Publications by authors named "Judith Breuer"

175 Publications

Predicted norovirus resurgence in 2021-2022 due to the relaxation of nonpharmaceutical interventions associated with COVID-19 restrictions in England: a mathematical modeling study.

BMC Med 2021 11 9;19(1):299. Epub 2021 Nov 9.

Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: To reduce the coronavirus disease burden in England, along with many other countries, the government implemented a package of non-pharmaceutical interventions (NPIs) that have also impacted other transmissible infectious diseases such as norovirus. It is unclear what future norovirus disease incidence is likely to look like upon lifting these restrictions.

Methods: Here we use a mathematical model of norovirus fitted to community incidence data in England to project forward expected incidence based on contact surveys that have been collected throughout 2020-2021.

Results: We report that susceptibility to norovirus infection has likely increased between March 2020 and mid-2021. Depending upon assumptions of future contact patterns incidence of norovirus that is similar to pre-pandemic levels or an increase beyond what has been previously reported is likely to occur once restrictions are lifted. Should adult contact patterns return to 80% of pre-pandemic levels, the incidence of norovirus will be similar to previous years. If contact patterns return to pre-pandemic levels, there is a potential for the expected annual incidence to be up to 2-fold larger than in a typical year. The age-specific incidence is similar across all ages.

Conclusions: Continued national surveillance for endemic diseases such as norovirus will be essential after NPIs are lifted to allow healthcare services to adequately prepare for a potential increase in cases and hospital pressures beyond what is typically experienced.
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http://dx.doi.org/10.1186/s12916-021-02153-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577179PMC
November 2021

Deep sequencing of HIV-1 reveals extensive subtype variation and drug resistance after failure of first-line antiretroviral regimens in Nigeria.

J Antimicrob Chemother 2021 Nov 6. Epub 2021 Nov 6.

Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK.

Background: Deep sequencing could improve understanding of HIV treatment failure and viral population dynamics. However, this tool is often inaccessible in low- and middle-income countries.

Objectives: To determine the genetic patterns of resistance emerging in West African HIV-1 subtypes during first-line virological failure, and the implications for future antiretroviral options.

Patients And Methods: Participants were selected from a Nigerian cohort of people living with HIV who had failed first-line ART and subsequently switched to second-line therapy. Whole HIV-1 genome sequences were generated from first-line virological failure samples with Illumina MiSeq. Mutations detected at ≥2% frequency were analysed and compared by subtype.

Results: HIV-1 sequences were obtained from 101 participants (65% female, median age 30 years, median 32.9 months of nevirapine- or efavirenz-based ART). Thymidine analogue mutations (TAMs) were detected in 61%, other core NRTI mutations in 92% and NNRTI mutations in 99%. Minority variants (<20% frequency) comprised 18% of all mutations. K65R was more prevalent in CRF02_AG than G subtypes (33% versus 7%; P = 0.002), and ≥3 TAMs were more common in G than CRF02_AG (52% versus 24%; P = 0.004). Subtype G viruses also contained more RT cleavage site mutations. Cross-resistance to at least one of the newer NNRTIs, doravirine, etravirine or rilpivirine, was predicted in 81% of participants.

Conclusions: Extensive drug resistance had accumulated in people with West African HIV-1 subtypes, prior to second-line ART. Deep sequencing significantly increased the detection of resistance-associated mutations. Caution should be used if considering newer-generation NNRTI agents in this setting.
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http://dx.doi.org/10.1093/jac/dkab385DOI Listing
November 2021

The Alpha variant was not associated with excess nosocomial SARS-CoV-2 infection in a multi-centre UK hospital study.

J Infect 2021 Oct 2. Epub 2021 Oct 2.

Department of Infectious Disease, Faculty of Medicine, Imperial College London, United Kingdom; Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom.

Objectives: Recently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals.

Methods: We collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences.

Results: Mixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages.

Conclusions: We find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern.
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http://dx.doi.org/10.1016/j.jinf.2021.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487101PMC
October 2021

The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model.

EBioMedicine 2021 Oct 24;72:103595. Epub 2021 Sep 24.

KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium; Global Virus Network, GVN, Baltimore, MD 21201, USA.

Background: Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.

