ORCID Profile
0000-0003-2399-9657
Current Organisations
Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery & Nuffield Department of Medicine, University of Oxford
,
Universiti Putra Malaysia
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Publisher: Elsevier BV
Date: 11-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-02-2022
Abstract: We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine in iduals with this variant had a 0.54 to 0.74 log
Publisher: Oxford University Press (OUP)
Date: 27-02-2020
DOI: 10.1093/JAC/DKAA033
Abstract: HIV-1 integrase inhibitors are recommended as first-line therapy by WHO, though efficacy and resistance data for non-B subtypes are limited. Two recent trials have identified the integrase L74I mutation to be associated with integrase inhibitor treatment failure in HIV-1 non-B subtypes. We sought to define the prevalence of integrase resistance mutations, including L74I, in West Africa. We studied a Nigerian cohort of recipients prior to and during receipt of second-line PI-based therapy, who were integrase inhibitor-naive. Illumina next-generation sequencing with target enrichment was used on stored plasma s les. Drug resistance was interpreted using the Stanford Resistance Database and the IAS-USA 2019 mutation lists. Of 115 in iduals, 59.1% harboured CRF02_AG HIV-1 and 40.9% harboured subtype G HIV-1. Four participants had major IAS-USA integrase resistance-associated mutations detected at low levels (2%–5% frequency). Two had Q148K minority variants and two had R263K (one of whom also had L74I). L74I was detected in plasma s les at over 2% frequency in 40% (46/115). Twelve (26.1%) had low-level minority variants of between 2% and 20% of the viral population s led. The remaining 34 (73.9%) had L74I present at & % frequency. L74I was more common among those with subtype G infection (55.3%, 26/47) than those with CRF02_AG infection (29.4%, 20/68) (P = 0.005). HIV-1 subtypes circulating in West Africa appear to have very low prevalence of major integrase mutations, but significant prevalence of L74I. A combination of in vitro and clinical studies is warranted to understand the potential implications.
Publisher: Oxford University Press (OUP)
Date: 08-08-2020
DOI: 10.1093/JAC/DKAA352
Abstract: To evaluate the performance of a high-throughput research assay for HIV drug resistance testing based on whole genome next-generation sequencing (NGS) that also quantifies HIV viral load. Plasma s les (n = 145) were obtained from HIV-positive MSM (HPTN 078). S les were analysed using clinical assays (the ViroSeq HIV-1 Genotyping System and the Abbott RealTime HIV-1 Viral Load assay) and a research assay based on whole-genome NGS (veSEQ-HIV). HIV protease and reverse transcriptase sequences (n = 142) and integrase sequences (n = 138) were obtained using ViroSeq. Sequences from all three regions were obtained for 100 (70.4%) of the 142 s les using veSEQ-HIV results were obtained more frequently for s les with higher viral loads (93.5% for 93 s les with & copies/mL 50.0% for 26 s les with 1000–5000 copies/mL 0% for 23 s les with & copies/mL). For s les with results from both methods, drug resistance mutations (DRMs) were detected in 33 s les using ViroSeq and 42 s les using veSEQ-HIV (detection threshold: 5.0%). Overall, 146 major DRMs were detected 107 were detected by both methods, 37 were detected by veSEQ-HIV only (frequency range: 5.0%–30.6%) and two were detected by ViroSeq only. HIV viral loads estimated by veSEQ-HIV strongly correlated with results from the Abbott RealTime Viral Load assay (R2 = 0.85 n = 142). The NGS-based veSEQ-HIV method provided results for most s les with higher viral loads, was accurate for detecting major DRMs, and detected mutations at lower levels compared with a method based on population sequencing. The veSEQ-HIV method also provided HIV viral load data.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2022
DOI: 10.1101/2022.05.15.22275117
Abstract: Estimating the time since HIV infection (TSI) at population level is essential for tracking changes in the global HIV epidemic. Most methods for determining duration of infection classify s les into recent and non-recent and are unable to give more granular TSI estimates. These binary classifications have a limited recency time window of several months, therefore requiring large s le sizes, and cannot assess the cumulative impact of an intervention. We developed a Random Forest Regression model, HIV-phyloTSI, that combines measures of within-host ersity and ergence to generate TSI estimates from viral deep-sequencing data, with no need for additional variables. HIV-phyloTSI provides a continuous measure of TSI up to 9 years, with a mean absolute error of less than 12 months overall and less than 5 months for infections with a TSI of up to a year. It performed equally well for all major HIV subtypes based on data from African and European cohorts. We demonstrate how HIV-phyloTSI can be used for incidence estimates on a population level.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2021
DOI: 10.1038/S41586-021-03412-7
Abstract: Transmission of SARS-CoV-2 is uncontrolled in many parts of the world control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant
Publisher: Public Library of Science (PLoS)
Date: 06-2010
Publisher: Mary Ann Liebert Inc
Date: 11-2017
Publisher: Cold Spring Harbor Laboratory
Date: 07-10-2020
DOI: 10.1101/2020.10.06.328328
Abstract: Genomic epidemiology has become an increasingly common tool for epidemic response. Recent technological advances have made it possible to sequence genomes rapidly enough to inform outbreak response, and cheaply enough to justify dense s ling of even large epidemics. With increased availability of sequencing it is possible for agile networks of sequencing facilities to collaborate on the sequencing and analysis of epidemic genomic data. In response to the ongoing SARS-CoV-2 pandemic in the United Kingdom, the COVID-19 Genomics UK (COG-UK) consortium was formed with the aim of rapidly sequencing SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of Majora, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and s le-associated metadata produced across the COG-UK network. The system was designed and implemented pragmatically to stand up capacity rapidly in a pandemic caused by a novel virus. This approach has underpinned the success of COG-UK, which has rapidly become the leading contributor of SARS-CoV-2 genomes to international databases and has generated over 60,000 sequences to date.
