School of Medical Sciences

A Systematic Review of Clinical and Genetic Approaches to VACTERL Association

2026-01-01T00:00:00Z

A Systematic Review of Clinical and Genetic Approaches to VACTERL Association Bowden, Rachel Aim: To systematically review clinical and genetic testing approaches to VACTERL association, a non-random co-occurrence of congenital anomalies involving the vertebrae, anus, cardiac system, trachea-oesophagus, renal system, and limbs. The review will examine investigation strategies used in clinical practice and evaluate the diagnostic yield of genetic testing in affected individuals. Methods: A systematic search of PubMed, MEDLINE, EMBASE, Web of Science, and CINAHL was conducted from database inception to 1 December 2024. Eligible studies included English-language human studies reporting genetic testing in individuals with VACTERL association. Grey literature and studies limited to management were excluded. Risk of bias and certainty of evidence were assessed using Joanna Briggs Institute tools and the Grading of Recommendations Assessment, Development, and Evaluation. Results: A total of 65 articles met inclusion criteria-32 observational studies, 20 case reports, 9 case series, and 4 expert opinions. Findings were tabulated and narratively synthesised. Reported diagnostic yields were 2%-31% for chromosomal microarrays and 5%-22% for whole-exome sequencing. Conclusions: Definitions of VACTERL and diagnostic approaches vary widely. Limitations of the evidence base include study heterogeneity, reliance on retrospective designs, outdated technologies, and lack of meta-analyses. Prospective studies are needed to develop protocols. In the interim, imaging, complete blood count and film, chromosomal microarray, chromosomal breakage studies, and exome or genome sequencing should be considered for patients with two or more VACTERL features, or selected individuals with an isolated feature. This recommendation is based on the implications of a molecular diagnosis for management. Key diagnostic elements and differential diagnoses are summarised.

VPS41 deletion triggers progressive loss of insulin stores and downregulation of beta-cell identity - Supplemental Material

2024-12-06T00:00:00Z

VPS41 deletion triggers progressive loss of insulin stores and downregulation of beta-cell identity - Supplemental Material Yau, Belinda; An, Yousun; Germanos, Mark; Schwarzkopf, Patricia; van der Kraan, A Gabrielle; Larance, Mark; Burns, Christian; Asensio, Cedric S; Kebede, Melkam A Supplemental Figures and Tables for the manuscript 'VPS41 deletion triggers progressive loss of insulin stores and downregulation of beta-cell identity'. Tables contain proteomics datasets of differentially expressed proteins in VPS41HET and VPS41KO mouse islets, and VPS41 CTRL and KD INS1 cells.

Using a patient-reported outcome measure to assess quality of life at Western Sydney Sexual Health Centre

2024-01-01T00:00:00Z

Using a patient-reported outcome measure to assess quality of life at Western Sydney Sexual Health Centre Mason, E.; Lewis, D. A.; Zablotska, I.; Tomlins, L. Background. Attaining a good quality of life (QOL) is a priority for people living with HIV (PLHIV). We explored the interaction between QOL and the associated demographic, behavioural and clinical factors for PLHIV attending an outer-metropolitan clinical setting in Western Sydney, Australia. The clinic’s cohort of PLHIV is characterised by relatively high proportions of women, heterosexual men, and patients from culturally and linguistically diverse (CALD) communities. Methods. We assessed QOL using the PozQol tool that is specifically designed for PLHIV. QOL scores and de-identified socio-demographic and clinical data were extracted from the electronic and paper medical records of PLHIV who completed a PozQol tool (September 2020–March 2022). We performed descriptive analyses and logistic regression to identify associations. Results. Among 188 patients, there were 77.7% men, 21.3% women, 1.1% transwomen; 67.0% were born overseas, 85.1% spoke English, 84.4% were Medicare-eligible, 85.9% were employed, 58.5% were diagnosed with HIV 6–20 years ago, and 33.0% within the past 5 years. Overall, 58.0% had a high or very high QOL. A low score in any domain was associated with Medicare-ineligibility. Low QOL scores in specificdomains were associated with the following factors: health (being born overseas, having partners of both sexes), psychological (unemployment, having a mental health condition, having a viral load >20 copies/mL), social (unemployment), and functional (Medicare-eligibility, unemployment, having a viral load >20 copies/mL). Conclusions. The PozQol tool has enhanced understanding of factors impacting on QOL for PLHIV attending our service in Western Sydney. Identifying patients with low QOL scores allows targeted clinical interventions to improve QOL, and re-alignment of clinical services to better support PLHIV.

echoMRI data

2024-08-16T00:00:00Z

echoMRI data Mojadadi, Albaraa This study investigates the effects of different selenium compounds on body composition in mice using EchoMRI data. The experiment involved 40 mice divided into five groups, each consisting of eight mice: Control, Sodium Selenite, Methylselenocysteine, Diphenyl Diselenide, and Nanoselenium. Over the course of the study, the mice were fed diets supplemented with one of the specified selenium compounds. EchoMRI technology was utilized to non-invasively assess body composition, including fat mass, lean mass, and total body water, at multiple time points. The resulting dataset provides detailed information on how each selenium compound affects body composition over time. Analysis of this EchoMRI data reveals significant differences in body composition changes among the groups, indicating that the various forms of selenium have distinct impacts on fat and lean mass distribution. These findings contribute to a deeper understanding of how dietary selenium influences body composition, with potential implications for nutritional strategies and health outcomes related to selenium supplementation.

Promethion Data

2024-08-16T00:00:00Z

Promethion Data Mojadadi, Albaraa This study examines the metabolic effects of different selenium compounds in mice using Promethion metabolic data. Forty mice were divided into five groups, each containing eight mice: Control, Sodium Selenite, Methylselenocysteine, Diphenyl Diselenide, and Nanoselenium. Each group was fed a diet supplemented with one of these selenium compounds. Promethion metabolic cages were used to collect detailed data on energy expenditure, activity levels, food intake, and respiratory exchange ratios over the course of the experiment. The resulting dataset provides a comprehensive view of how each selenium compound influences metabolic parameters in the mice. Analysis of this data reveals significant differences in metabolic profiles between the groups, highlighting the specific impacts of each selenium form on energy metabolism. This study's findings, derived from Promethion metabolic data, offer valuable insights into the metabolic consequences of dietary selenium supplementation, with potential implications for understanding the role of selenium in overall health and metabolic regulation.

Microbiome Data

2024-08-16T00:00:00Z

Microbiome Data Mojadadi, Albaraa This study investigates the impact of different selenium compounds on the gut microbiome of mice. Forty mice were divided into five groups, each consisting of eight mice: a control group, and four treatment groups that were administered Sodium Selenite, Methylselenocysteine, Diphenyl Diselenide, and Nanoselenium, respectively. Over the course of the experiment, the mice were fed diets supplemented with these specific selenium compounds. The primary objective was to evaluate how these different forms of selenium influence the composition and diversity of the gut microbiome. Microbiome data were collected and analyzed to identify shifts in microbial populations, with the aim of understanding the potential health implications of selenium supplementation in relation to gut health. The results of this study provide insights into the specific effects of various selenium compounds on the gut microbiota, contributing to the broader understanding of how dietary selenium may influence gut microbial ecosystems.

Adding a diazo-transfer reagent to culture to generate secondary metabolite probes for click chemistry

2022-01-01T00:00:00Z

Adding a diazo-transfer reagent to culture to generate secondary metabolite probes for click chemistry Gotsbacher, Michael P; Codd, Rachel Converting discrete microbial metabolites into chemical probes for chemical biology and medicinal chemistry studies is typically preceded by lengthy purification and chemical derivatization processes. Standard practice involves purifying the target microbial metabolite from culture, followed by derivatization and/or conjugation chemistry to convert the pure metabolite into a tagged species. This multistep approach can pose difficulties in generating useful yields of chemical probes, particularly in the case of low-abundant metabolites,as common in metabolomes. This chapter describes a methodological approach to simplify the steps towards generating chemical probes from complex mixtures, that combines: (a) tailored purification processes; (b) compound identification using state-of-the-art tandem mass spectrometry and data-dependent fragmentation; and (c) in situ bioorthogonal bioconjugation chemistries. The combination of these methods,as illustrated by the conversion of a set of amine-bearing metabolites to the cognate azide analogs suitable for biotinylation through azide-alkyne cycloaddition, describes a powerful approach to access new chemical probes of low-abundant metabolites that might otherwise be inaccessible using traditional methods.