Methods: We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.

Findings: When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination.

Interpretation: Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19.

Funding: stated in the acknowledgment.
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http://dx.doi.org/10.1016/j.ebiom.2021.103595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461366PMC
October 2021

SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men: multicentre cohort study.

BMJ Open Respir Res 2021 09;8(1)

Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK.

Background: SARS-CoV-2 lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented.

Methods: We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16 November 2020 to 10 January 2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity.

Findings: Sequences were obtained from 2341 inpatients (HOCI cases=786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The HR for mortality of B.1.1.7 compared with other lineages was 1.01 (95% CI 0.79 to 1.28, p=0.94) and for ITU admission was 1.01 (95% CI 0.75 to 1.37, p=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95 to 1.78, p=0.096) and ITU admission (HR 1.82, 95% CI 1.15 to 2.90, p=0.011) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61 to 1.10, p=0.177; ITU HR 0.74, 95% CI 0.52 to 1.04, p=0.086).

Interpretation: In common with smaller studies of patients hospitalised with SARS-CoV-2, we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared with other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.
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http://dx.doi.org/10.1136/bmjresp-2021-001029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453594PMC
September 2021

Epstein-Barr virus (EBV) deletions as biomarkers of response to treatment of chronic active EBV.

Br J Haematol 2021 Oct 24;195(2):249-255. Epub 2021 Aug 24.

Institute of Child Health, University College London, London, UK.

Chronic active Epstein-Barr virus (CAEBV) disease is a rare condition characterised by persistent EBV infection in previously healthy individuals. Defective EBV genomes were found in East Asian patients with CAEBV. In the present study, we sequenced 14 blood EBV samples from three UK patients with CAEBV, comparing the results with saliva CAEBV samples and other conditions. We observed EBV deletions in blood, some of which may disrupt viral replication, but not saliva in CAEBV. Deletions were lost overtime after successful treatment. These findings are compatible with CAEBV being associated with the evolution and persistence of EBV haematological clones that are lost on successful treatment.
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http://dx.doi.org/10.1111/bjh.17790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589012PMC
October 2021

Evolution of viral variants in remdesivir-treated and untreated SARS-CoV-2-infected pediatrics patients.

J Med Virol 2022 01 4;94(1):161-172. Epub 2021 Sep 4.

Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.

Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.
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http://dx.doi.org/10.1002/jmv.27285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426849PMC
January 2022

Post-vaccination COVID-19: A case-control study and genomic analysis of 119 breakthrough infections in partially vaccinated individuals.

Clin Infect Dis 2021 Aug 19. Epub 2021 Aug 19.

Department of Virology, Royal Free London NHS Foundation Trust, London, United Kingdom.

Background: Post-vaccination infections challenge the control of the COVID-19 pandemic.

Methods: We matched 119 cases of post-vaccination SARS-CoV-2 infection with BNT162b2 mRNA, or ChAdOx1 nCOV-19, to 476 unvaccinated patients with COVID-19 (Sept 2020-March 2021), according to age and sex. Differences in 60-day all-cause mortality, hospital admission, and hospital length of stay were evaluated. Phylogenetic, single nucleotide polymorphism (SNP) and minority variant allele (MVA) full genome sequencing analysis was performed.

Results: 116/119 cases developed COVID-19 post first vaccination dose (median 14 days, IQR 9 - 24 days). Overall, 13/119 (10∙9%) cases and 158/476 (33∙2%) controls died (p<0.001), corresponding to 4∙5 number needed to treat (NNT). Multivariably, vaccination was associated with 69∙3% (95%CI 45∙8 - 82∙6) relative risk (RR) reduction in mortality. Similar results were seen in subgroup analysis for patients with infection onset ≥14 days after first vaccination (RR reduction 65∙1%, 95%CI 27∙2 - 83∙2, NNT 4∙5), and across vaccine subgroups (BNT162b2: RR reduction 66%, 95%CI 34∙9 - 82∙2, NNT 4∙7, ChAdOx1: RR reduction 78∙4%, 95%CI 30∙4 - 93∙3, NNT 4∙1). Hospital admissions (OR 0∙80, 95%CI 0∙51 - 1∙28), and length of stay (-1∙89 days, 95%CI -4∙57 - 0∙78) were lower for cases, while Ct values were higher (30∙8 versus 28∙8, p = 0.053). B.1.1.7 was the predominant lineage in cases (100/108, 92.6%) and controls (341/446, 76.5%). Genomic analysis identified one post-vaccination case harboring the E484K vaccine escape mutation (B.1.525 lineage).