Publisher: Oxford University Press (OUP)
Date: 23-11-2017
Publisher: eLife Sciences Publications, Ltd
Date: 03-2022
DOI: 10.7554/ELIFE.72657
Abstract: Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials, we quantified the contribution of geographic-location, gender, age, and randomized-HIV-intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana. We sequenced HIV viral whole genomes from 5114 trial participants among the 30 trial communities. Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 – 56.7] vs. 3% [0.1 – 27.3]) than at baseline (7% [1.5 – 25.3] vs. 5% [0.9 – 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies. This study was supported by the National Institute of General Medical Sciences (U54GM088558), the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610), and the President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911).
Publisher: Springer Science and Business Media LLC
Date: 06-10-2021
DOI: 10.1038/S41467-021-25982-W
Abstract: Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases ( N = 18) were available for analysis. VE was 64% (−2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.
Publisher: Research Square Platform LLC
Date: 17-03-2023
DOI: 10.21203/RS.3.RS-2696883/V1
Abstract: HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years, but as new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance and longitudinal deep- sequence viral phylogenetics to assess how HIV incidence and the population groups driving transmission have evolved over a 15-year period from 2003 to 2018 in Uganda. HIV viral suppression increased more rapidly in women than men, resulting in 1.5-2 fold higher suppression rates in women with HIV by 2018 across age groups. Incidence declined more slowly in women than men, increasing pre-existing gender imbalance in HIV burden. Age-specific transmission flows shifted the share of transmission to girls and women aged 15-24 years from older men declined by approximately one third, whereas the contribution of transmission to women aged 25-34 years from men aged 0-6 years older doubled from 2003 to 2018. We estimated closing the gender gap in viral sup- pression could have reduced HIV incidence in women by half in 2018 and ended gender disparities in incidence. This study suggests that male-targeted HIV pro- grams to increase HIV suppression are critical to reduce incidence in women, close gender gaps in infection burden and improve men’s health in Africa.
Publisher: Cold Spring Harbor Laboratory
Date: 07-10-2021
DOI: 10.1101/2021.10.04.21263560
Abstract: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, and appears to have contributed to reduced rates of new infections. In iduals acting as sources of infection need to be characterised to design effective prevention strategies. We used viral genomes to investigate the demographic characteristics of sources of HIV-1 infection. Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral s les from 7,124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We identified 300 likely HIV-1 transmission pairs and investigated the source in iduals in those pairs to better understand transmission in the general population. After demographic weighting, 59.4% of transmissions were male to female, with 43·2% (95% CI: 36·8%-49·7%) of transmissions being from males aged 25-40. Overall, men transmitted 2.09-fold (2·06-2·29) more infections per capita than women, a ratio peaking, when stratified by source age, at 5.88 (2·78-15·8) in the 35-39 age group. 17·4% of sources (12·5%-22·4%) carried viruses resistant to first-line ART. 12·9% (8·5%-17·3%) of transmissions linked in iduals from different communities in the trial. HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and that there is no outsized contribution of importation or drug resistance mutations to new infections. Men aged 25-40, under-served by current treatment and prevention service, should be prioritised for HIV testing and ART. National Institute of Allergy and Infectious Diseases, US President’s Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health We searched PubMed, with no date or language filters, to identify previous quantitative studies investigating the role of age, sex, mobility and drug resistance mutations (separately or in combination) as drivers of new HIV transmissions in heterosexual transmission in sub-Saharan Africa. Observational studies were considered along with those using phylogenetic or mathematical modelling methodologies. In observational studies, having an older partner or a migrant partner is frequently identified as a risk factor for HIV acquisition, particularly in women, but this is a slightly separate question to the quantification of the overall frequency of these demographics amongst the sources of new infections. The most recent studies of drug resistance have shown an increasing prevalence, particularly in NNRTI resistance. The ability to use phylogenetics to investigate HIV transmission is reasonably recent, and the ability to use it to reconstruct who infected whom in transmission pairs is more recent still. One previous, influential study in South Africa posited a key role of men in their 30s in infecting very young women, and being themselves infected by women in their 30s, but that work did not use a methodology that was able to conclusively reconstruct direction of transmission. A more recent study in Botswana found similar age distributions for male and female sources of transmission, with the average in idual being in their late 30s or early 40s. However, these ages were recorded at the time of study enrolment and do not take into account the time from infection to s ling. The paper also showed that, in that setting, the majority of transmissions were between members of the same community. A number of other phylogenetic studies have been concerned with the very specific dynamics of HIV-1 in the fishing communities of Lake Victoria. No previous phylogenetics work to our knowledge has considered the distribution of drug resistance mutations in sources, and none considered the interaction between source characteristics. We were unable to find any previous mathematical modelling studies for which the characterisation of sources according to these variables was a major focus. Our methodology uses a phylogenetic approach to identify likely transmission pairs and the direction of transmission between their members. We find a total of 300 pairs, larger than any previous study. We demonstrate a novel and simple new approach to accounting for potential s ling bias. We also employ a methodology that allows us to estimate the ages of the in iduals involved at the time of transmission, rather than that of s ling, countering a key bias in previous approaches. Partly for this reason, our age profiles for sources peak at earlier ages than in previous work, with an average in the early 30s for male sources and mid-20s for females. We fail to confirm the existence of a “renewal cycle” of transmission involving a major contribution from women in older age groups. We also examine the contribution of outside-community transmission and drug resistant mutations, and, for the first time, show that these three characteristics (age/sex, migration, and drug resistance) operate on separate axes and do not cluster together. We use our results to calculate the relative contribution of male to female sources to transmission in age bands, finding that this grows to a peak in the 35-39 age group in which men are responsible for almost six times as many new infections per capita as women. The heterosexual HIV epidemic in sub-Saharan Africa appears to be maintained by transmissions from young women and slightly, but not dramatically, older men. The contributions of sources transmitting drug-resistant virus, or sources who reside outside a focal community, is not particularly large, and there is no disproportionate contribution from in iduals who share any combination of a high-risk age group, a residence outside the community, and drug-resistant virus. In generalised HIV epidemics, it is tempting to attempt to identify particular demographic groups, of relatively small sizes, for whom intensive targeting of prevention measures will have a major effect on transmission in the general population. The current state of the evidence suggests that this may not be possible, as the demographic profile of sources of transmission is not dissimilar to that of the general population. While it may be more difficult and resource-intensive to design universal interventions for the whole population, there may be no shortcuts.
