVES: Streptococcus pneumoniae serotype 1 (S1) is a major cause of invasive pneumococcal disease. Despite its high attack rate, S1 exhibits a low carriage prevalence within the population, which raises questions ab...OBJECTIVES: Streptococcus pneumoniae serotype 1 (S1) is a major cause of invasive pneumococcal disease. Despite its high attack rate, S1 exhibits a low carriage prevalence within the population, which raises questions about the relationship between nasopharyngeal carriage and transmission of hypervirulent strains between individuals. We compared the transmission dynamics of S1 to serotypes 2 (S2) and 3 (S3) using a novel model of transmission in adolescent mice. METHODS: Donor "index" mice were intranasally infected with S1, S2, S3 or isogenic pneumolysin-deficient mutants and co-housed with naïve recipient "contact" mice. Three days later, all mice were infected with influenza A virus (IAV). Pneumococcal transmission was analysed during colonisation alone and co-infection with IAV by quantification of the nasal shedding and nasopharyngeal bacterial density in both index and contact mice. The role of the polysaccharide capsule and toxin pneumolysin, as well as biofilm production in shedding and transmission, and the host nasopharyngeal immune response, were investigated. RESULTS: We show that S1 was shed at significantly greater levels than S2 and S3 in index mice, which led to significantly higher shedding and transmission rates in contact mice. S1 produced less biofilm and a thick capsule that promoted its increased shedding and transmission. Interestingly, pneumococcal acquisition led to pneumolysin-dependant macrophage recruitment in the nasopharynx of contact mice. CONCLUSION: Our results show that rapid and high transmission rate of serotype 1 is a key factor for its success in disseminating quickly within the population and causing outbreaks.
Prediction of outcomes of SARS-CoV-2 infection remains challenging, particularly in the early days following exposure. To better understand the heterogeneity of disease progression, we investigated the early immune respo...Prediction of outcomes of SARS-CoV-2 infection remains challenging, particularly in the early days following exposure. To better understand the heterogeneity of disease progression, we investigated the early immune response in the upper respiratory tract using transcriptomic analysis, comparing individuals who remained asymptomatic to those who developed symptoms of COVID-19. We conducted a study of 74 individuals (43 children, 31 adults) with confirmed SARS-CoV-2 infection. Mid-turbinate nasal swabs were collected during the first few days of infection and again one week later. We performed a paired analysis comparing baseline and follow-up nasal human gene expression. Additionally, we conducted a predictive analysis to identify transcripts associated with the development of symptomatic infection. From the differentially expressed transcripts in both analyses, we developed a predictive model to assess the likelihood of symptomatic disease. We also compared gene expression patterns between children and adults. A robust interferon response in the upper respiratory tract was strongly associated with the development of symptomatic infection. A panel of five interferon-stimulated genes (TAP2, DDX60, IFIT5, APOL6, and IFI6) predicted symptomatic infection with reasonable accuracy (area under the curve = 0.84). Notably, adaptive immune responses, including T-cell activation and cytokine signaling, differed substantially between children and adults. Our findings suggest that early measurement of interferon-stimulated gene expression may help identify individuals at risk of developing symptomatic COVID-19.
Kelly E, Greenland M, de Whalley P
… +36 more, Macaulay GC, Aley PK, Plested E, Koleva S, Cotton J, Kinch J, Madupuri T, Read RC, Ramsay M, Cameron C, Turner DPJ, Heath P, Connor P, Cathie K, Faust SN, Banerjee I, Man K, Shackley F, O' Riordan S, Owens S, Polychronakis T, Trari Belhadef H, Mujadidi Y, Singha A, Cantrell L, Clutterbuck E, Anslow R, James T, Hallis B, Matheson M, Chang L, Lambe T, Nguyen-Van-Tam JS, Snape MD, Minassian AM, Liu X
BACKGROUND: The emergence of SARS-CoV2 variants combined with waning vaccine-induced immunity and breakthrough infections has highlighted the need for booster doses to maintain protection against SARS-CoV2 infection and...BACKGROUND: The emergence of SARS-CoV2 variants combined with waning vaccine-induced immunity and breakthrough infections has highlighted the need for booster doses to maintain protection against SARS-CoV2 infection and disease. METHODS: Com-COV3 was a phase II, multicentre, randomised controlled trial, recruiting across 11 UK sites from June 2022 to June 2023, with follow-up visits to February 2024. Healthy 12-15-year-olds who had received a two-30 μg dose BNT162b2 primary regimen at least 90 days previously were randomised 1:1:1:1:1 to receive either BNT162b2 30 μg, BNT162b2 10 μg (adult vaccine formulation), BNT162b2 10 μg (paediatric formulation), NVXCoV2373, or Meningococcal B vaccine (control). The primary objective was to determine if SARS-CoV-2 anti-spike antibody following a 10 μg dose of the adult formulation of BNT162b2 was non-inferior to the paediatric formulation at 28 days post-third vaccination. The last five participants were randomised using a 1:3:3:1:1 ratio to prioritise recruitment to the study groups required for the co-primary endpoint. Although recruitment ceased early, the sample size required to fulfil the primary objective was met. FINDINGS: 281 participants were recruited (mean age 14 years old, 57% female). Adverse reactions were mostly mild-to-moderate. Local reactogenicity was mildest following NVXCoV2373. Frequency of adverse events was similar for both full dose and fractional dose BNT162b2 groups. Four serious adverse events occurred: three in the paediatric and one in the adult 10 μg BNT162b2 group. Immunogenicity of 10 μg BNT162b2 (adult) was both non-inferior and superior to that of 10 μg BNT162b2 (paediatric); adjusted geometric mean ratio (aGMR) anti-spike IgG 1.50 (one-sided 95% CI 1.25 to ∞). Compared with 30 μg BNT162b2, anti-spike IgG at day 28 post-third dose were similar in the 10 μg BNT162b2 (adult) group [aGMR 0.93 (95% CI 0.75-1.14)] and significantly lower in the 10 μg BNT162b2 (paediatric) [aGMR 0.64 (95% CI 0.52-0.78)] and NVXCoV2373 [aGMR 0.77 (95% CI 0.63-0.95)] groups. Compared with 30 μg BNT162b2, levels of neutralising antibodies against Omicron BA.5 and XBB.15 were similar across vaccine groups. INTERPRETATION: All booster regimens evaluated elicited a robust immune response. 10 μg fractional adult BNT162b2 vaccine demonstrated similar immunogenicity compared with 30 μg BNT162b2 and superior immunogenicity compared with 10 μg paediatric BNT162b2 vaccine. Fractional doses of the adult BNT162b2 vaccine are an alternative to the paediatric formulation for booster campaigns in adolescents.