Conclusions: Previous vaccination reduces mortality when B.1.1.7 is the predominant lineage. No significant lineage-specific genomic changes during phylogenetic, SNP and MVA analysis were detected.
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http://dx.doi.org/10.1093/cid/ciab714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513403PMC
August 2021

Varicella-Zoster Virus-Genetics, Molecular Evolution and Recombination.

Curr Top Microbiol Immunol 2021 Aug 11. Epub 2021 Aug 11.

Department of Infection & Immunology, University College London, London, UK.

This chapter first details the structure, organization and coding content of the VZV genome to provide a foundation on which the molecular evolution of the virus can be projected. We subsequently describe the evolution of molecular profiling approaches from restriction fragment length polymorphisms to single nucleotide polymorphism profiling to modern day high-throughput sequencing approaches. We describe how the application of these methodologies led to our current model of VZV phylogeograpy including the number and structure of geographic clades and the role of recombination in reshaping these.
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http://dx.doi.org/10.1007/82_2021_238DOI Listing
August 2021

Predicted Norovirus Resurgence in 2021-2022 Due to the Relaxation of Nonpharmaceutical Interventions Associated with COVID-19 Restrictions in England: A Mathematical Modelling Study.

medRxiv 2021 Sep 3. Epub 2021 Sep 3.

Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: To reduce the coronavirus disease burden in England, along with many other countries, the Government implemented a package of non-pharmaceutical interventions (NPIs) that have also impacted other transmissible infectious diseases such as norovirus. It is unclear what future norovirus disease incidence is likely to look like upon lifting these restrictions.

Methods: Here we use a mathematical model of norovirus fitted to community incidence data in England to project forward expected incidence based on contact surveys that have been collected throughout 2020-2021.

Results: We report that susceptibility to norovirus infection has likely increased between March 2020 to mid-2021. Depending upon assumptions of future contact patterns incidence of norovirus that is similar to pre-pandemic levels or an increase beyond what has been previously reported is likely to occur once restrictions are lifted. Should adult contact patterns return to 80% of pre-pandemic levels the incidence of norovirus will be similar to previous years. If contact patterns return to pre-pandemic levels there is a potential for the expected annual incidence to be up to 2-fold larger than in a typical year. The age-specific incidence is similar across all ages.

Conclusions: Continued national surveillance for endemic diseases such as norovirus will be essential after NPIs are lifted to allow healthcare services to adequately prepare for a potential increase in cases and hospital pressures beyond what is typically experienced.
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http://dx.doi.org/10.1101/2021.07.09.21260277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288156PMC
September 2021

Using Whole Genome Sequences to Investigate Adenovirus Outbreaks in a Hematopoietic Stem Cell Transplant Unit.

Front Microbiol 2021 2;12:667790. Epub 2021 Jul 2.

Division of Infection and Immunity, University College London, London, United Kingdom.

A recent surge in human mastadenovirus (HAdV) cases, including five deaths, amongst a haematopoietic stem cell transplant population led us to use whole genome sequencing (WGS) to investigate. We compared sequences from 37 patients collected over a 20-month period with sequences from GenBank and our own database of HAdVs. Maximum likelihood trees and pairwise differences were used to evaluate genotypic relationships, paired with the epidemiological data from routine infection prevention and control (IPC) records and hospital activity data. During this time period, two formal outbreaks had been declared by IPC, while WGS detected nine monophyletic clusters, seven were corroborated by epidemiological evidence and by comparison of single-nucleotide polymorphisms. One of the formal outbreaks was confirmed, and the other was not. Of the five HAdV-associated deaths, three were unlinked and the remaining two considered the source of transmission. Mixed infection was frequent (10%), providing a sentinel source of recombination and superinfection. Immunosuppressed patients harboring a high rate of HAdV positivity require comprehensive surveillance. As a consequence of these findings, HAdV WGS is being incorporated routinely into clinical practice to influence IPC policy contemporaneously.
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http://dx.doi.org/10.3389/fmicb.2021.667790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284422PMC
July 2021

Benchmark of thirteen bioinformatic pipelines for metagenomic virus diagnostics using datasets from clinical samples.