Publisher: Elsevier BV
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 05-02-2021
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.TALANTA.2022.123659
Abstract: Quartz crystal microbalance (QCM)-based biosensors are highly attractive as rapid diagnostic devices for detecting infectious diseases. However, the fabrication of QCM-based biosensors often involves tedious processes due to the poor stability of the biological recognition elements. In this work, the simple self-polymerisation of dopamine was used to functionalise the QCM crystal surface with a molecularly imprinted polydopamine (MIPDA) sensing film for detecting the hepatitis B core antigen (HBcAg), a serological biomarker of hepatitis B. Recognition cavities that complemented the size and shape of HBcAg were observed on the QCM crystal surface after functionalisation with the MIPDA film. The MIPDA-QCM biosensor showed a selective affinity for HBcAg, recording frequency responses up to 7.8 folds larger towards HBcAg compared to human serum albumin at the same analyte concentrations. The biosensor response was enhanced by using the optimal concentrations of 10 mg mL
Publisher: Cold Spring Harbor Laboratory
Date: 07-09-2020
DOI: 10.1101/2020.09.04.20188516
Abstract: The timing of SARS-CoV-2 transmission is a critical factor to understand the epidemic trajectory and the impact of isolation, contact tracing and other non-pharmaceutical interventions on the spread of COVID-19 epidemics. We examined the distribution of transmission events with respect to exposure and onset of symptoms. We show that for symptomatic in iduals, the timing of transmission of SARS-CoV-2 is more strongly linked to the onset of clinical symptoms of COVID-19 than to the time since infection. We found that it was approximately centered and symmetric around the onset of symptoms, with three quarters of events occurring in the window from 2-3 days before to 2-3 days after. However, we caution against overinterpretation of the right tail of the distribution, due to its dependence on behavioural factors and interventions. We also found that the pre-symptomatic infectious period extended further back in time for in iduals with longer incubation periods. This strongly suggests that information about when a case was infected should be collected where possible, in order to assess how far into the past their contacts should be traced. Overall, the fraction of transmission from strictly pre-symptomatic infections was high (41% 95%CI 31-50%), which limits the efficacy of symptom-based interventions, and the large fraction of transmissions (35% 95%CI 26-45%) that occur on the same day or the day after onset of symptoms underlines the critical importance of in iduals distancing themselves from others as soon as they notice any symptoms, even if they are mild. Rapid or at-home testing and contextual risk information would greatly facilitate efficient early isolation.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-04-2021
Abstract: A year into the severe acute respiratory syndrome coronavirus 2 pandemic, we are experiencing waves of new variants emerging. Some of these variants have worrying functional implications, such as increased transmissibility or antibody treatment escape. Lythgoe et al. have undertaken in-depth sequencing of more than 1000 hospital patients' isolates to find out how the virus is mutating within in iduals. Overall, there seem to be consistent and reproducible patterns of within-host virus ersity. The authors observed only one or two variants in most s les, but a few carried many variants. Although the evidence indicates strong purifying selection, including in the spike protein responsible for viral entry, the authors also saw evidence for transmission clusters associated with households and other possible superspreader events. After transmission, most variants fizzled out, but occasionally some initiated ongoing transmission and wider dissemination. Science , this issue p. eabg0821
Publisher: MDPI AG
Date: 18-03-2020
DOI: 10.3390/V12030331
Abstract: Across sub-Saharan Africa, key populations with elevated HIV-1 incidence and/or prevalence have been identified, but their contribution to disease spread remains unclear. We performed viral deep-sequence phylogenetic analyses to quantify transmission dynamics between the general population (GP), fisherfolk communities (FF), and women at high risk of infection and their clients (WHR) in central and southwestern Uganda. Between August 2014 and August 2017, 6185 HIV-1 positive in iduals were enrolled in 3 GP and 10 FF communities, 3 WHR enrollment sites. A total of 2531 antiretroviral therapy (ART) naïve participants with plasma viral load copies/mL were deep-sequenced. One hundred and twenty-three transmission networks were reconstructed, including 105 phylogenetically highly supported source–recipient pairs. Only one pair involved a WHR and male participant, suggesting that improved population s ling is needed to assess empirically the role of WHR to the transmission dynamics. More transmissions were observed from the GP communities to FF communities than vice versa, with an estimated flow ratio of 1.56 (95% CrI 0.68–3.72), indicating that fishing communities on Lake Victoria are not a net source of transmission flow to neighboring communities further inland. Men contributed disproportionally to HIV-1 transmission flow regardless of age, suggesting that prevention efforts need to better aid men to engage with and stay in care.
Publisher: Springer Science and Business Media LLC
Date: 04-2017
DOI: 10.1038/NATURE22040
Publisher: Elsevier BV
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 02-12-2022
DOI: 10.1101/2022.12.02.518847
Abstract: In this study, we evaluated the impact of viral variant, in addition to other variables, on within-host viral burdens, by analysing cycle threshold (Ct) values derived from nose and throat swabs, collected as part of the UK COVID-19 Infection Survey. Because viral burden distributions determined from community survey data can be biased due to the impact of variant epidemiology on the time-since-infection of s les, we developed a method to explicitly adjust observed Ct value distributions to account for the expected bias. Analysing the adjusted Ct values using partial least squares regression, we found that among unvaccinated in iduals with no known prior infection, the average Ct value was 0.94 lower among Alpha variant infections, compared those with the predecessor strain, B.1.177. However, among vaccinated in iduals, it was 0.34 lower among Delta variant infections, compared to those with the Alpha variant. In addition, the average Ct value decreased by 0.20 for every 10 year age increment of the infected in idual. In summary, within-host viral burdens are associated with age, in addition to the interplay of vaccination status and viral variant.