Siderophores and iron transport

2023-01-01T00:00:00Z

Siderophores and iron transport Codd, Rachel Siderophores are low-molecular-weight organic compounds produced by bacteria and fungi for Fe(III) supply. Bacteria and fungi biosynthesize siderophores in response to low iron, which are released into the local environment to sequester Fe(III) to form a high-affinity Fe(III)-siderophore complex. This complex can be avidly recognized by selective proteins at the cell surface of the producing species. Following active transport, the Fe(III)–siderophore complex reaches its destination in the cytoplasm, where the element is released for downstream processing and incorporation into enzymes and proteins essential for growth. This elegant supply mechanism traverses a broad intellectual base across inorganic and coordination chemistry, bioorganic chemistry, molecular microbiology, natural product biosynthesis, medicinal chemistry, and chemical and structural biology. Added interest in the field of siderophores is founded upon the potential of these ligands in metal sequestration in other settings, including environmental metals as contaminants or commodities, and as agents for maintaining metal homeostasis or delivering radiometals for imaging. This chapter seeks to provide the reader with an understanding of foundational knowledge of siderophores and iron transport and to ignite a sense of wonder that has captured many researchers worldwide.

Engineering a cleavable disulfide bond into a natural product siderophore using precursor-directed biosynthesis

2018-01-01T00:00:00Z

Engineering a cleavable disulfide bond into a natural product siderophore using precursor-directed biosynthesis Richardson-Sanchez, Tomas; Codd, Rachel An analogue of the bacterial siderophore desferrioxamine B (DFOB) containing a disulfide motif in the backbone was produced from Streptomyces pilosus cultures supplemented with cystamine. Cystamine competed against native 1,5-diaminopentane during assembly. DFOB(SS)1[001] and its complexes with Fe(III) or Ga(III) were cleaved upon incubation with dithiothreitol. Compounds such as DFOB-(SS)1[001] and its thiol-containing cleavage products could expand antibiotic strategies and Au-S-based nanotechnologies.

Fluorinated Analogues of Desferrioxamine B from Precursor-Directed Biosynthesis Provide New Insight into the Capacity of DesBCD

2018-01-01T00:00:00Z

Fluorinated Analogues of Desferrioxamine B from Precursor-Directed Biosynthesis Provide New Insight into the Capacity of DesBCD Telfer, Thomas J.; Codd, Rachel The siderophore desferrioxamine B (DFOB, 1) native to Streptomyces pilosus is biosynthesized by the DesABCD enzyme cluster. DesA-mediated decarboxylation of l-lysine gives 1,5-diaminopentane (DP) for processing by DesBCD. S. pilosus culture medium was supplemented with rac-1,4-diamino-2-fluorobutane (rac-FDB) to compete against DP to generate fluorinated analogues of DFOB, as agents of potential clinical interest. LC-MS/MS analysis identified fluorinated analogues of DFOB with one, two, or three DP units (binary notation: 0) exchanged for one (DFOA-F1[001] (2), DFOA-F1[010] (3), DFOA-F1[100] (4)), two (DFOA-F2[011] (5), DFOA-F2[110] (6), DFOA-F2[101] (7)), or three (DFOA-F3[111] (8)) rac-FDB units (binary notation: 1). The two sets of constitutional isomers 2–4 and 5–7 arose from the position of the substrates in the N-acetyl, internal, or amine-containing regions of the DFOB trimer. N-Acetylated fluorinated DFOB analogues were formed where the rac-FDB substrate was positioned in the amine region (e.g., N-Ac-DFOA-F1[001] (2a)). Other analogues contained two hydroxamic acid groups and three amide bonds. Experiments using rac-FDB, R-FDB, or S-FDB showed a similar species profile between rac-FDB and R-FDB. These data are consistent with the following. (i) DesB can act on rac-FDB. (ii) DesC can act directly on rac-FDB. (iii) The products of DesBC or DesC catalysis of rac-FDB can undergo a second round of DesC catalysis at the free amine. (iv) DesD catalysis of these products gives N,N′-diacetylated compounds. (v) A minimum of two hydroxamic acid groups is required to form a viable DesD-substrate(s) precomplex. (vi) One or more DesBCD-catalyzed steps in DFOB biosynthesis is enantioselective. This work has provided a potential path to access fluorinated analogues of DFOB and new insight into its biosynthesis.

Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent

2020-01-01T00:00:00Z

Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent Gotsbacher, Michael P; Codd, Rachel This work aimed to undertake the in situ conversion of the terminal amine groups of bacterial desferrioxamine (DFO) siderophores, including desferrioxamine B (DFOB), to azide groups to enable downstream click chemistry. Initial studies trialed a precursor-directed biosynthesis (PDB) approach. Supplementing Streptomyces pilosus culture with blunt-end azido/amine non-native substrates designed to replace 1,5-diaminopentane as the native diamine substrate in the terminal amine position of DFOB did not produce azido-DFOB. Addition of the diazo-transfer reagent imidazole-1-sulfonyl azide hydrogen sulfate to spent S. pilosus medium that had been cultured in the presence of 1,4-diaminobutane, as a viable native substrate to expand the suite of native DFO-type siderophores, successfully generated the cognate suite of azido-DFO analogues. CuI-mediated or strain-promoted CuI-free click chemistry reactions between this minimally processed mixture and the appropriate alkyne-bearing biotin reagents produced the cognate suite of 1,4-disubstituted triazole-linked DFO-biotin compounds as potential molecular probes, detected as FeIII-loaded species. The amine-to-azide transformation of amine-bearing natural products in complex mixtures by the direct addition of a diazo-transfer reagent to deliver functional click chemistry reagents adds to the toolbox for chemical proteomics, chemical biology, and drug discovery.

Immobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors

2020-01-01T00:00:00Z

Immobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors Roth, Lukas; Gotsbacher, Michael P; Codd, Rachel Immobilized metal-ion affinity chromatography (IMAC) used to purify recombinant proteins features a resin-bound 1:1 Ni(II)-iminodiacetic acid (IDA) complex. This hemi-saturated Ni(II)-IDA system containing exchangeable sites at the metal ion is re-cast as a surrogate of a coordinatively-unsaturated metalloenzyme active site, with utility for selecting compounds with metal-binding groups from mixtures as potential metalloenzyme inhibitors. Exchanging Ni(II) for other metal ions could broaden the scope of metalloenzyme target. This work examined the performance of Cu(II)-, Fe(III)-, Ga(III)-, Ni(II)-, or Zn(II)-IMAC resins to reversibly bind experimental or clinical metalloenzyme inhibitors of Zn(II)-ACE1, Zn(II)-HDAC, Fe(II)/(III)-5-LO or Cu(II)-tyrosinase from a curated mixture (1-17). Each IMAC system gave a distinct selection profile. The Zn(II)-IMAC system selectively bound the thiol-containing Zn(II)-ACE1 inhibitors captopril and omapatrilat, and the Fe(III)-IMAC system selectively bound the Fe(II)/(III)-5-LO inhibitor licofelone, demonstrating a remarkable IMAC-metalloenzyme metal ion match. IMAC provides a simple, water-compatible platform, which could accelerate metalloenzyme inhibitor discovery.

Sexual And Reproductive Health Needs, Experiences, Access To Services, And Interventions Among The Rohingya And The Afghan Refugee Women Of Reproductive Age In Asia: A Mixed Methods Systematic Review Protocol

2021-01-01T00:00:00Z

Sexual And Reproductive Health Needs, Experiences, Access To Services, And Interventions Among The Rohingya And The Afghan Refugee Women Of Reproductive Age In Asia: A Mixed Methods Systematic Review Protocol Hossain, Muhammad Anwar; Dawson, Angela Background: A humanitarian crisis disrupts the existing health care system limiting access to sexual reproductive health (SRH) services. The Asia and the Pacific region is home to 9.2 million refugees as of September 2020, most originating from Afghanistan and Myanmar. Afghan and Rohingya refugees have long been deprived of formal SRH education and face decades of discrimination in SRH services that can affect health outcomes. Purpose: This review examines the SRH status of Afghan and Rohingya refugee women of reproductive age in Asia and their needs and experiences in accessing these services and commodities. Methods: This protocol will follow the PRISMA checklist and standards for quality assessment of systematic reviews. The search strategy will be sought out all relevant peer-reviewed literature from five online bibliographic databases—SCOPUS, EMBASE (Ovid), MEDLINE (Ovid), CINAHL, and PROQUEST— using search terms related to the research questions. The review will include qualitative, quantitative, and mixed-method studies to understand the status of SRH of Rohingya and Afghan refugees across Asia. Content analysis will undertake following the Minimum Initial Service Package (MISP) objectives. The review will use the mixed methods appraisal tool (MMAT) to assess the quality of individual studies. However, no studies will be excluded based on this assessment. Result: The findings of this review will provide insight into the needs, status, and experiences of SRH of the Afghan and Rohingya refugee women of reproductive age in Asia and could contribute to health service planning to deliver evidence-based interventions and policies to improve SRH outcomes in humanitarian settings across Asia. Systematic review registration: The review was registered in the PROSPERO database with ID CRD42021253975.

iEngage: a digital health education program designed to enhance physical activity in adolescents

2022-01-01T00:00:00Z

iEngage: a digital health education program designed to enhance physical activity in adolescents Caillaud, Corinne; Ledger, Susan; Diaz, Claudio; Clerc, Gael; Galy, Olivier; Yacef, Kalina iEngage is a modular health education and behavioural change program designed to help adolescents increase moderate to vigorous physical activity (MVPA). The program is delivered through the iEngage app which integrates activity trackers data (Misfit Ray©) within 10 interactive learning modules. Key features include guidance to set goals, self-monitor and assess achievements, and experiential learning via the connected activity trackers which allows for continuous steps recording during the program. iEngage was implemented in schools over 5 weeks with 10-12 years old adolescents (57 iEngage and 26 controls participants). Results show that adolescents successfully set goals and self-assessed achievements during the program, progressing toward higher physical activity (PA) levels as shown by the increase in daily steps through the program (+30%, + 2647 steps/day, P < .001). The consistency of days totalling at least 11,000 steps/day increased from 35% at the start to 48% at the end of the program. Average MVPA during schooldays was assessed pre- and post- program via research grade wrist accelerometers in students participating in iEngage and in control participants. Contrasting with the control group, MVPA increased after the program (~+5 min/day, P = .023) in short bouts, during lunch time, recess and after school. This study shows that a digital program incorporating health education, goals setting and self-monitoring of PA, helped young adolescents enhance PA goals and achievements and increase MVPA in daily life; validating the concept.