J Clin Virol 2021 08 8;141:104908. Epub 2021 Jul 8.

Clinical Microbiological Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Introduction: Metagenomic sequencing is increasingly being used in clinical settings for difficult to diagnose cases. The performance of viral metagenomic protocols relies to a large extent on the bioinformatic analysis. In this study, the European Society for Clinical Virology (ESCV) Network on NGS (ENNGS) initiated a benchmark of metagenomic pipelines currently used in clinical virological laboratories.

Methods: Metagenomic datasets from 13 clinical samples from patients with encephalitis or viral respiratory infections characterized by PCR were selected. The datasets were analyzed with 13 different pipelines currently used in virological diagnostic laboratories of participating ENNGS members. The pipelines and classification tools were: Centrifuge, DAMIAN, DIAMOND, DNASTAR, FEVIR, Genome Detective, Jovian, MetaMIC, MetaMix, One Codex, RIEMS, VirMet, and Taxonomer. Performance, characteristics, clinical use, and user-friendliness of these pipelines were analyzed.

Results: Overall, viral pathogens with high loads were detected by all the evaluated metagenomic pipelines. In contrast, lower abundance pathogens and mixed infections were only detected by 3/13 pipelines, namely DNASTAR, FEVIR, and MetaMix. Overall sensitivity ranged from 80% (10/13) to 100% (13/13 datasets). Overall positive predictive value ranged from 71-100%. The majority of the pipelines classified sequences based on nucleotide similarity (8/13), only a minority used amino acid similarity, and 6 of the 13 pipelines assembled sequences de novo. No clear differences in performance were detected that correlated with these classification approaches. Read counts of target viruses varied between the pipelines over a range of 2-3 log, indicating differences in limit of detection.

Conclusion: A wide variety of viral metagenomic pipelines is currently used in the participating clinical diagnostic laboratories. Detection of low abundant viral pathogens and mixed infections remains a challenge, implicating the need for standardization and validation of metagenomic analysis for clinical diagnostic use. Future studies should address the selective effects due to the choice of different reference viral databases.
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http://dx.doi.org/10.1016/j.jcv.2021.104908DOI Listing
August 2021

Long-Term Persistence of Spike Antibody and Predictive Modeling of Antibody Dynamics Following Infection with SARS-CoV-2.

Clin Infect Dis 2021 Jul 4. Epub 2021 Jul 4.

Department of Infection, Inflammation and Immunity, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, UK.

Background: Antibodies to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) have been shown to neutralize the virus in-vitro and prevent disease in animal challenge models upon re-exposure. However, current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting.

Methods: The Co-Stars study prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike (S), receptor-binding-domain (RBD) and nucleoprotein (N) antibodies in parallel. Participants screening seropositive had serial monthly serological testing for a maximum of 7 months with the Mesoscale Discovery Assay. Survival analysis determined the proportion of sero-reversion while two hierarchical Gamma models predicted the upper- and lower-bounds of long-term antibody trajectory.

Results: A total of 1163 monthly samples were provided from 349 seropositive participants. At 200 days post-symptoms, >95% of participants had detectable S-antibodies compared to 75% with detectable N-antibodies. S-antibody was predicted to remain detectable in 95% of participants until 465 days [95%CI 370-575] using a 'continuous-decay' model and indefinitely using a 'decay-to-plateau' model to account for antibody secretion by long-lived plasma cells. S-antibody titers correlated strongly with surrogate neutralization in-vitro (R 2=0.72). N-antibodies, however, decayed rapidly with a half-life of 60 days [95%CI 52-68].

Conclusions: The Co-STAR's study data presented here provides evidence for long-term persistence of neutralizing S-antibodies. This has important implications for the duration of functional immunity following SARS-CoV-2 infection. In contrast, the rapid decay of N-antibodies must be considered in future seroprevalence studies and public health decision-making. This is the first study to establish a mathematical framework capable of predicting long-term humoral dynamics following SARS-CoV-2 infection.
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http://dx.doi.org/10.1093/cid/ciab607DOI Listing
July 2021

Rapid feedback on hospital onset SARS-CoV-2 infections combining epidemiological and sequencing data.