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2020
DOI: 10.1101/2020.05.28.118992
Abstract: Extensive global s ling and whole genome sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to characterise its spread, and to identify mutations that may increase transmission or enable the virus to escape therapies or vaccines. Two important components of viral spread are how frequently variants arise within in iduals, and how likely they are to be transmitted. Here, we characterise the within-host ersity of SARS-CoV-2, and the extent to which genetic ersity is transmitted, by quantifying variant frequencies in 1390 clinical s les from the UK, many from in iduals in known epidemiological clusters. We show that SARS-CoV-2 infections are characterised by low levels of within-host ersity across the entire viral genome, with evidence of strong evolutionary constraint in Spike, a key target of vaccines and antibody-based therapies. Although within-host variants can be observed in multiple in iduals in the same phylogenetic or epidemiological cluster, highly infectious in iduals with high viral load carry only a limited repertoire of viral ersity. Most viral variants are either lost, or occasionally fixed, at the point of transmission, consistent with a narrow transmission bottleneck. These results suggest potential vaccine-escape mutations are likely to be rare in infectious in iduals. Nonetheless, we identified Spike variants present in multiple in iduals that may affect receptor binding or neutralisation by antibodies. Since the fitness advantage of escape mutations in highly-vaccinated populations is likely to be substantial, resulting in rapid spread if and when they do emerge, these findings underline the need for continued vigilance and monitoring.
Publisher: American Society for Microbiology
Date: 11-2003
DOI: 10.1128/CDLI.10.6.1078-1084.2003
Abstract: The capsular polysaccharide Vi antigen (ViCPS) is an essential virulence factor and also a protective antigen of Salmonella enterica serovar Typhi. A random 12-mer phage-displayed peptide library was used to identify mimotopes (epitope analogues) of this antigen by panning against a ViCPS-specific monoclonal antibody (MAb) ATVi. Approximately 75% of the phage clones selected in the fourth round carried the peptide sequence TSHHDSHGLHRV, and the rest of the clones harbored ENHSPVNIAHKL and other related sequences. These two sequences were also obtained in a similar panning process by using pooled sera from patients with a confirmed diagnosis of typhoid fever, suggesting they mimic immunodominant epitopes of ViCPS antigens. Binding of MAb ATVi to the mimotopes was specifically blocked by ViCPS, indicating that they interact with the same binding site (paratope) of the MAb. Data and reagents generated in this study have important implications for the development of peptide-base diagnostic tests and peptide vaccines and may also provide a better understanding of the pathogenesis of typhoid fever.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Cold Spring Harbor Laboratory
Date: 14-12-2021
DOI: 10.1101/2021.12.13.21267267
Abstract: The scale of data produced during the SARS-CoV-2 pandemic has been unprecedented, with more than 5 million sequences shared publicly at the time of writing. This wealth of sequence data provides important context for interpreting local outbreaks. However, placing sequences of interest into national and international context is difficult given the size of the global dataset. Often outbreak investigations and genomic surveillance efforts require running similar analyses again and again on the latest dataset and producing reports. We developed civet (cluster investigation and virus epidemiology tool) to aid these routine analyses and facilitate virus outbreak investigation and surveillance. Civet can place sequences of interest in the local context of background ersity, resolving the query into different ’catchments’ and presenting the phylogenetic results alongside metadata in an interactive, distributable report. Civet can be used on a fine scale for clinical outbreak investigation, for local surveillance and cluster discovery, and to routinely summarise the virus ersity circulating on a national level. Civet reports have helped researchers and public health bodies feedback genomic information in the appropriate context within a timeframe that is useful for public health.
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2017
DOI: 10.1101/157768
Abstract: A central feature of pathogen genomics is that different infectious particles (virions, bacterial cells, etc.) within an infected in idual may be genetically distinct, with patterns of relatedness amongst infectious particles being the result of both within-host evolution and transmission from one host to the next. Here we present a new software tool, phyloscanner, which analyses pathogen ersity from multiple infected hosts. phyloscanner provides unprecedented resolution into the transmission process, allowing inference of the direction of transmission from sequence data alone. Multiply infected in iduals are also identified, as they harbour subpopulations of infectious particles that are not connected by within-host evolution, except where recombinant types emerge. Low-level contamination is flagged and removed. We illustrate phyloscanner on both viral and bacterial pathogens, namely HIV-1 sequenced on Illumina and Roche 454 platforms, HCV sequenced with the Oxford Nanopore MinION platform, and Streptococcus pneumoniae with sequences from multiple colonies per in idual. phyloscanner is available from github.com/BDI-pathogens hyloscanner .
Publisher: American Society for Microbiology
Date: 22-09-2020
DOI: 10.1128/JCM.00382-20
Abstract: Viral genetic sequencing can be used to monitor the spread of HIV drug resistance, identify appropriate antiretroviral regimes, and characterize transmission dynamics. Despite decreasing costs, next-generation sequencing (NGS) is still prohibitively costly for routine use in generalized HIV epidemics in low- and middle-income countries. Here, we present veSEQ-HIV, a high-throughput, cost-effective NGS sequencing method and computational pipeline tailored specifically to HIV, which can be performed using leftover blood drawn for routine CD4 cell count testing.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.CHROMA.2016.03.066
Abstract: Purification of virus-like particles (VLPs) in bind-and-elute mode has reached a bottleneck. Negative chromatography has emerged as the alternative solution however, benchmark of negative chromatography media and their respective optimized conditions are absent. Hence, this study was carried out to compare the performance of different negative chromatography media for the purification of hepatitis B VLPs (HB-VLPs) from clarified Escherichia coli feedstock. The modified anion exchange media, core-shell adsorbents (InertShell and InertLayer 1000) and polymer grafted adsorbents (SQ) were compared. The results of chromatography from packed bed column of core-shell adsorbents showed that there is a trade-off between the purity and recovery of HB-VLPs in the flowthrough fraction due to the shell thickness. Atomic force microscopic analysis revealed funnel-shaped pore channels in the shell layer which may contribute to the entrapment of HB-VLPs. A longer residence time at a lower feed flow rate (0.5ml/min) improved slightly the HB-VLPs purity in all modified adsorbents, but the recovery in InertShell reduced substantially. The preheat-treatment is not recommended for the negative chromatography as the thermal-induced co-aggregation of HCPs and HB-VLPs would flow along with HB-VLPs and thus reduced the HB-VLPs purity in the flowthrough. Further reduction in the feedstock concentration enhanced the purity of HB-VLPs especially in InertLayer 1000 but reduced substantially the recovery of HB-VLPs. In general, the polymer grafted adsorbent, SQ, performed better than the core-shell adsorbents in handling a higher feedstock concentration.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2019
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2021
DOI: 10.1101/2021.01.12.20249080
Abstract: A new variant of SARS-CoV-2 has emerged which is increasing in frequency, primarily in the South East of England (lineage B.1.1.7 ( 1 ) VUI-202012/01). One potential hypothesis is that infection with the new variant results in higher viral loads, which in turn may make the virus more transmissible. We found higher (sequence derived) viral loads in s les from in iduals infected with the new variant with median inferred viral loads were three-fold higher in in iduals with the new variant. Most of the new variants were s led in Kent and Greater London. We observed higher viral loads in Kent compared to Greater London for both the new variant and other circulating lineages. Outside Greater London, the variant has higher viral loads, whereas within Greater London, the new variant does not have significantly higher viral loads compared to other circulating lineages. Higher variant viral loads outside Greater London could be due to demographic effects, such as a faster variant growth rate compared to other lineages or concentration in particular age-groups. However, our analysis does not exclude a causal link between infection with the new variant and higher viral loads. This is a preliminary analysis and further work is needed to investigate any potential causal link between infection with this new variant and higher viral loads, and whether this results in higher transmissibility, severity of infection, or affects relative rates of symptomatic and asymptomatic infection This is an updated report submitted to NERVTAG in December 2020 as part of urgent investigations into the new variant of SARS-COV-2 (VUI-202012/01). It makes full use of (and is restricted to) all sequence data and associated metadata available to us at the time this original report was submitted and remains provisional. Under normal circumstances more genomes and metadata would be obtained and included before making this report public. We will update this preprint when more genomes and metadata are available and before submitting for peer review.
Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
DOI: 10.1038/S41467-019-09139-4
Abstract: To prevent new infections with human immunodeficiency virus type 1 (HIV-1) in sub-Saharan Africa, UNAIDS recommends targeting interventions to populations that are at high risk of acquiring and passing on the virus. Yet it is often unclear who and where these ‘source’ populations are. Here we demonstrate how viral deep-sequencing can be used to reconstruct HIV-1 transmission networks and to infer the direction of transmission in these networks. We are able to deep-sequence virus from a large population-based s le of infected in iduals in Rakai District, Uganda, reconstruct partial transmission networks, and infer the direction of transmission within them at an estimated error rate of 16.3% [8.8–28.3%]. With this error rate, deep-sequence phylogenetics cannot be used against in iduals in legal contexts, but is sufficiently low for population-level inferences into the sources of epidemic spread. The technique presents new opportunities for characterizing source populations and for targeting of HIV-1 prevention interventions in Africa.
Publisher: The Royal Society
Date: 16-11-2022
Abstract: The raw material for viral evolution is provided by intra-host mutations occurring during replication, transcription or post-transcription. Replication and transcription of Coronaviridae proceed through the synthesis of negative-sense ‘antigenomes’ acting as templates for positive-sense genomic and subgenomic RNA. Hence, mutations in the genomes of SARS-CoV-2 and other coronaviruses can occur during (and after) the synthesis of either negative-sense or positive-sense RNA, with potentially distinct patterns and consequences. We explored for the first time the mutational spectrum of SARS-CoV-2 (sub)genomic and anti(sub)genomic RNA. We use a high-quality deep sequencing dataset produced using a quantitative strand-aware sequencing method, controlled for artefacts and sequencing errors, and scrutinized for accurate detection of within-host ersity. The nucleotide differences between negative- and positive-sense strand consensus vary between patients and do not show dependence on age or sex. Similarities and differences in mutational patterns between within-host minor variants on the two RNA strands suggested strand-specific mutations or editing by host deaminases and oxidative damage. We observe generally neutral and slight negative selection on the negative strand, contrasting with purifying selection in ORF1a, ORF1b and S genes of the positive strand of the genome.
Publisher: Springer Science and Business Media LLC
Date: 25-03-2021
DOI: 10.1038/S41586-021-03470-X
Abstract: The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2020
DOI: 10.1101/2020.07.17.20155218
Abstract: ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) partnerships and outbreak preparedness initiatives enabled the rapid launch of standardised clinical data collection on COVID-19 in Jan 2020. Extensive global participation has resulted in a large, standardised collection of comprehensive clinical data from hundreds of sites across dozens of countries. Data are analysed regularly and reported publicly to inform patient care and public health response. This report, our 17th report, is a part of a series published over the past 2 years. Data have been entered for 800,459 in iduals from 1701 partner institutions and networks across 60 countries. The comprehensive analyses detailed in this report includes hospitalised in iduals of all ages for whom data collection occurred between 30 January 2020 and up to and including 5 January 2022, AND who have laboratory-confirmed SARS-COV-2 infection or clinically diagnosed COVID-19. For the 699,014 cases who meet eligibility criteria for this report, selected findings include: median age of 58 years, with an approximately equal (50/50) male:female sex distribution 29% of the cohort are at least 70 years of age, whereas 4% are 0-19 years of age the most common symptom combination in this hospitalised cohort is shortness of breath, cough, and history of fever, which has remained constant over time the five most common symptoms at admission were shortness of breath, cough, history of fever, fatigue/malaise, and altered consciousness/confusion, which is unchanged from the previous reports age-associated differences in symptoms are evident, including the frequency of altered consciousness increasing with age, and fever, respiratory and constitutional symptoms being present mostly in those 40 years and above 16% of patients with relevant data available were admitted at some point during their illness into an intensive care unit (ICU), which is slightly lower than previously reported (19%) antibiotic agents were used in 35% of patients for whom relevant data are available (669,630), a significant reduction from our previous reports (80%) which reflects a shifting proportion of data contributed by different institutions in ICU/HDU admitted patients with data available (50,560), 91% received antibiotics use of corticosteroids was reported in 24% of all patients for whom data were available (677,012) in ICU/HDU admitted patients with data available (50,646), 69% received corticosteroids outcomes are known for 632,518 patients and the overall estimated case fatality ratio (CFR) is 23.9% (95%CI 23.8-24.1), rising to 37.1% (95%CI 36.8-37.4) for patients who were admitted to ICU/HDU, demonstrating worse outcomes in those with the most severe disease To access previous versions of ISARIC COVID-19 Clinical Data Report please use the link below: esearch/covid-19-clinical-research-resources/evidence-reports/
Publisher: Oxford University Press (OUP)
Date: 03-06-2020
Abstract: Phylogenetic mapping of HIV-1 lineages circulating across defined geographical locations is promising for better understanding HIV transmission networks to design optimal prevention interventions. We obtained near full-length HIV-1 genome sequences from people living with HIV (PLWH), including participants on antiretroviral treatment in the Botswana Combination Prevention Project, conducted in 30 Botswana communities in 2013–2018. Phylogenetic relationships among viral sequences were estimated by maximum likelihood. We obtained 6078 near full-length HIV-1C genome sequences from 6075 PLWH. We identified 984 phylogenetically distinct HIV-1 lineages (molecular HIV clusters) circulating in Botswana by mid-2018, with 2–27 members per cluster. Of these, dyads accounted for 62%, approximately 32% (n = 316) were found in single communities, and 68% (n = 668) were spread across multiple communities. Men in clusters were approximately 3 years older than women (median age 42 years, vs 39 years P & .0001). In 65% of clusters, men were older than women, while in 35% of clusters women were older than men. The majority of identified viral lineages were spread across multiple communities. A large number of circulating phylogenetically distinct HIV-1C lineages (molecular HIV clusters) suggests highly ersified HIV transmission networks across Botswana communities by 2018.