Zoonotic disease and virome diversity in bats

2022-01-01T00:00:00Z

Zoonotic disease and virome diversity in bats Van, Brussel, K.; Holmes, E.C. The emergence of zoonotic viral diseases in humans commonly reflects exposure to mammalian wildlife. Bats (order Chiroptera) are arguably the most important mammalian reservoir for zoonotic viruses, with notable examples including Severe Acute Respiratory Syndrome coronaviruses 1 and 2, Middle East Respiratory Syndrome coronavirus, henipaviruses and lyssaviruses. Herein, we outline our current knowledge on the diversity of bat viromes, particularly through the lens of metagenomic next-generation sequencing and in the context of disease emergence. A key conclusion is that although bats harbour abundant virus diversity, the vast majority of bat viruses have not emerged to cause disease in new hosts such that bats are better regarded as critical but endangered components of global ecosystems.

Australian hospital outpatient pharmacies: service adaptations during the 2020 national coronavirus disease 2019 lockdown

2022-01-01T00:00:00Z

Australian hospital outpatient pharmacies: service adaptations during the 2020 national coronavirus disease 2019 lockdown Wise, Sarah; Coleshill, Matthew J.; Taylor, Natalie; Le, Michelle; Debono, Deborah; Day, Richard O.; Melocco, Terry; Baysari, Melissa T.; Laba, Tracey‐Lea; Carland, Jane E.

Educational attainment and willingness to use technology for health and to share health information – The reimagining healthcare survey

2022-01-01T00:00:00Z

Educational attainment and willingness to use technology for health and to share health information – The reimagining healthcare survey Lee, Crystal Man Ying; Thomas, Elizabeth; Norman, Richard; Wells, Leanne; Shaw, Tim; Nesbitt, Julia; Frean, Isobel; Baxby, Luke; Bennett, Sabine; Robinson, Suzanne BACKGROUND: Australia has seen a rapid uptake of virtual care since the start of the COVID-19 pandemic. We aimed to describe the willingness of consumers to use digital technology for health and to share their health information; and explore differences by educational attainment and area of remoteness. METHODS: We conducted an online survey on consumer preferences for virtual modes of healthcare delivery between June and September 2021. Participants were recruited through the study's partner organisations and an online market research company. Australian residents aged ≥18 years who provided study consent and completed the survey were included in the analysis. We reported the weighted percentages of participants who selected negative response to the questions to understand the size of the population that were unlikely to adopt virtual care. Age-adjusted Poisson regression models were used to estimate the prevalence ratios for selecting negative response associated with education and remoteness. RESULTS: Of the 1778 participants included, 29% were not aware of digital technologies for monitoring/supporting health, 22% did not have access to technologies to support their health, and 19% were not willing to use technologies for health. Over a fifth of participants (range: 21-34%) were not at all willing to use seven of the 15 proposed alternative methods of care. Between 21% and 36% of participants were not at all willing to share de-identified health information tracked in apps/devices with various not-for-profit organisations compared to 47% with private/for-profit health businesses. Higher proportions of participants selected negative response to the questions in the lower educational attainment groups than those with bachelor's degree or above. No difference was observed between area of remoteness. CONCLUSIONS: Improving the digital health literacy of people, especially those with lower educational attainment, will be required for virtual care to become an equitable part of normal healthcare delivery in Australia.

Molecular Monitoring of SARS-CoV‑2 in Different Sewage Plants in Venice and the Implications for Genetic Surveillance

2022-01-01T00:00:00Z

Molecular Monitoring of SARS-CoV‑2 in Different Sewage Plants in Venice and the Implications for Genetic Surveillance Brian, Irene; Manuzzi, Alice; Rovere, Giulia Dalla; Giussani, Edoardo; Palumbo, Elisa; Fusaro, Alice; Bonfante, Francesco; Bortolami, Alessio; Quaranta, Erika Giorgia; Monne, Isabella; Patarnello, Tomaso; Bargelloni, Luca; Terregino, Calogero; Holmes, Edward C.; Todesco, Giovanna; Sorrentino, Francesco; Berton, Andrea; Badetti, Christian; Carrer, Claudio; Ferrari, Giorgio; Zincone, Cinzia; Milan, Massimo; Panzarin, Valentina The analysis of different samples from the purification lines in WWTPs provides valuable data on SARS-CoV-2 prevalence, the predominant variants, and decontamination efficacy.

Antiviral cyclic peptides targeting the main protease of SARS-CoV-2

2022-01-01T00:00:00Z

Antiviral cyclic peptides targeting the main protease of SARS-CoV-2 Johansen-Leete, Jason; Ullrich, Sven; Fry, Sarah E.; Frkic, Rebecca; Bedding, Max J.; Aggarwal, Anupriya; Ashhurst, Anneliese S.; Ekanayake, Kasuni B.; Mahawaththa, Mithun C.; Sasi, Vishnu M.; Luedtke, Stephanie; Ford, Daniel J.; O'Donoghue, Anthony J.; Passioura, Toby; Larance, Mark; Otting, Gottfried; Turville, Stuart; Jackson, Colin J.; Nitsche, Christoph; Payne, Richard J. Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (Mpro) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 Mpro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of Mpro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these Mpro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.

Co-infection with SARS-CoV-2 Omicron and Delta variants revealed by genomic surveillance

2022-01-01T00:00:00Z

Co-infection with SARS-CoV-2 Omicron and Delta variants revealed by genomic surveillance Rockett, Rebecca J.; Draper, Jenny; Gall, Mailie; Sim, Eby M.; Arnott, Alicia; Agius, Jessica E.; Johnson-Mackinnon, Jessica; Fong, Winkie; Martinez, Elena; Drew, Alexander P.; Lee, Clement; Ngo, Christine; Ramsperger, Marc; Ginn, Andrew N.; Wang, Qinning; Fennell, Michael; Ko, Danny; Hueston, Linda; Kairaitis, Lukas; Holmes, Edward C.; O’Sullivan, Matthew N.; Chen, Sharon C.-A.; Kok, Jen; Dwyer, Dominic E.; Sintchenko, Vitali Co-infections with different variants of SARS-CoV-2 are a key precursor to recombination events that are likely to drive SARS-CoV-2 evolution. Rapid identification of such co-infections is required to determine their frequency in the community, particularly in populations at-risk of severe COVID-19, which have already been identified as incubators for punctuated evolutionary events. However, limited data and tools are currently available to detect and characterise the SARS-CoV-2 co-infections associated with recognised variants of concern. Here we describe co-infection with the SARS-CoV-2 variants of concern Omicron and Delta in two epidemiologically unrelated adult patients with chronic kidney disease requiring maintenance haemodialysis. Both variants were co-circulating in the community at the time of detection. Genomic surveillance based on amplicon- and probe-based sequencing using short- and long-read technologies identified and quantified subpopulations of Delta and Omicron viruses in respiratory samples. These findings highlight the importance of integrated genomic surveillance in vulnerable populations and provide diagnostic pathways to recognise SARS-CoV-2 co-infection using genomic data.

Co-infection with SARS-COV-2 Omicron and Delta Variants Revealed by Genomic Surveillance

2022-01-01T00:00:00Z

Co-infection with SARS-COV-2 Omicron and Delta Variants Revealed by Genomic Surveillance Rockett, Rebecca J; Draper, Jenny; Gall, Mailie; Sim, Eby M; Arnott, Alicia; Agius, Jessica E; Johnson-Mackinnon, Jessica; Martinez, Elena; Drew, Alexander P; Lee, Clement; Ngo, Christine; Ramsperger, Marc; Ginn, Andrew N; Wang, Qinning; Fennell, Michael; Ko, Danny; Huston, Linda; Kairaitis, Lukas; Holmes, Edward C.; O'Sullivan, Matthew N; Chen, Sharon C-A; Kok, Jen; Dwyer, Dominic E; Sintchenko, Vitali We identified the co-infection of the SARS-CoV-2 Omicron and Delta variants in two epidemiologically unrelated patients with chronic kidney disease requiring haemodialysis. Both SARS-CoV-2 variants were co-circulating locally at the time of detection. Amplicon- and probe-based sequencing using short- and long-read technologies identified and quantified Omicron and Delta subpopulations in respiratory samples from the two patients. These findings highlight the importance of genomic surveillance in vulnerable populations.