Elife 2021 06 29;10. Epub 2021 Jun 29.

Division of Infection and Immunity, University College London, London, United Kingdom.

Background: Rapid identification and investigation of healthcare-associated infections (HCAIs) is important for suppression of SARS-CoV-2, but the infection source for hospital onset COVID-19 infections (HOCIs) cannot always be readily identified based only on epidemiological data. Viral sequencing data provides additional information regarding potential transmission clusters, but the low mutation rate of SARS-CoV-2 can make interpretation using standard phylogenetic methods difficult.

Methods: We developed a novel statistical method and sequence reporting tool (SRT) that combines epidemiological and sequence data in order to provide a rapid assessment of the probability of HCAI among HOCI cases (defined as first positive test >48 hr following admission) and to identify infections that could plausibly constitute outbreak events. The method is designed for prospective use, but was validated using retrospective datasets from hospitals in Glasgow and Sheffield collected February-May 2020.

Results: We analysed data from 326 HOCIs. Among HOCIs with time from admission ≥8 days, the SRT algorithm identified close sequence matches from the same ward for 160/244 (65.6%) and in the remainder 68/84 (81.0%) had at least one similar sequence elsewhere in the hospital, resulting in high estimated probabilities of within-ward and within-hospital transmission. For HOCIs with time from admission 3-7 days, the SRT probability of healthcare acquisition was >0.5 in 33/82 (40.2%).

Conclusions: The methodology developed can provide rapid feedback on HOCIs that could be useful for infection prevention and control teams, and warrants further prospective evaluation. The integration of epidemiological and sequence data is important given the low mutation rate of SARS-CoV-2 and its variable incubation period.

Funding: COG-UK HOCI funded by COG-UK consortium, supported by funding from UK Research and Innovation, National Institute of Health Research and Wellcome Sanger Institute.
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http://dx.doi.org/10.7554/eLife.65828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285103PMC
June 2021

Genetic epidemiology of SARS-CoV-2 transmission in renal dialysis units - A high risk community-hospital interface.

J Infect 2021 07 22;83(1):96-103. Epub 2021 Apr 22.

Renal Unit, University Hospital Monklands, Monkscourt Ave, Airdrie ML6 0JS, Canada; Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.

Objectives: Patients requiring haemodialysis are at increased risk of serious illness with SARS-CoV-2 infection. To improve the understanding of transmission risks in six Scottish renal dialysis units, we utilised the rapid whole-genome sequencing data generated by the COG-UK consortium.

Methods: We combined geographical, temporal and genomic sequence data from the community and hospital to estimate the probability of infection originating from within the dialysis unit, the hospital or the community using Bayesian statistical modelling and compared these results to the details of epidemiological investigations.

Results: Of 671 patients, 60 (8.9%) became infected with SARS-CoV-2, of whom 16 (27%) died. Within-unit and community transmission were both evident and an instance of transmission from the wider hospital setting was also demonstrated.

Conclusions: Near-real-time SARS-CoV-2 sequencing data can facilitate tailored infection prevention and control measures, which can be targeted at reducing risk in these settings.
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http://dx.doi.org/10.1016/j.jinf.2021.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061788PMC
July 2021

The influence of human genetic variation on Epstein-Barr virus sequence diversity.

Sci Rep 2021 02 25;11(1):4586. Epub 2021 Feb 25.

School of Life Sciences, EPFL, Lausanne, Switzerland.

Epstein-Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4 + T cell count < 200/mm and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.
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http://dx.doi.org/10.1038/s41598-021-84070-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907281PMC
February 2021

GRACy: A tool for analysing human cytomegalovirus sequence data.

Virus Evol 2021 Jan 30;7(1):veaa099. Epub 2020 Dec 30.

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.