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2014
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of nosocomial infection. Whole-genome sequencing of MRSA has been used to define phylogeny and transmission in well-resourced healthcare settings, yet the greatest burden of nosocomial infection occurs in resource-restricted settings where barriers to transmission are lower. Here, we study the flux and genetic ersity of MRSA on ward and in idual patient levels in a hospital where transmission was common. We repeatedly screened all patients on two intensive care units for MRSA carriage over a 3-mo period. All MRSA belonged to multilocus sequence type 239 (ST 239). We defined the population structure and charted the spread of MRSA by sequencing 79 isolates from 46 patients and five members of staff, including the first MRSA-positive screen isolates and up to two repeat isolates where available. Phylogenetic analysis identified a flux of distinct ST 239 clades over time in each intensive care unit. In total, five main clades were identified, which varied in the carriage of plasmids encoding antiseptic and antimicrobial resistance determinants. Sequence data confirmed intra- and interwards transmission events and identified in idual patients who were colonized by more than one clade. One patient on each unit was the source of numerous transmission events, and deep s ling of one of these cases demonstrated colonization with a “cloud” of related MRSA variants. The application of whole-genome sequencing and analysis provides novel insights into the transmission of MRSA in under-resourced healthcare settings and has relevance to wider global health.
Publisher: PeerJ
Date: 05-04-2019
DOI: 10.7717/PEERJ.6225
Abstract: Shigella -infected bacillary dysentery or commonly known as Shigellosis is a leading cause of morbidity and mortality worldwide. The gradual emergence of multidrug resistant Shigella spp. has triggered the search for alternatives to conventional antibiotics. Phage therapy could be one such suitable alternative, given its proven long term safety profile as well as the rapid expansion of phage therapy research. To be successful, phage therapy will need an adequate regulatory framework, effective strategies, the proper selection of appropriate phages, early solutions to overcome phage therapy limitations, the implementation of safety protocols, and finally improved public awareness. To achieve all these criteria and successfully apply phage therapy against multidrug resistant shigellosis, a comprehensive study is required. In fact, a variety of phage-based approaches and products including single phages, phage cocktails, mutated phages, genetically engineered phages, and combinations of phages with antibiotics have already been carried out to test the applications of phage therapy against multidrug resistant Shigella. This review provides a broad survey of phage treatments from past to present, focusing on the history, applications, limitations and effective solutions related to, as well as the prospects for, the use of phage therapy against multidrug resistant Shigella spp. and other multidrug resistant bacterial pathogens.
Publisher: Cold Spring Harbor Laboratory
Date: 23-06-2021
DOI: 10.1101/2021.06.19.21259186
Abstract: Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 – 56.7] versus 3% [0.1 – 27.3]) than at baseline (7% [1.5 – 25.3] versus 5% [0.9 – 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.CHROMA.2015.08.056
Abstract: Poly(oligo(ethylene glycol) methacrylate) (POEGMA), an inert polymer was grafted onto an anion exchange adsorbent for the exclusion of relatively larger hepatitis B virus-like particles (HB-VLPs) from the anion exchange ligand (Q) and at the same time this process allowed the selective adsorption of smaller size Escherichia coli host cell proteins (HCPs). The chain lengths of the POEGMA grafted were modulated by varying the amount of monomers used in the polymer grafting. The purification factor and yield of the HB-VLPs obtained from the flow-through of negative chromatography were 2.3 and 66.0±3.1%, respectively, when shorter chain length of POEGMA (SQ) was grafted. Adsorbent grafted with longer chain of POEGMA (LQ) excluded some HCPs that are larger in size together with the HB-VLPs, reducing the purity of the recovered HB-VLPs. Further heat-treatment of the flow-through pool from SQ followed by centrifugation increased the purity of heat stable HB-VLPs to 87.5±1.1%. Heat-treatment of the flow through s le resulted in thermal denaturation and aggregation of HCPs, while the heat stable HB-VLPs still remained intact as observed under a transmission electron microscope. The performance of the negative chromatography together with heat treatment in the purification of HB-VLPs is far better than the reported bind-and-elute techniques.
Publisher: Cold Spring Harbor Laboratory
Date: 06-01-2022
DOI: 10.1101/2022.01.05.21268323
Abstract: The Office for National Statistics COVID-19 Infection Survey (ONS-CIS) is the largest surveillance study of SARS-CoV-2 positivity in the community, and collected data on the United Kingdom (UK) epidemic from April 2020 until March 2023 before being paused. Here, we report on the epidemiological and evolutionary dynamics of SARS-CoV-2 determined by analysing the sequenced s les collected by the ONS-CIS during this period. We observed a series of sweeps or partial sweeps, with each sweeping lineage having a distinct growth advantage compared to their predecessors. The sweeps also generated an alternating pattern in which most s les had either S-gene target failure (SGTF) or non- SGTF over time. Evolution was characterised by steadily increasing ergence and ersity within lineages, but with step increases in ergence associated with each sweeping major lineage. This led to a faster overall rate of evolution when measured at the between-lineage level compared to within lineages, and fluctuating levels of ersity. These observations highlight the value of viral sequencing integrated into community surveillance studies to monitor the viral epidemiology and evolution of SARS-CoV-2, and potentially other pathogens, particularly in the current phase of the pandemic with routine RT-PCR testing now ended in the community.