Virome characterization of game animals in China reveals a spectrum of emerging pathogens

2022-01-01T00:00:00Z

Virome characterization of game animals in China reveals a spectrum of emerging pathogens He, Wan-Ting; Hou, Xin; Zhao, Jin; Sun, Jiumeng; He, Haijian; Si, Wei; Wang, Jing; Jiang, Zhiwen; Yan, Ziqing; Xing, Gang; Lu, Meng; Suchard, Marc A.; Ji, Xiang; Gong, Wenjie; He, Biao; Li, Jun; Lemey, Philippe; Guo, Deyin; Tu, Changchun; Holmes, Edward C.; Shi, Mang; Su, Shuo Game animals are wildlife species traded and consumed as food, and potential reservoirs for SARS-CoV and SARS-CoV-2. We performed a meta-transcriptomic analysis of 1941 game animals, representing 18 species and five mammalian orders, sampled across China. From this we identified 102 mammalian-infecting viruses, with 65 described for the first time. Twenty-one viruses were considered as potentially high risk to humans and domestic animals. Civets (Paguma larvata) carried the highest number of potentially high-risk viruses. We inferred the transmission of Bat coronavirus HKU8 from bats to civets, as well as cross-species jumps of coronaviruses from bats to hedgehogs, from birds to porcupines, and from dogs to raccoon dogs. Of note, we identified avian Influenza A virus H9N2 in civets and Asian badgers, with the latter displaying respiratory symptoms, as well as cases of likely human-to-wildlife virus transmission. These data highlight the importance of game animals as potential drivers of disease emergence.

Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) trial.

2022-01-01T00:00:00Z

Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) trial. Cromer, Deborah; Reynaldi, Arnold; Steain, Megan; Triccas, James A; Davenport, Miles P; Khoury, David S The vaccine candidate CVnCoV (CUREVAC) showed surprisingly low efficacy in a recent phase 3 trial compared with other mRNA vaccines. Here we show that the low efficacy follows from the dose used and the presence of SARS-CoV-2 variants, and is predicted by the neutralising antibody response induced by the vaccine.

Understanding STEM academics' responses and resilience to educational reform of academic roles in higher education

2022-01-01T00:00:00Z

Understanding STEM academics' responses and resilience to educational reform of academic roles in higher education Ross, Pauline Mary; Scanes, E.; Poronnik, P.; Coates, H.; Locke, W. Background: Across the globe, there have been significant reforms to improve STEM education at all levels. A significant part of this has been teacher reform. While the responses and resilience of STEM teachers to educational reforms in secondary education have received significant attention, the responses and resilience of STEM teachers in higher education remains understudied. In higher education, educational reforms of academic roles have seen increasing numbers of STEM academics focussed on education. Responses of STEM academics to education reform of the academic role have some parallels with teacher resilience, but there are also potential misalignments within a culture which values and prioritises science disciplinary research. This study examined the responses of STEM academics in higher education to educational reform of the academic role using the theoretical construct of resilience and Bronfenbrenner's socio-ecological model. This was a 2-year case study of 32 academics and senior educational leaders in higher education in STEM. Data collection included semi-structured interviews which were theme coded and inductively analysed.ResultsThe responses and resilience of STEM academics focussed on education appeared to be dependent on interactions between individual disposition in the microsystem and influences of the exosystem and the external macrosystem. Five major themes emerged about the value and quality, scholarship and expertise, progress and mobility, status and identity and community and culture of STEM academics focussed on education. The exosystem was a significant unidirectional influence on STEM academics where judgements were made concerning academic performance, awards, and promotion. Responses of senior leaders in the exosystem were influenced by the macrosystem and culture of science. Academics focussed on research, rather than education were more valued and more likely to be both financially rewarded and promoted.ConclusionDuring this pressured decade, where COVID-19 has intensified stress, more attention on the direction and reciprocal relationships in the socio-ecological model of higher education is needed in order for educational reform in higher education STEM to be effective. Resilience of STEM academics to educational reform in higher education is a dynamic quality, and the capacity to "bounce back", learn from challenges, and realise expectations of educational reform will depend on an understanding of resilience and support of Bronfenbrenner's spheres of influence.

Replacement of the Gamma by the Delta variant in Brazil: Impact of lineage displacement on the ongoing pandemic

2022-01-01T00:00:00Z

Replacement of the Gamma by the Delta variant in Brazil: Impact of lineage displacement on the ongoing pandemic Giovanetti, Marta; Fonseca, Vagner; Wilkinson, Eduan; Tegally, Houriiyah; San, Emmanuel James; Althaus, Christian L; Xavier, Joilson; Nanev Slavov, Svetoslav; Viala, Vincent Louis; Ranieri Jerônimo Lima, Alex; Ribeiro, Gabriela; Souza-Neto, Jayme A; Fukumasu, Heidge; Lehmann Coutinho, Luiz; Venancio da Cunha, Rivaldo; Freitas, Carla; Campelo de A E Melo, Carlos F; Navegantes de Araújo, Wildo; Do Carmo Said, Rodrigo Fabiano; Almiron, Maria; de Oliveira, Tulio; Coccuzzo Sampaio, Sandra; Elias, Maria Carolina; Covas, Dimas Tadeu; Holmes, Edward C; Lourenço, José; Kashima, Simone; de Alcantara, Luiz Carlos Junior The coronavirus disease 2019 (COVID-19) epidemic in Brazil was driven mainly by the spread of Gamma (P.1), a locally emerged variant of concern (VOC) that was first detected in early January 2021. This variant was estimated to be responsible for more than 96_per cent of cases reported between January and June 2021, being associated with increased transmissibility and disease severity, a reduction in neutralization antibodies and effectiveness of treatments or vaccines, and diagnostic detection failure. Here we show that, following several importations predominantly from the USA, the Delta variant rapidly replaced Gamma after July 2021. However, in contrast to what was seen in other countries, the rapid spread of Delta did not lead to a large increase in the number of cases and deaths reported in Brazil. We suggest that this was likely due to the relatively successful early vaccination campaign coupled with natural immunity acquired following prior infection with Gamma. Our data reinforce reports of the increased transmissibility of the Delta variant and, considering the increasing concern due to the recently identified Omicron variant, argues for the necessity to strengthen genomic monitoring on a national level to quickly detect the emergence and spread of other VOCs that might threaten global health.

Diversity and evolution of the animal virome

2022-01-01T00:00:00Z

Diversity and evolution of the animal virome Harvey, Erin; Holmes, Edward C. The COVID-19 pandemic has given the study of virus evolution and ecology new relevance. Although viruses were first identified more than a century ago, we likely know less about their diversity than that of any other biological entity. Most documented animal viruses have been sampled from just two phyla - the Chordata and the Arthropoda - with a strong bias towards viruses that infect humans or animals of economic and social importance, often in association with strong disease phenotypes. Fortunately, the recent development of unbiased metagenomic next-generation sequencing is providing a richer view of the animal virome and shedding new light on virus evolution. In this Review, we explore our changing understanding of the diversity, composition and evolution of the animal virome. We outline the factors that determine the phylogenetic diversity and genomic structure of animal viruses on evolutionary timescales and show how this impacts assessment of the risk of disease emergence in the short term. We also describe the ongoing challenges in metagenomic analysis and outline key themes for future research. A central question is how major events in the evolutionary history of animals, such as the origin of the vertebrates and periodic mass extinction events, have shaped the diversity and evolution of the viruses they carry.

Assessment of Coronavirus Disease 2019 Intervention Strategies in the Nordic Countries Using Genomic Epidemiology

2022-01-01T00:00:00Z

Assessment of Coronavirus Disease 2019 Intervention Strategies in the Nordic Countries Using Genomic Epidemiology Duchene, Sebastian; Featherstone, Leo; Freiesleben de Blasio, Birgitte; Holmes, Edward C.; Bohlin, Jon; Pettersson, John H O We explored how the duration, size, and number of virus transmission clusters, defined as country-specific monophyletic groups in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) phylogenetic tree, differed among the Nordic countries of Norway, Sweden, Denmark, Finland, and Iceland. Our results suggest that although geographical connectivity, population density, and openness influence the spread and the size of SARS-CoV-2 transmission clusters, the different country-specific intervention strategies had the largest impact. We also found a significant positive association between the size and duration of transmission clusters in the Nordic countries, suggesting that the rapid deployment of contact tracing is a key response measure in reducing virus transmission.

COVID-19 - lessons for zoonotic disease

2022-01-01T00:00:00Z

COVID-19 - lessons for zoonotic disease Holmes, Edward C. Disease emergence is driven by human-animal contact in a global viral ecosystem.