Modern DNA sequencing has instituted a new era in human cytomegalovirus (HCMV) genomics. A key development has been the ability to determine the genome sequences of HCMV strains directly from clinical material. This involves the application of complex and often non-standardized bioinformatics approaches to analysing data of variable quality in a process that requires substantial manual intervention. To relieve this bottleneck, we have developed GRACy (Genome Reconstruction and Annotation of Cytomegalovirus), an easy-to-use toolkit for analysing HCMV sequence data. GRACy automates and integrates modules for read filtering, genotyping, genome assembly, genome annotation, variant analysis, and data submission. These modules were tested extensively on simulated and experimental data and outperformed generic approaches. GRACy is written in Python and is embedded in a graphical user interface with all required dependencies installed by a single command. It runs on the Linux operating system and is designed to allow the future implementation of a cross-platform version. GRACy is distributed under a GPL 3.0 license and is freely available at https://bioinformatics.cvr.ac.uk/software/ with the manual and a test dataset.
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http://dx.doi.org/10.1093/ve/veaa099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816668PMC
January 2021

NIX-mediated mitophagy regulate metabolic reprogramming in phagocytic cells during mycobacterial infection.

Tuberculosis (Edinb) 2021 01 30;126:102046. Epub 2020 Dec 30.

Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India; Laboratory of Host Defense, WPI Immunology Frontier Research Centre, Osaka University, Osaka, Japan. Electronic address:

RNASeq analysis of PBMCs from treatment naïve TB patients and healthy controls revealed that M. tuberculosis (Mtb) infection dysregulates several metabolic pathways and upregulates BNIP3L/NIX receptor mediated mitophagy. Analysis of publicly available transcriptomic data from the NCBI-GEO database indicated that M. bovis (BCG) infection also induces similar rewiring of metabolic and mitophagy pathways. Mtb chronic infection and BCG in-vitro infection both downregulated oxidative phosphorylation and upregulated glycolysis and mitophagy; therefore, we used non-pathogenic mycobacterial species BCG as a model for Mtb infection to gain molecular insights and outcomes of this phenomenon. BCG infection in PBMCs and THP-1 macrophages induce mitophagy and glycolysis, leading to differentiation of naïve macrophage to M1 phenotype. Glucose consumption and lactate production were quantified by NMR, while the mitochondrial mass assessment was performed by mitotracker red uptake assay. Infected macrophages predominantly exhibit M1-phenotype, which is indicated by an increase in M1 specific cytokines (IL-6, TNF-α, and IL-1β) and increased NOS2/ARG1, CD86/CD206 ratio. NIX knockdown abrogates this upregulation of glycolysis, mitophagy, and secretion of pro-inflammatory cytokines in BCG infected cells, indicating that mycobacterial infection-induced immunometabolic changes are executed via NIX mediated mitophagy and are essential for macrophage differentiation and resolution of infection.
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http://dx.doi.org/10.1016/j.tube.2020.102046DOI Listing
January 2021

Mixed cytomegalovirus genotypes in HIV-positive mothers show compartmentalization and distinct patterns of transmission to infants.

Elife 2020 12 31;9. Epub 2020 Dec 31.

Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Cytomegalovirus (CMV) is the commonest cause of congenital infection and particularly so among infants born to HIV-infected women. Studies of congenital CMV infection (cCMVi) pathogenesis are complicated by the presence of multiple infecting maternal CMV strains, especially in HIV-positive women, and the large, recombinant CMV genome. Using newly developed tools to reconstruct CMV haplotypes, we demonstrate anatomic CMV compartmentalization in five HIV-infected mothers and identify the possibility of congenitally transmitted genotypes in three of their infants. A single CMV strain was transmitted in each congenitally infected case, and all were closely related to those that predominate in the cognate maternal cervix. Compared to non-transmitted strains, these congenitally transmitted CMV strains showed statistically significant similarities in 19 genes associated with tissue tropism and immunomodulation. In all infants, incident superinfections with distinct strains from breast milk were captured during follow-up. The results represent potentially important new insights into the virologic determinants of early CMV infection.
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http://dx.doi.org/10.7554/eLife.63199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806273PMC
December 2020

Preadaptation of pandemic GII.4 noroviruses in unsampled virus reservoirs years before emergence.

Virus Evol 2020 Jul 21;6(2):veaa067. Epub 2020 Nov 21.