OBJECTIVES: The aim of this meta-analysis was to assess the diagnostic performance of metagenomic next-generation sequencing and targeted next-generation sequencing for periprosthetic joint infection (PJI). BACKGROUND: N...OBJECTIVES: The aim of this meta-analysis was to assess the diagnostic performance of metagenomic next-generation sequencing and targeted next-generation sequencing for periprosthetic joint infection (PJI). BACKGROUND: Next-generation sequencing (NGS) is increasingly used for diagnosing periprosthetic joint infection (PJI), but its clinical utility remains poorly defined. Discrepancies between metagenomic NGS (mNGS) and targeted NGS (tNGS) results pose a significant clinical challenge for PJI diagnosis. To address this, we conducted a systematic review and meta-analysis comparing the diagnostic accuracy of mNGS and tNGS for PJI. METHODS: This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We comprehensively searched PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus from inception through June 1, 2025. Two reviewers independently extracted data and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and the area under the hierarchical summary receiver operating characteristic curve (AUC) were calculated. RESULTS: Following screening and eligibility assessment, 23 studies were included in the analysis. The pooled sensitivity and specificity for diagnosing PJI were 0.89 (95% CI: 0.84-0.93) and 0.92 (95% CI: 0.89-0.95) for mNGS, and 0.84 (95% CI: 0.74-0.91) and 0.97 (95% CI: 0.88-0.99) for tNGS. The DORs were 58.56 (95% CI: 38.41-89.26) for mNGS and 106.67 (95% CI: 40.93-278.00) for tNGS. The areas under the summary receiver-operating characteristic curves (AUCs) were 0.935 (95% CI: 0.90-0.95) for mNGS and 0.911 (95% CI: 0.85-0.95) for tNGS. Comparisons of DOR and AUC between mNGS and tNGS revealed no statistically significant differences (P > 0.05). CONCLUSIONS: This meta-analysis indicates that mNGS demonstrates higher sensitivity and a numerically greater AUC than tNGS for diagnosing PJI, with acceptable specificity, although the difference in AUC was not statistically significant. Conversely, tNGS exhibits higher specificity and DOR, alongside acceptable sensitivity, making it valuable for confirming PJI. Overall, the diagnostic accuracy of both next-generation sequencing (NGS) methods is comparable, with each possessing distinct advantages and limitations.
OBJECTIVES: To compare the clinical utility of DNA- and RNA-metagenomic next-generation sequencing (mNGS) for pathogen detection in lower respiratory tract infections (LRTIs), and evaluate strategies to optimize RNA-mNGS...OBJECTIVES: To compare the clinical utility of DNA- and RNA-metagenomic next-generation sequencing (mNGS) for pathogen detection in lower respiratory tract infections (LRTIs), and evaluate strategies to optimize RNA-mNGS performance. METHODS: We retrospectively analyzed 82 patients with suspected LRTI undergoing simultaneous DNA-mNGS and RNA-mNGS testing. The concordance of two methods in detecting microorganisms was assessed. Performance in detecting causative pathogens was compared using multi-label classification metrics. Impacts of RNA-mNGS workflow adjustments were evaluated using mock samples. RESULTS: In a total of 196 microbial detections, DNA-mNGS and RNA-mNGS showed poor overall agreement (Cohen's κ=0.166, p<0.01). In identifying causative pathogens, RNA-mNGS demonstrated significantly higher precision (1.00 vs. 0.50, p<0.05) and F1 scores (0.80 vs. 0.67, p<0.05) compared to DNA-mNGS. DNA-mNGS possessed higher sensitivity for bacteria, fungi, and atypical pathogens, while RNA-mNGS excelled in detecting RNA viruses. Improved RNA-mNGS sensitivity and significant DNA-RNA read correlations were observed in causative pathogens at high abundance. Neither homogenization nor increased sequencing depth improved RNA-mNGS testing. CONCLUSIONS: DNA-mNGS and RNA-mNGS exhibited low overall consistency. However, RNA-mNGS showed superior precision in identifying causative pathogens in LRTI and additional capacity for RNA virus detections, while DNA-mNGS possessed essential sensitivity for low abundance pathogens.