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2018
DOI: 10.1101/397083
Abstract: High-throughput viral genetic sequencing is needed to monitor the spread of drug resistance, direct optimal antiretroviral regimes, and to identify transmission dynamics in generalised HIV epidemics. Public health efforts to sequence HIV genomes at scale face three major technical challenges: (i) minimising assay cost and protocol complexity, (ii) maximising sensitivity, and (iii) recovering accurate and unbiased sequences of both the genome consensus and the within-host viral ersity. Here we present a novel, high-throughput, virus-enriched sequencing method and computational pipeline tailored specifically to HIV (veSEQ-HIV), which addresses all three technical challenges, and can be used directly on leftover blood drawn for routine CD4 testing. We demonstrate its performance on 1,620 plasma s les collected from consenting in iduals attending 10 large urban clinics in Zambia, partners of HPTN 071 (PopART). We show that veSEQ-HIV consistently recovers complete HIV genomes from the majority of s les of different subtypes, and is also quantitative: the number of HIV reads per s le obtained by veSEQ-HIV estimates viral load without the need for additional testing. Both quantitativity and sensitivity were assessed on a subset of 126 s les with clinically measured viral loads, and with standardized quantification controls (VL 100 – 5,000,000 RNA copies/ml). Complete HIV genomes were recovered from 93% (85/91) of s les when viral load was over 1,000 copies per ml. The quantitative nature of the assay implies that variant frequencies estimated with veSEQ-HIV are representative of true variant frequencies in the s le. Detection of minority variants can be exploited for epidemiological analysis of transmission and drug resistance, and we show how the information contained in in idual reads of a veSEQ-HIV s le can be used to detect linkage between multiple mutations associated with resistance to antiretroviral therapy. Less than 2% of reads obtained by veSEQ-HIV were identified as in silico contamination events using updates to the phyloscanner software ( phyloscanner clean ) that we show to be 95% sensitive and 99% specific at ‘decontaminating’ NGS data. The cost of the assay — approximately 45 USD per s le — compares favourably with existing VL and HIV genotyping tests, and provides the additional value of viral load quantification and inference of drug resistance with a single test. veSEQ-HIV is well suited to large public health efforts and is being applied to all ∼9000 s les collected for the HPTN 071-2 (PopART Phylogenetics) study.
Publisher: Cold Spring Harbor Laboratory
Date: 04-01-2021
DOI: 10.1101/2020.12.30.20249034
Abstract: The SARS-CoV-2 lineage B.1.1.7, now designated Variant of Concern 202012/01 (VOC) by Public Health England, originated in the UK in late Summer to early Autumn 2020. We examine epidemiological evidence for this VOC having a transmission advantage from several perspectives. First, whole genome sequence data collected from community-based diagnostic testing provides an indication of changing prevalence of different genetic variants through time. Phylodynamic modelling additionally indicates that genetic ersity of this lineage has changed in a manner consistent with exponential growth. Second, we find that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S-gene target failures (SGTF) in community-based diagnostic PCR testing. Third, we examine growth trends in SGTF and non-SGTF case numbers at local area level across England, and show that the VOC has higher transmissibility than non-VOC lineages, even if the VOC has a different latent period or generation time. Available SGTF data indicate a shift in the age composition of reported cases, with a larger share of under 20 year olds among reported VOC than non-VOC cases. Fourth, we assess the association of VOC frequency with independent estimates of the overall SARS-CoV-2 reproduction number through time. Finally, we fit a semi-mechanistic model directly to local VOC and non-VOC case incidence to estimate the reproduction numbers over time for each. There is a consensus among all analyses that the VOC has a substantial transmission advantage, with the estimated difference in reproduction numbers between VOC and non-VOC ranging between 0.4 and 0.7, and the ratio of reproduction numbers varying between 1.4 and 1.8. We note that these estimates of transmission advantage apply to a period where high levels of social distancing were in place in England extrapolation to other transmission contexts therefore requires caution.
Publisher: Wiley
Date: 05-04-2021
DOI: 10.1111/RAQ.12562
Abstract: The Macrobrachium rosenbergii nodavirus causes white tail disease, which primarily infects giant freshwater prawns, Macrobrachium rosenbergii . The infection leads to almost 100% mortality in post‐larvae, causing significant economic losses in aquaculture farms. To develop effective measures against outbreaks, a good understanding of the virus is essential. In this review, we discuss key aspects of the Macrobrachium rosenbergii nodavirus including its structure, mechanisms of transmission and infection and common strategies for detection and prevention of outbreaks. Structurally, cryogenic electron microscopy revealed that the nodavirus has a T = 3 icosahedral structure with dimeric blade‐like spikes on its surface. Homology modelling comparing wild‐type and enzymatically cleaved Macrobrachium rosenbergii nodavirus‐like particles revealed the significance of these spikes or protruding domains for binding. In vitro and in vivo studies have identified key aspects of Macrobrachium rosenbergii nodavirus infectivity, including (i) the viral binding targets such as transglutaminase and caveolin‐1, (ii) utilisation of B2‐like proteins in promoting infectivity and intracellular migration, (iii) replication mechanisms and (iv) co‐infection with the extra small virus. Though susceptible at a post‐larvae stage, adult Macrobrachium rosenbergii is immune to Macrobrachium rosenbergii nodavirus infection. During outbreaks, polymerase chain reaction and in situ hybridisation‐based detection techniques are commonly used to identify infected populations. Currently, the most useful strategies for an outbreak are physical biosecurity measures and prophylaxis such as vaccination and immunostimulants. Finally, critical gaps in research include development of immortalised shrimp cell models, elucidation of time‐resolved protein changes post‐infection and development of therapies to treat infections to mitigate economic losses during outbreaks.