Division of Infection and Immunity, University College London, London WC1E 6BT, UK.

The control of re-occurring pandemic pathogens requires understanding the origins of new pandemic variants and the factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have hypothesized that new GII.4 pandemic viruses arise when previously circulating pandemic or pre-pandemic variants undergo substitutions in antigenic regions that enable evasion of host population immunity, as described by conventional models of antigenic drift. In contrast, we show here that the acquisition of new genetic and antigenic characteristics cannot be the proximal driver of new pandemics. Pandemic GII.4 viruses diversify and spread over wide geographical areas over several years prior to simultaneous pandemic emergence of multiple lineages, indicating that the necessary sequence changes must have occurred before diversification, years prior to pandemic emergence. We confirm this result through serological assays of reconstructed ancestral virus capsids, demonstrating that by 2003, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.
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http://dx.doi.org/10.1093/ve/veaa067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751145PMC
July 2020

Detection of Norovirus Variant GII.4 Hong Kong in Asia and Europe, 2017-2019.

Emerg Infect Dis 2021 01;27(1):289-293

We report a new norovirus GII.4 variant, GII.4 Hong Kong, with low-level circulation in 4 Eurasia countries since mid-2017. Amino acid substitutions in key residues on the virus capsid associated with the emergence of pandemic noroviruses suggest that GII.4 Hong Kong has the potential to become the next pandemic variant.
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http://dx.doi.org/10.3201/eid2701.203351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774557PMC
January 2021

Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency.

Nat Commun 2020 12 10;11(1):6324. Epub 2020 Dec 10.

Division of Clinical Virology, Center for Infectious Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Varicella-zoster virus (VZV) establishes lifelong neuronal latency in most humans world-wide, reactivating in one-third to cause herpes zoster and occasionally chronic pain. How VZV establishes, maintains and reactivates from latency is largely unknown. VZV transcription during latency is restricted to the latency-associated transcript (VLT) and RNA 63 (encoding ORF63) in naturally VZV-infected human trigeminal ganglia (TG). While significantly more abundant, VLT levels positively correlated with RNA 63 suggesting co-regulated transcription during latency. Here, we identify VLT-ORF63 fusion transcripts and confirm VLT-ORF63, but not RNA 63, expression in human TG neurons. During in vitro latency, VLT is transcribed, whereas VLT-ORF63 expression is induced by reactivation stimuli. One isoform of VLT-ORF63, encoding a fusion protein combining VLT and ORF63 proteins, induces broad viral gene transcription. Collectively, our findings show that VZV expresses a unique set of VLT-ORF63 transcripts, potentially involved in the transition from latency to lytic VZV infection.
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http://dx.doi.org/10.1038/s41467-020-20031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730162PMC
December 2020

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity.

Proc Natl Acad Sci U S A 2020 10 9;117(43):26955-26965. Epub 2020 Oct 9.

Drug Delivery & Disposition, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.
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http://dx.doi.org/10.1073/pnas.2014441117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604414PMC
October 2020

Genomics of Ocular Chlamydia trachomatis after 5 years of SAFE interventions for trachoma in Amhara, Ethiopia.

J Infect Dis 2020 Oct 9. Epub 2020 Oct 9.

The Carter Center, Atlanta, USA.

To eliminate trachoma as a public health problem, the WHO recommends the SAFE (Surgery, Antibiotics, Facial cleanliness, and Environmental improvement) strategy. As part of the SAFE strategy in the Amhara Region, Ethiopia, the Trachoma Control Program distributed over 124 million doses of antibiotic between 2007 and 2015. Despite this, trachoma remained hyperendemic in many districts and a considerable level of Chlamydia trachomatis (Ct) infection was evident. We utilised residual material from Abbott m2000 Ct diagnostic tests to sequence 99 ocular Ct samples from Amhara and investigated the role of Ct genomic variation in continued transmission of Ct. Sequences were typical of ocular Ct, at the whole-genome level and in tissue tropism-associated genes. There was no evidence of macrolide-resistance in this population. Polymorphism around ompA gene was associated with village-level trachomatous inflammation-follicular prevalence. Greater ompA diversity at the district-level was associated with increased Ct infection prevalence. We found no evidence for Ct genomic variation contributing to continued transmission of Ct after treatment, adding to evidence that azithromycin does not drive acquisition of macrolide resistance in Ct. Increased Ct infection in areas with more ompA variants requires longitudinal investigation to understand what impact this may have on treatment success and host immunity.
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http://dx.doi.org/10.1093/infdis/jiaa615DOI Listing
October 2020

Decoding the Architecture of the Varicella-Zoster Virus Transcriptome.

mBio 2020 10 6;11(5). Epub 2020 Oct 6.