Total infectome characterization of respiratory infections in pre-COVID-19 Wuhan, China

2022-01-01T00:00:00Z

Total infectome characterization of respiratory infections in pre-COVID-19 Wuhan, China Shi, Mang; Zhao, Su; Yu, Bin; Wu, Wei-Chen; Hu, Yi; Tian, Jun-Hua; Yin, Wen; Ni, Fang; Hu, Hong-Ling; Geng, Shuang; Tan, Li; Peng, Ying; Song, Zhi-Gang; Wang, Wen; Chen, Yan-Mei; Holmes, Edward C.; Zhang, Yong-Zhen At the end of 2019 Wuhan witnessed an outbreak of "atypical pneumonia" that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus denoted SARS-CoV-2. To provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their "total infectome", including viruses, bacteria and fungi. We identified 35 pathogen species, comprising 13 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (13.5%). SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen-Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.

High-Titer Neutralizing Antibodies against the SARS-CoV-2 Delta Variant Induced by Alhydroxyquim-II-Adjuvanted Trimeric Spike Antigens

2022-01-01T00:00:00Z

High-Titer Neutralizing Antibodies against the SARS-CoV-2 Delta Variant Induced by Alhydroxyquim-II-Adjuvanted Trimeric Spike Antigens Counoupas, Claudio; Pino, Paco; Stella, Alberto O.; Ashley, Caroline; Lukeman, Hannah; Bhattacharyya, Nayan D.; Tada, Takuya; Anchisi, Stephanie; Metayer, Charles; Martinis, Jacopo; Aggarwal, Anupriya; Dcosta, Belinda M.; Britton, Warwick J.; Kint, Joeri; Wurm, Maria J.; Landau, Nathaniel R.; Steain, Megan; Turville, Stuart G.; Wurm, Florian M.; David, Sunil A.; Triccas, James A. Global control of COVID-19 will require the deployment of vaccines capable of inducing long-term protective immunity against SARS-CoV-2 variants. In this report, we describe an adjuvanted subunit candidate vaccine that affords elevated, sustained, and cross-variant SARS-CoV-2 neutralizing antibodies (NAbs) in multiple animal models. Alhydroxiquim-II is a Toll-Like Receptor (TLR) 7/8 small-molecule agonist chemisorbed on aluminum hydroxide (Alhydrogel). Vaccination with Alhydroxiquim-II combined with a stabilized, trimeric form of the SARS-CoV-2 spike protein (termed CoVac-II) resulted in high-titer NAbs in mice, with no decay in responses over an 8-month period. NAbs from sera of CoVac-II-immunized mice, horses and rabbits were broadly neutralizing against SARS-CoV-2 variants. Boosting long-term CoVac-II-immunized mice with adjuvanted spike protein from the Beta variant markedly increased levels of NAb titers against multiple SARS-CoV-2 variants; notably, high titers against the Delta variant were observed. These data strongly support the clinical assessment of Alhydroxiquim-II-adjuvanted spike proteins to protect against SARS-CoV-2 variants of concern. IMPORTANCE There is an urgent need for next-generation COVID-19 vaccines that are safe, demonstrate high protective efficacy against SARS-CoV-2 variants and can be manufactured at scale. We describe a vaccine candidate (CoVac-II) that is based on stabilized, trimeric spike antigen produced in an optimized, scalable and chemically defined production process. CoVac-II demonstrates strong and persistent immunity after vaccination of mice, and is highly immunogenic in multiple animal models, including rabbits and horses. We further show that prior immunity can be boosted using a recombinant spike antigen from the Beta variant; importantly, plasma from boosted mice effectively neutralize multiple SARS-CoV-2 variants in vitro, including Delta. The strong humoral and Th1-biased immunogenicity of CoVac-II is driven by use of Alhydroxiquim-II (AHQ-II), the first adjuvant in an authorized vaccine that acts through the dual Toll-like receptor (TLR)7 and TLR8 pathways, as part of the Covaxin vaccine. Our data suggest AHQ-II/spike protein combinations could constitute safe, affordable, and mass-manufacturable COVID-19 vaccines for global distribution.

Co-infecting pathogens can contribute to inflammatory responses and severe symptoms in COVID-19

2022-01-01T00:00:00Z

Co-infecting pathogens can contribute to inflammatory responses and severe symptoms in COVID-19 Chen, Liping; Shen, Lihan; Wu, Weichen; Guan, Wenda; Zhou, Jinchao; Luo, Gengyan; Chen, Qimin; Zhou, Hongxia; Deng, Zhenxuan; Chen, Yaoqing; Zhao, Wenjing; Jin, Wenxiang; Qiu, Minshan; Zheng, Qianwei; Wang, Yutao; Liu, Chen; Bai, Xiangxiang; Guo, Deyin; Holmes, Edward C.; Zhong, Nanshan; Shi, Mang; Yang, Zifeng Background: The current COVID-19 pandemic is posing a major challenge to public health on a global scale. While it is generally believed that severe COVID-19 results from over-expression of inflammatory mediators (i.e., a "cytokine storm"), it is still unclear whether and how co-infecting pathogens contribute to disease pathogenesis. To address this, we followed the entire course of the disease in cases with severe or critical COVID-19 to determine the presence and abundance of all potential pathogens present-the total "infectome"-and how they interact with the host immune system in the context of severe COVID-19. Methods: We examined one severe and three critical cases of COVID-19, as well as a set of healthy controls, with longitudinal samples (throat swab, whole blood, and serum) collected from each case. Total RNA sequencing (meta-transcriptomics) was performed to simultaneously investigate pathogen diversity and abundance, as well as host immune responses, in each sample. A Bio-Plex method was used to measure serum cytokine and chemokine levels. Results: Eight pathogens, SARS-CoV-2, Aspergillus fumigatus (A. fumigatus), Mycoplasma orale (M. orale), Myroides odoratus (M. odoratus), Acinetobacter baumannii (A. baumannii), Candida tropicalis, herpes simplex virus (HSV) and human cytomegalovirus (CMV), identified in patients with COVID-19 appeared at different stages of the disease. The dynamics of inflammatory mediators in serum and the respiratory tract were more strongly associated with the dynamics of the infectome compared with SARS-CoV-2 alone. Correlation analysis revealed that pulmonary injury was directly associated with cytokine levels, which in turn were associated with the proliferation of SARS-CoV-2 and co-infecting pathogens. Conclusions: For each patient, the cytokine storm that resulted in acute lung injury and death involved a dynamic and highly complex infectome, of which SARS-CoV-2 was a component. These results indicate the need for a precision medicine approach to investigate both the infection and host response as a standard means of infectious disease characterization.

A Public Health Research Agenda for Managing Infodemics: Methods and Results of the First WHO Infodemiology Conference

2021-01-01T00:00:00Z

A Public Health Research Agenda for Managing Infodemics: Methods and Results of the First WHO Infodemiology Conference Calleja, Neville; AbdAllah, AbdelHalim; Abad, Neetu; Ahmed, Naglaa; Albarracin, Dolores; Altieri, Elena; Anoko, Julienne N; Arcos, Ruben; Azlan, Arina Anis; Bayer, Judit; Bechmann, Anja; Bezbaruah, Supriya; Briand, Sylvie C; Brooks, Ian; Bucci, Lucie M; Burzo, Stefano; Czerniak, Christine; De Domenico, Manlio; Dunn, Adam G; Ecker, Ullrich K H; Espinosa, Laura; Francois, Camille; Gradon, Kacper; Gruzd, Anatoliy; Gülgün, Beste Sultan; Haydarov, Rustam; Hurley, Cherstyn; Astuti, Santi Indra; Ishizumi, Atsuyoshi; Johnson, Neil; Johnson Restrepo, Dylan; Kajimoto, Masato; Koyuncu, Aybüke; Kulkarni, Shibani; Lamichhane, Jaya; Lewis, Rosamund; Mahajan, Avichal; Mandil, Ahmed; McAweeney, Erin; Messer, Melanie; Moy, Wesley; Ndumbi Ngamala, Patricia; Nguyen, Tim; Nunn, Mark; Omer, Saad B; Pagliari, Claudia; Patel, Palak; Phuong, Lynette; Prybylski, Dimitri; Rashidian, Arash; Rempel, Emily; Rubinelli, Sara; Sacco, PierLuigi; Schneider, Anton; Shu, Kai; Smith, Melanie; Sufehmi, Harry; Tangcharoensathien, Viroj; Terry, Robert; Thacker, Naveen; Trewinnard, Tom; Turner, Shannon; Tworek, Heidi; Uakkas, Saad; Vraga, Emily; Wardle, Claire; Wasserman, Herman; Wilhelm, Elisabeth; Würz, Andrea; Yau, Brian; Zhou, Lei; Purnat, Tina D Background: An infodemic is an overflow of information of varying quality that surges across digital and physical environments during an acute public health event. It leads to confusion, risk-taking, and behaviors that can harm health and lead to erosion of trust in health authorities and public health responses. Owing to the global scale and high stakes of the health emergency, responding to the infodemic related to the pandemic is particularly urgent. Building on diverse research disciplines and expanding the discipline of infodemiology, more evidence-based interventions are needed to design infodemic management interventions and tools and implement them by health emergency responders. Objective: The World Health Organization organized the first global infodemiology conference, entirely online, during June and July 2020, with a follow-up process from August to October 2020, to review current multidisciplinary evidence, interventions, and practices that can be applied to the COVID-19 infodemic response. This resulted in the creation of a public health research agenda for managing infodemics. Methods: As part of the conference, a structured expert judgment synthesis method was used to formulate a public health research agenda. A total of 110 participants represented diverse scientific disciplines from over 35 countries and global public health implementing partners. The conference used a laddered discussion sprint methodology by rotating participant teams, and a managed follow-up process was used to assemble a research agenda based on the discussion and structured expert feedback. This resulted in a five-workstream frame of the research agenda for infodemic management and 166 suggested research questions. The participants then ranked the questions for feasibility and expected public health impact. The expert consensus was summarized in a public health research agenda that included a list of priority research questions. Results: The public health research agenda for infodemic management has five workstreams: (1) measuring and continuously monitoring the impact of infodemics during health emergencies; (2) detecting signals and understanding the spread and risk of infodemics; (3) responding and deploying interventions that mitigate and protect against infodemics and their harmful effects; (4) evaluating infodemic interventions and strengthening the resilience of individuals and communities to infodemics; and (5) promoting the development, adaptation, and application of interventions and toolkits for infodemic management. Each workstream identifies research questions and highlights 49 high priority research questions. Conclusions: Public health authorities need to develop, validate, implement, and adapt tools and interventions for managing infodemics in acute public health events in ways that are appropriate for their countries and contexts. Infodemiology provides a scientific foundation to make this possible. This research agenda proposes a structured framework for targeted investment for the scientific community, policy makers, implementing organizations, and other stakeholders to consider.