Publisher: Cold Spring Harbor Laboratory
Date: 21-09-2021
DOI: 10.1101/2021.09.11.21263419
Abstract: Policymakers need robust data to respond to the COVID-19 pandemic. We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, the world’s largest international, standardised cohort of hospitalised patients. The dataset analysed includes COVID-19 patients hospitalised between January 2020 and May 2021. We investigated how symptoms on admission, comorbidities, risk factors, and treatments varied by age, sex, and other characteristics. We used Cox proportional hazards models to investigate associations between demographics, symptoms, comorbidities, and other factors with risk of death, admission to intensive care unit (ICU), and invasive mechanical ventilation (IMV). 439,922 patients with laboratory-confirmed (91.7%) or clinically-diagnosed (8.3%) SARS-CoV-2 infection from 49 countries were enrolled. Age (adjusted hazard ratio [HR] per 10 years 1.49 [95% CI 1.49-1.50]) and male sex (1.26 [1.24-1.28]) were associated with a higher risk of death. Rates of admission to ICU and use of IMV increased with age up to age 60, then dropped. Symptoms, comorbidities, and treatments varied by age and had varied associations with clinical outcomes. Tuberculosis was associated with an 86% higher risk of death, and HIV with an 87% higher risk of death. Case fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients. The size of our international database and the standardized data collection method makes this study a reliable and comprehensive international description of COVID-19 clinical features. This is a viable model to be applied to future epidemics. UK Foreign, Commonwealth and Development Office, the Bill & Melinda Gates Foundation and Wellcome. See acknowledgements section for funders of sites that contributed data. To identify large, international analyses of hospitalised COVID-19 patients that used standardised data collection, we conducted a systematic review of the literature from 1 Jan 2020 to 28 Apr 2020. We identified 78 studies, with data from 77,443 people (1) predominantly from China. We could not find any studies including data from low and middle-income countries. We repeated our search on 18 Aug 2021 but could not identify any further studies that met our inclusion criteria. Our study uses standardised clinical data collection to collect data from a vast number of patients across the world, including patients from low-, middle-, and high-income countries. The size of our database gives us great confidence in the accuracy of our descriptions of the global impact of COVID-19. We can confirm findings reported by smaller, country-specific studies and compare clinical data between countries. We have demonstrated that it is possible to collect large volumes of standardised clinical data during a pandemic of a novel acute respiratory infection. The results provide a valuable resource for present policymakers and future global health researchers. Presenting symptoms of SARS-CoV-2 infection in patients requiring hospitalisation are now well-described globally, with the most common being fever, cough, and shortness of breath. Other symptoms also commonly occur, including altered consciousness in older adults and gastrointestinal symptoms in younger patients, and age can influence the likelihood of a patient having symptoms that match one or more case definitions. There are geographic and temporal variations in the case fatality rate (CFR), but overall, CFR was 20.6% in this large international cohort of hospitalised patients with a median age of 60 years (IQR: 45 to 74 years).
Publisher: Springer Science and Business Media LLC
Date: 25-06-2021
DOI: 10.1007/S15010-021-01599-5
Abstract: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69% at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23 85%), older adults (≥ 70 years: 61, 62, 65 90%), and women (66, 66, 64 90% vs. men 71, 70, 67 93%, each P 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1093/VE/VEY007
Publisher: Research Square Platform LLC
Date: 12-07-2021
DOI: 10.21203/RS.3.RS-654257/V1
Abstract: Background Emerging evidence shows the substantial real-world impact of authorised vaccines against COVID-19 and provides insight into the potential role of vaccines in curbing the pandemic. However, there remains uncertainty about the efficacy of vaccines against different variants of the virus. Here we assessed efficacy of ChAdOx1 nCoV-19 (AZD1222) against lineages of SARS-CoV-2 circulating in Brazil from June 2020 until early 2021. Methods Participants aged 18 and above were enrolled into a randomised phase 3 trial of ChAdOx1 nCoV-19 vaccine against symptomatic SARS-CoV-2 infection. Participants received two doses of ChAdOx1 nCoV-19 or control (1st dose: Men ACWY vaccine, 2nd dose: normal saline). Nasopharyngeal and oropharyngeal swabbing was performed if participants developed symptoms of COVID-19 (cough, shortness of breath, fever .8°C, ageusia, anosmia). Swabs were tested by nucleic acid lification (NAAT) for SARS-CoV-2, sequenced, and viral load determined. For those s les where a genotype could not be ascertained from sequencing, allele specific PCR was performed. The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were unblinded after the vaccine was authorised for use, and the control participants offered vaccination. Infections occurring after unblinding were excluded from analysis. Vaccine efficacy was calculated as 100% x (1 – relative risk (RR)), where RR was estimated from a robust Poisson model. The trial is registered at ISRCTN89951424. Findings 9433 participants were eligible for inclusion in the pre-specified primary efficacy population, having reached more than 14 days after a second dose of ChAdOx1 nCoV-19, of whom 307 were NAAT+, in this post-hoc analysis. From June 2020 to February 2021, the two most frequently identified lineages were P.2 (N=153) and B.1.1.28 (N=49). P.1 emerged during the study (N=18) but became dominant only after study unblinding. Viral loads were highest amongst those with P.1 infection. Vaccine efficacy (VE) for B.1.1.33 (88.2%, 95%CI 5, 99), B.1.1.28 (73%, 95% CI, 46, 86), P.2 (69% 95% CI, 55, 78) and P.1 (64%, 95% CI, -2, 87) was estimated. In participants who had received two doses of vaccine, one COVID-19 hospitalisation occurred in the ChAdOx1 nCoV-19 group and 18 in the control group, with VE against hospitalisation 95% (95% CI 61, 99). There were 2 COVID-19 deaths in the control group and none in the vaccine group. Interpretation ChAdOx1 nCoV-19 provides high efficacy against hospitalisation, severe disease and death from COVID-19 in Brazil and there is strong evidence of protection being maintained against P.2, despite the presence of the spike protein mutation E484K. Real world effectiveness studies are ongoing in Brazil to further establish protection against P.1 and other emerging variants.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christophe Fraser.