Department of Medicine, New York University School of Medicine, New York, New York, USA

Varicella-zoster virus (VZV), a double-stranded DNA virus, causes varicella, establishes lifelong latency in ganglionic neurons, and reactivates later in life to cause herpes zoster, commonly associated with chronic pain. The VZV genome is densely packed and produces multitudes of overlapping transcripts deriving from both strands. While 71 distinct open reading frames (ORFs) have thus far been experimentally defined, the full coding potential of VZV remains unknown. Here, we integrated multiple short-read RNA sequencing approaches with long-read direct RNA sequencing on RNA isolated from VZV-infected cells to provide a comprehensive reannotation of the lytic VZV transcriptome architecture. Through precise mapping of transcription start sites, splice junctions, and polyadenylation sites, we identified 136 distinct polyadenylated VZV RNAs that encode canonical ORFs, noncanonical ORFs, and ORF fusions, as well as putative noncoding RNAs (ncRNAs). Furthermore, we determined the kinetic class of all VZV transcripts and observed, unexpectedly, that transcripts encoding the ORF62 protein, previously designated , were expressed with kinetics. Our work showcases the complexity of the VZV transcriptome and provides a comprehensive resource that will facilitate future functional studies of coding RNAs, ncRNAs, and the biological mechanisms underlying the regulation of viral transcription and translation during lytic VZV infection. Transcription from herpesviral genomes, executed by the host RNA polymerase II and regulated by viral proteins, results in coordinated viral gene expression to efficiently produce infectious progeny. However, the complete coding potential and regulation of viral gene expression remain ill-defined for the human alphaherpesvirus varicella-zoster virus (VZV), causative agent of both varicella and herpes zoster. Here, we present a comprehensive overview of the VZV transcriptome and the kinetic class of all identified viral transcripts, using two virus strains and two biologically relevant cell types. Additionally, our data provide an overview of how VZV diversifies its transcription from one of the smallest herpesviral genomes. Unexpectedly, the transcript encoding the major viral transactivator protein (pORF62) was expressed with kinetics, whereas orthologous transcripts in other alphaherpesviruses are typically expressed during the immediate early phase. Therefore, our work both establishes the architecture of the VZV transcriptome and provides insight into regulation of alphaherpesvirus gene expression.
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http://dx.doi.org/10.1128/mBio.01568-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542360PMC
October 2020

SARS-CoV-2 Polymorphisms and Multisystem Inflammatory Syndrome in Children.

Pediatrics 2020 12 9;146(6). Epub 2020 Sep 9.

Department of Infection, Immunity and Inflammation, University College London Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; and

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http://dx.doi.org/10.1542/peds.2020-019844DOI Listing
December 2020

A large effective population size for established within-host influenza virus infection.

Elife 2020 08 10;9. Epub 2020 Aug 10.

Department of Genetics, University of Cambridge, Cambridge, United Kingdom.

Strains of the influenza virus form coherent global populations, yet exist at the level of single infections in individual hosts. The relationship between these scales is a critical topic for understanding viral evolution. Here we investigate the within-host relationship between selection and the stochastic effects of genetic drift, estimating an effective population size of infection N for influenza infection. Examining whole-genome sequence data describing a chronic case of influenza B in a severely immunocompromised child we infer an N of 2.5 × 10 (95% confidence range 1.0 × 10 to 9.0 × 10) suggesting that genetic drift is of minimal importance during an established influenza infection. Our result, supported by data from influenza A infection, suggests that positive selection during within-host infection is primarily limited by the typically short period of infection. Atypically long infections may have a disproportionate influence upon global patterns of viral evolution.
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http://dx.doi.org/10.7554/eLife.56915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431133PMC
August 2020
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