Emergence and spread of SARS-CoV-2 lineages B.1.1.7 and P.1 in Italy

2021-01-01T00:00:00Z

Emergence and spread of SARS-CoV-2 lineages B.1.1.7 and P.1 in Italy Di Giallonardo, Francesca; Puglia, Ilaria; Curini, Valentina; Cammà, Cesare; Mangone, Iolanda; Calistri, Paolo; Cobbin, Joanna C.A.; Holmes, Edward C.; Lorusso, Alessio Italy’s second wave of SARS-CoV-2 has hit hard, with more than 3 million cases and over 100,000 deaths, representing an almost ten-fold increase on the numbers reported by August 2020. Herein, we present the analysis of 6,515 SARS-CoV-2 sequences sampled in Italy between 29 th January 2020 and 1 st March 2021 and show how different lineages emerged multiple times independently despite lockdown restrictions. Virus lineage B.1.177 became the dominant variant in November 2020, when cases peaked at 40,000 a day, but since January 2021 this is being replaced by the B.1.1.7 ‘variant of concern’. In addition, we report a sudden increase in another documented variant of concern – lineage P.1 – from December 2020 onwards, most likely caused by a single introduction into Italy. We again highlight how international importations drive the emergence of new lineages and that genome sequencing should remain a top priority for ongoing surveillance in Italy.

Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) trial

2021-01-01T00:00:00Z

Relating in vitro neutralisation level and protection in the CVnCoV (CUREVAC) trial Cromer, Deborah; Reynaldi, Arnold; Steain, Megan; Triccas, James A; Davenport, Miles P; Khoury, David S Abstract A recent study analysed the relationship between neutralising antibody response and protection from SARS-CoV-2 infection across eight vaccine platforms 1 . The efficacy results from a phase 2b/3 trial of a ninth vaccine candidate, CVnCoV (CUREVAC), was announced on 16 June 2021 2 . The low efficacy of this new mRNA vaccine, which showed only 47% protection from symptomatic SARS-CoV-2 infection, was surprising given the high efficacy of two previous mRNA-based vaccines 3,4 . A number of factors have been suggested to play a role in the low efficacy in the CVnCoV study, particularly around the dose and immunogenicity of the vaccine (which uses an unmodified mRNA construct 5,6 ) and the potential role of infection with SARS-CoV-2 variants (which were the dominant strains observed in the CVnCoV trial) 2 .

Total virome characterizations of game animals in China reveals a spectrum of emerging viral pathogens

2021-01-01T00:00:00Z

Total virome characterizations of game animals in China reveals a spectrum of emerging viral pathogens He, Wan-Ting; Hou, Xin; Zhao, Jin; Sun, Jiumeng; He, Haijian; Si, Wei; Wang, Jing; Jiang, Zhiwen; Yan, Ziqing; Xing, Gang; Lu, Meng; Suchard, Marc A.; Ji, Xiang; Gong, Wenjie; He, Biao; Li, Jun; Lemey, Philippe; Guo, Deyin; Tu, Changchun; Holmes, Edward C.; Shi, Mang; Su, Shuo Game animals are wildlife species often traded and consumed as exotic food, and are potential reservoirs for SARS-CoV and SARS-CoV-2. We performed a meta-transcriptomic analysis of 1725 game animals, representing 16 species and five mammalian orders, sampled across China. From this we identified 71 mammalian viruses, with 45 described for the first time. Eighteen viruses were considered as potentially high risk to humans and domestic animals. Civets (Paguma larvata) carried the highest number of potentially high risk viruses. We identified the transmission of Bat coronavirus HKU8 from a bat to a civet, as well as cross-species jumps of coronaviruses from bats to hedgehogs and from birds to porcupines. We similarly identified avian Influenza A virus H9N2 in civets and Asian badgers, with the latter displaying respiratory symptoms, as well as cases of likely human-to-wildlife virus transmission. These data highlight the importance of game animals as potential drivers of disease emergence. 1725 game animals from five mammalian orders were surveyed for viruses 71 mammalian viruses were discovered, 18 with a potential risk to humans Civets harbored the highest number of potential 'high risk' viruses A species jump of an alphacoronavirus from bats to a civet was identified H9N2 influenza virus was detected in a civet and an Asian badger Humans viruses were also identified in game animals

Pathogenicity and transmissibility of a novel respirovirus isolated from a Malayan pangolin.

2021-01-01T00:00:00Z

Pathogenicity and transmissibility of a novel respirovirus isolated from a Malayan pangolin. Yang, Rou; Peng, Jinyu; Zhai, Junqiong; Xiao, Kangpeng; Zhang, Xu; Li, Xiaobing; Chen, Xiaoyuan; Chen, Zu-Jin; Holmes, Edward C.; Irwin, David M.; Shan, Fen; Shen, Xuejuan; Chen, Wu; Shen, Yongyi The identification of SARS-CoV-2-like viruses in Malayan pangolins (Manis javanica) has focused attention on these endangered animals and the viruses they carry. We successfully isolated a novel respirovirus from the lungs of a dead Malayan pangolin. Similar to murine respirovirus, the full-length genome of this novel virus was 15_384 nucleotides comprising six genes in the order 3'-(leader)-NP-P-M-F-HN-l-(trailer)-5'. Phylogenetic analysis revealed that this virus belongs to the genus Respirovirus and is most closely related to murine respirovirus. Notably, animal infection experiments indicated that the pangolin virus is highly pathogenic and transmissible in mice, with inoculated mice having variable clinical symptoms and a fatality rate of 70.37_%. The virus was found to replicate in most tissues with the exception of muscle and heart. Contact transmission of the virus was 100_% efficient, although the mice in the contact group displayed milder symptoms, with the virus mainly being detected in the trachea and lungs. The isolation of a novel respirovirus from the Malayan pangolin provides new insight into the evolution and distribution of this important group of viruses and again demonstrates the potential infectious disease threats faced by endangered pangolins.

IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study

2021-01-01T00:00:00Z

IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study Shojaei, Maryam; Shamshirian, Amir; Monkman, James; Grice, Laura; Tran, Minh; Tan, Chin Wee; Rossi, Gustavo Rodrigues; McCulloch, Timothy R.; Nalos, Marek; Chew, Keng Yih; Zhu, Yanshan; Xia, Yao; Wells, Timothy J.; Senegaglia, Alexandra Cristina; Rebelatto, Carmen Lúcia Kuniyoshi; Franck, Claudio Luciano; dos Santos, Anna Flavia Ribeiro; de Noronha, Lucia; Motamen, Sepideh; Valadan, Reza; Amjadi, Omolbanin; Gogna, Rajan; Madan, Esha; Alizadeh-Navaei, Reza; Lamperti, Liliana; Zuñiga, Felipe; Nova-Lamperti, Estefania; Labarca, Gonzalo; Knippenberg, Ben; Herwanto, Velma; Wang, Ya; Phu, Amy; Chew, Tracy; Kwan, Timothy; Kim, Karan; Teoh, Sally; Pelaia, Tiana M; Kuan, Win Sen; Jee, Yvette; Iredell, Jon; O’Byrne, Ken; Fraser, John F.; Davis, Melissa J.; Belz, Gabrielle; Warkiani, Majid; Gallo, Carlos Salomon; Souza-Fonseca-Guimaraes, Fernando; Nguyen, Quan; Mclean, Anthony; Kulasinghe, Arutha; Short, Kirsty R.; Tang, Benjamin Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus. We searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms “IFI27”, “COVID-19, “gene expression” and “outcome prediction”. We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of “gene expression” and “COVID-19”, IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic. Here, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic. This is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.

The impact of public health interventions in the Nordic countries during the first year of SARS-CoV-2 transmission and evolution.

2021-01-01T00:00:00Z

The impact of public health interventions in the Nordic countries during the first year of SARS-CoV-2 transmission and evolution. Duchene, Sebastian; Featherstone, Leo; Freiesleben de Blasio, Birgitte; Holmes, Edward C.; Bohlin, Jon; Pettersson, John H-O BackgroundMany countries have attempted to mitigate and control COVID-19 through non-pharmaceutical interventions, particularly with the aim of reducing population movement and contact. However, it remains unclear how the different control strategies impacted the local phylodynamics of the causative SARS-CoV-2 virus.AimWe aimed to assess the duration of chains of virus transmission within individual countries and the extent to which countries exported viruses to their geographical neighbours.MethodsWe analysed complete SARS-CoV-2 genomes to infer the relative frequencies of virus importation and exportation, as well as virus transmission dynamics, in countries of northern Europe. We examined virus evolution and phylodynamics in Denmark, Finland, Iceland, Norway and Sweden during the first year of the COVID-19 pandemic.ResultsThe Nordic countries differed markedly in the invasiveness of control strategies, which we found reflected in transmission chain dynamics. For example, Sweden, which compared with the other Nordic countries relied more on recommendation-based rather than legislation-based mitigation interventions, had transmission chains that were more numerous and tended to have more cases. This trend increased over the first 8 months of 2020. Together with Denmark, Sweden was a net exporter of SARS-CoV-2. Norway and Finland implemented legislation-based interventions; their transmission chain dynamics were in stark contrast to their neighbouring country Sweden.ConclusionSweden constituted an epidemiological and evolutionary refugium that enabled the virus to maintain active transmission and spread to other geographical locations. Our analysis reveals the utility of genomic surveillance where monitoring of active transmission chains is a key metric.

Vaccine nationalism and the dynamics and control of SARS-CoV-2

2021-01-01T00:00:00Z

Vaccine nationalism and the dynamics and control of SARS-CoV-2 Wagner, Caroline E.; Saad-Roy, Chadi M.; Morris, Sinead E.; Baker, Rachel E.; Mina, Michael J.; Farrar, Jeremy; Holmes, Edward C.; Pybus, Oliver G.; Graham, Andrea L.; Emanuel, Ezekiel J.; Levin, Simon A.; Metcalf, C. Jessica E.; Grenfell, Bryan T. Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing SARS-CoV-2 pandemic continues to exert globally, yet vaccine distribution remains unequal between countries. To examine the potential epidemiological and evolutionary impacts of 'vaccine nationalism', we extend previous models to include simple scenarios of stockpiling. In general, we find that stockpiling vaccines by countries with high availability leads to large increases in infections in countries with low vaccine availability, the magnitude of which depends on the strength and duration of natural and vaccinal immunity. Additionally, a number of subtleties arise when the populations and transmission rates in each country differ depending on evolutionary assumptions and vaccine availability. Furthermore, the movement of infected individuals between countries combined with the possibility of increases in viral transmissibility may greatly magnify local and combined infection numbers, suggesting that countries with high vaccine availability must invest in surveillance strategies to prevent case importation. Dose-sharing is likely a high-return strategy because equitable allocation brings non-linear benefits and also alleviates costs of surveillance (e.g. border testing, genomic surveillance) in settings where doses are sufficient to maintain cases at low numbers. Across a range of immunological scenarios, we find that vaccine sharing is also a powerful tool to decrease the potential for antigenic evolution, especially if infections after the waning of natural immunity contribute most to evolutionary potential. Overall, our results stress the importance of equitable global vaccine distribution.

The role of gene segment interactions in driving the emergence of dominant gene constellations during influenza virus reassortment

2021-01-01T00:00:00Z

The role of gene segment interactions in driving the emergence of dominant gene constellations during influenza virus reassortment Trifkovic, Sanja; Gilbertson, Brad; Fairmaid, Emily; Cobbin, Joanna; Rockman, Steven; Brown, Lorena E. Abstract A segmented genome enables influenza virus to undergo reassortment when two viruses infect the same cell. Resulting reassorted progeny have a spectrum of gene constellations and potentially different phenotypes. Although reassortment is involved in the creation of pandemic influenza strains and is routinely used to produce influenza vaccines, our understanding of the factors that drive the emergence of dominant gene constellations during this process is incomplete. Using an influenza vaccine seed production model, reassortant genotypes were tracked through the reassortment process under antibody selective pressure. We discovered that certain gene constellations conferring low replicative fitness were selected at the expense of more fit progeny. Nevertheless, relatively unfit reassortants likely provide high hemagglutinin antigen yields through co-production of non-infectious particles and/or by more hemagglutinin molecules per virion. Our data illustrate the dynamics and complexity of reassortment and highlight how gene segment interactions formed during packaging, in addition to antibody pressure, restrict the final viruses that dominate.

Infectious disease phylodynamics with occurrence data

2021-01-01T00:00:00Z

Infectious disease phylodynamics with occurrence data Featherstone, Leo A.; Di Giallonardo, Francesca; Holmes, Edward C.; Vaughan, Timothy G.; Duchêne, Sebastián Phylodynamic models use pathogen genome sequence data to infer epidemiological dynamics. With the increasing genomic surveillance of pathogens, especially during the SARS_CoV_2 pandemic, new practical questions about their use are emerging. One such question focuses on the inclusion of un_sequenced case occurrence data alongside sequenced data to improve phylodynamic analyses. This approach can be particularly valuable if sequencing efforts vary over time. Using simulations, we demonstrate that birth-death phylodynamic models can employ occurrence data to eliminate bias in estimates of the basic reproductive number due to misspecification of the sampling process. In contrast, the coalescent exponential model is robust to such sampling biases, but in the absence of a sampling model it cannot exploit occurrence data. Subsequent analysis of the SARS_CoV_2 epidemic in the northwest USA supports these results. We conclude that occurrence data are a valuable source of information in combination with birth-death models. These data should be used to bolster phylodynamic analyses of infectious diseases and other rapidly spreading species in the future.

Innovation During a Pandemic: Developing a Guideline for Infection Prevention and Control to Support Education Through Virtual Reality

2021-01-01T00:00:00Z

Innovation During a Pandemic: Developing a Guideline for Infection Prevention and Control to Support Education Through Virtual Reality Moore, Nathan; Dempsey, Kathy; Hockey, Peter; Jain, Susan; Poronnik, Philip; Shaban, Ramon Z.; Ahmadpour, Naseem

Immune responses in COVID-19 respiratory tract and blood reveal mechanisms of disease severity

2021-01-01T00:00:00Z

Immune responses in COVID-19 respiratory tract and blood reveal mechanisms of disease severity Zhang, Wuji; Chua, Brendon Y.; Selva, Kevin J.; Kedzierski, Lukasz; Ashhurst, Thomas M.; Haycroft, Ebene R.; Shoffner, Suzanne K.; Hensen, Luca; Boyd, David F.; James, Fiona; Mouhtouris, Effie; Kwong, Jason C.; Chua, Kyra Y. L.; Drewett, George; Copaescu, Ana; Dobson, Julie E.; Rowntree, Louise C.; Habel, Jennifer R.; Allen, Lilith F.; Koay, Hui-Fern; Neil, Jessica A.; Gartner, Matthew; Lee, Christina Y.; Andersson, Patiyan; Seemann, Torsten; Sherry, Norelle L.; Amanat, Fatima; Krammer, Florian; Londrigan, Sarah L.; Wakim, Linda M.; King, Nicholas J.C.; Godfrey, Dale I.; Mackay, Laura K.; Thomas, Paul G.; Nicholson, Suellen; Arnold, Kelly B.; Chung, Amy W.; Holmes, Natasha E.; Smibert, Olivia C.; Trubiano, Jason A.; Gordon, Claire L.; Nguyen, Thi H.O.; Kedzierska, Katherine ABSTRACT Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.

Sequence dynamics of three influenza A virus strains grown in different MDCK cell lines, including those expressing different sialic acid receptors

2021-01-01T00:00:00Z

Sequence dynamics of three influenza A virus strains grown in different MDCK cell lines, including those expressing different sialic acid receptors Barnard, Karen N.; Wasik, Brian R.; Alford, Brynn K.; Hayward, Jessica J.; Weichert, Wendy S.; Voorhees, Ian E. H.; Holmes, Edward C.; Parrish, Colin R. Viruses are often cultured in cell lines for research and vaccine development, and those often differ from the natural hosts or tissues. Cell lines can also differ in the presence of virus receptors, such as the sialic acid (Sia) receptors used by influenza A viruses (IAV), which can vary in linkage (_2,3- or _2,6-linkage) and form (N-glycolylneuraminic acid [Neu5Gc] or N-acetylneuraminic acid [Neu5Ac]). The selective pressures resulting from passaging viruses in cell types with host-specific variations in viral receptors are still only partially understood. IAV are commonly cultured in MDCK cells which are both derived from canine kidney tubule epithelium and inherently heterogeneous. MDCK cells naturally present Neu5Ac and _2,3-linked Sia forms. Here, we examine natural MDCK variant lineages, as well as engineered variants that synthesize Neu5Gc and/or _2,6-linkages. We determined how viral genetic variation occurred within human H3N2, H1N1 pandemic and canine H3N2 IAV populations when serially passaged in MDCK cell lines that vary in cell type (MDCK-Type I or MDCK-Type II clones) and in Sia display. Deep sequencing of viral genomes showed small numbers of consensus-level mutations, mostly within the hemagglutinin (HA) gene. Both human IAV showed variants in the HA stem and the HA receptor-binding site of populations passaged in cells displaying Neu5Gc. Canine H3N2 showed variants near the receptor-binding site when passaged in cells displaying Neu5Gc or _2,6-linkages. Viruses replicated to low titres in MDCK-Type II cells, suggesting that not all cell types in heterogeneous MDCK cell populations are equally permissive to infection.

Erratum for Zhao et al., "Structural Basis and Function of the N Terminus of SARS-CoV-2 Nonstructural Protein 1".

2021-01-01T00:00:00Z

Erratum for Zhao et al., "Structural Basis and Function of the N Terminus of SARS-CoV-2 Nonstructural Protein 1". Zhao, Kaitao; Ke, Zunhui; Hu, Hongbing; Liu, Yahui; Li, Aixin; Hua, Rong; Guo, Fangteng; Xiao, Junfeng; Zhang, Yu; Duan, Ling; Yan, Xin-Fu; Gao, Yong-Gui; Liu, Bing; Xia, Yuchen; Li, Yan

Discovery of Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 via mRNA Display

2021-01-01T00:00:00Z

Discovery of Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 via mRNA Display Johansen-Leete, Jason; Ullrich, Sven; Fry, Sarah E.; Frkic, Rebecca; Bedding, Max J.; Aggarwal, Anupriya; Ashhurst, Anneliese S.; Ekanayake, Kasuni B.; Mahawaththa, Mithun C.; Sasi, Vishnu M.; Passioura, Toby; Larance, Mark; Otting, Gottfried; Turville, Stuart; Jackson, Colin J.; Nitsche, Christoph; Payne, Richard J. Abstract Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M pro ) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 M pro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M pro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S 1 and S 2 , respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these M pro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC 50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.

The Origins of SARS-CoV-2: A Critical Review

2021-01-01T00:00:00Z

The Origins of SARS-CoV-2: A Critical Review Holmes, Edward C.; Goldstein, Stephen A.; Rasmussen, Angela L.; Robertson, David L.; Crits-Christoph, Alexander; Wertheim, Joel O.; Anthony, Simon J.; Barclay, Wendy S.; Boni, Maciej F.; Doherty, Peter C.; Farrar, Jeremy; Geoghegan, Jemma L.; Jiang, Xiaowei; Leibowitz, Julian L.; Neil, Stuart J.D.; Skern, Tim; Weiss, Susan R.; Worobey, Michael; Andersen, Kristian G.; Garry, Robert F.; Rambaut, Andrew Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a “laboratory escape” scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.

Neutralising antibodies against the SARS-CoV-2 Delta variant induced by Alhydroxyquim-II-adjuvanted trimeric spike antigens

2021-01-01T00:00:00Z

Neutralising antibodies against the SARS-CoV-2 Delta variant induced by Alhydroxyquim-II-adjuvanted trimeric spike antigens Counoupas, Claudio; Pino, Paco; Stella, Alberto O.; Ashley, Caroline; Lukeman, Hannah; Bhattacharyya, Nayan D.; Tada, Takuya; Anchisi, Stephanie; Metayer, Charles; Martinis, Jacopo; Aggarwal, Anupriya; Dcosta, Belinda M.; Kint, Joeri; Wurm, Maria J; Landau, Nathaniel R.; Steain, Megan; Turville, Stuart G; Wurm, Florian M; David, Sunil A.; Triccas, James A. ABSTRACT Global control of COVID-19 will require the deployment of vaccines capable of inducing long-term protective immunity against SARS-CoV-2 variants. In this report, we describe an adjuvanted subunit candidate vaccine that affords elevated, sustained and cross-variant SARS-CoV-2 neutralising antibodies (NAbs) in multiple animal models. Alhydroxiquim-II is a TLR7/8 small-molecule agonist chemisorbed on aluminium hydroxide. Vaccination with Alhydroxiquim-II combined with a stabilized, trimeric form of the SARS-CoV-2 spike protein (termed CoVac-II) resulted in high-titre NAbs in mice, with no decay in responses over an 8-month period. NAbs from sera of CoVac-II-immunized mice, horses and rabbits were broadly neutralising against SARS-CoV-2 variants. Boosting long-term CoVac-II-immunized mice with adjuvanted spike protein from the Beta variant markedly increased levels of NAb titres against multiple SARS-CoV-2 variants; notably high titres against the Delta variant were observed. These data strongly support the clinical assessment of Alhydroxiquim-II-adjuvanted spike proteins to protect against SARS-CoV-2 variants of concern.

Immunisation of ferrets and mice with recombinant SARS-CoV-2 spike protein formulated with Advax-SM adjuvant protects against COVID-19 infection

2021-01-01T00:00:00Z

Immunisation of ferrets and mice with recombinant SARS-CoV-2 spike protein formulated with Advax-SM adjuvant protects against COVID-19 infection Li, Lei; Honda-Okubo, Yoshikazu; Huang, Ying; Jang, Hyesun; Carlock, Michael A.; Baldwin, Jeremy; Piplani, Sakshi; Bebin-Blackwell, Anne G.; Forgacs, David; Sakamoto, Kaori; Stella, Alberto; Turville, Stuart; Chataway, Tim; Colella, Alex; Triccas, Jamie; Ross, Ted M; Petrovsky, Nikolai The development of a safe and effective vaccine is a key requirement to overcoming the COVID-19 pandemic. Recombinant proteins represent the most reliable and safe vaccine approach but generally require a suitable adjuvant for robust and durable immunity. We used the SARS-CoV-2 genomic sequence and in silico structural modelling to design a recombinant spike protein vaccine (Covax-19™). A synthetic gene encoding the spike extracellular domain (ECD) was inserted into a baculovirus backbone to express the protein in insect cell cultures. The spike ECD was formulated with Advax-SM adjuvant and first tested for immunogenicity in C57BL/6 and BALB/c mice. The Advax-SM adjuvanted vaccine induced high titers of binding antibody against spike protein that were able to neutralise the original wildtype virus on which the vaccine was based as well as the variant B.1.1.7 lineage virus. The Covax-19 vaccine also induced potent spike-specific CD4+ and CD8+ memory T-cells with a dominant Th1 phenotype, and this was shown to be associated with cytotoxic T lymphocyte killing of spike labelled target cells in vivo. Ferrets immunised with Covax-19 vaccine intramuscularly twice 2 weeks apart made spike receptor binding domain (RBD) IgG and were protected against an intranasal challenge with SARS-CoV-2 virus 2 weeks after the second immunisation. Notably, ferrets that received two 25 or 50μg doses of Covax-19 vaccine had no detectable virus in their lungs or in nasal washes at day 3 post-challenge, suggesting the possibility that Covax-19 vaccine may in addition to protection against lung infection also have the potential to block virus transmission. This data supports advancement of Covax-19 vaccine into human clinical trials.

Total Infectomes Characterization of Respiratory Infections in pre-COVID-19 Wuhan, China

2021-01-01T00:00:00Z

Total Infectomes Characterization of Respiratory Infections in pre-COVID-19 Wuhan, China Shi, Mang; Zhao, Su; Yu, Bin; Wu, Wei-Chen; Hu, Yi; Tian, Jun-Hua; Yin, Wen; Ni, Fang; Hu, Hong-Ling; Geng, Shuang; Tan, Li; Peng, Ying; Song, Zhi-Gang; Wang, Wen; Chen, Yan-Mei; Holmes, Edward C.; Zhang, Yong-Zhen At the end of 2019 Wuhan witnessed an outbreak of “atypical pneumonia” that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus - SARS-CoV-2. Herein, to provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their “total infectome”, including viruses, bacteria and fungi. Consequently, we identified 37 pathogen species, comprising 15 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (12.8%). However, SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen – Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.