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1.
Pathogens ; 11(11)2022 Nov 03.
Article in English | MEDLINE | ID: covidwho-2312880

ABSTRACT

In Australia, there is a paucity of data about the extent and impact of zoonotic tick-related illnesses. Even less is understood about a multifaceted illness referred to as Debilitating Symptom Complexes Attributed to Ticks (DSCATT). Here, we describe a research plan for investigating the aetiology, pathophysiology, and clinical outcomes of human tick-associated disease in Australia. Our approach focuses on the transmission of potential pathogens and the immunological responses of the patient after a tick bite. The protocol is strengthened by prospective data collection, the recruitment of two external matched control groups, and sophisticated integrative data analysis which, collectively, will allow the robust demonstration of associations between a tick bite and the development of clinical and pathological abnormalities. Various laboratory analyses are performed including metagenomics to investigate the potential transmission of bacteria, protozoa and/or viruses during tick bite. In addition, multi-omics technology is applied to investigate links between host immune responses and potential infectious and non-infectious disease causations. Psychometric profiling is also used to investigate whether psychological attributes influence symptom development. This research will fill important knowledge gaps about tick-borne diseases. Ultimately, we hope the results will promote improved diagnostic outcomes, and inform the safe management and treatment of patients bitten by ticks in Australia.

2.
PLoS Pathog ; 18(11): e1010951, 2022 11.
Article in English | MEDLINE | ID: covidwho-2140720

ABSTRACT

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all single amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Alpha variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu-1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , Angiotensin-Converting Enzyme 2/genetics , Spike Glycoprotein, Coronavirus , SARS-CoV-2/genetics , COVID-19/genetics , Antibodies, Neutralizing/chemistry , Mutation
3.
Sci Immunol ; : eadf1421, 2022 Nov 10.
Article in English | MEDLINE | ID: covidwho-2116491

ABSTRACT

Numerous safe and effective COVID-19 vaccines have been developed worldwide that utilize various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.

4.
Science ; 378(6620): 619-627, 2022 11 11.
Article in English | MEDLINE | ID: covidwho-2078696

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant-neutralizing antibody that is a strong candidate for clinical development.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , COVID-19 , Immune Evasion , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Neutralization Tests , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Immunologic Memory , Memory B Cells/immunology
5.
JAMA Netw Open ; 5(10): e2236397, 2022 10 03.
Article in English | MEDLINE | ID: covidwho-2059210

ABSTRACT

Importance: Understanding the severity of postvaccination SARS-CoV-2 (ie, COVID-19) breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations. Objective: To estimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection. Design, Setting, and Participants: In this cohort study, the Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration included adults (aged ≥18 years) with HIV who were receiving care and were fully vaccinated by June 30, 2021, along with PWoH matched according to date fully vaccinated, age group, race, ethnicity, and sex from 4 US integrated health systems and academic centers. Those with postvaccination COVID-19 breakthrough before December 31, 2021, were eligible. Exposures: HIV infection. Main Outcomes and Measures: The main outcome was severe COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. Discrete time proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% CIs of severe breakthrough illness within 28 days of breakthrough COVID-19 by HIV status adjusting for demographic variables, COVID-19 vaccine type, and clinical factors. The proportion of patients who received mechanical ventilation or died was compared by HIV status. Results: Among 3649 patients with breakthrough COVID-19 (1241 PWH and 2408 PWoH), most were aged 55 years or older (2182 patients [59.8%]) and male (3244 patients [88.9%]). The cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs 6.7%; risk difference, -0.67%; 95% CI, -2.58% to 1.23%). The risk of severe breakthrough illness was 59% higher in PWH with CD4 cell counts less than 350 cells/µL compared with PWoH (aHR, 1.59; 95% CI, 0.99 to 2.46; P = .049). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 cell count were associated with increased risk of severe breakthrough illness, whereas previous COVID-19 was associated with reduced risk. Among 249 hospitalized patients, 24 (9.6%) were mechanically ventilated and 20 (8.0%) died, with no difference by HIV status. Conclusions and Relevance: In this cohort study, the risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. PWH with moderate or severe immune suppression had a higher risk of severe breakthrough infection and should be included in groups prioritized for additional vaccine doses and risk-reduction strategies.


Subject(s)
COVID-19 Vaccines , COVID-19 , HIV Infections , Adolescent , Adult , Female , Humans , Male , Cohort Studies , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , HIV Infections/complications , HIV Infections/epidemiology , SARS-CoV-2
6.
Science ; 377(6607): 735-742, 2022 08 12.
Article in English | MEDLINE | ID: covidwho-1949931

ABSTRACT

The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide-specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , Antibodies, Viral/immunology , Antibodies, Viral/isolation & purification , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Humans , Peptides/immunology , Protein Binding , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
7.
Science ; 377(6608): 890-894, 2022 08 19.
Article in English | MEDLINE | ID: covidwho-1949930

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunization, Secondary , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
8.
JAMA Netw Open ; 5(6): e2215934, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1877538

ABSTRACT

Importance: Recommendations for additional doses of COVID-19 vaccines for people with HIV (PWH) are restricted to those with advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk after vaccination among PWH is essential for informing vaccination guidelines. Objective: To estimate the rate and risk of breakthrough infections among fully vaccinated PWH and people without HIV (PWoH) in the United States. Design, Setting, and Participants: This cohort study used the Corona-Infectious-Virus Epidemiology Team (CIVET)-II (of the North American AIDS Cohort Collaboration on Research and Design [NA-ACCORD], which is part of the International Epidemiology Databases to Evaluate AIDS [IeDEA]), collaboration of 4 prospective, electronic health record-based cohorts from integrated health systems and academic health centers. Adult PWH who were fully vaccinated prior to June 30, 2021, were matched with PWoH on date of full vaccination, age, race and ethnicity, and sex and followed up through December 31, 2021. Exposures: HIV infection. Main Outcomes and Measures: COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after a patient was fully vaccinated. Results: Among 113 994 patients (33 029 PWH and 80 965 PWoH), most were 55 years or older (80 017 [70%]) and male (104 967 [92%]); 47 098 (41%) were non-Hispanic Black, and 43 218 (38%) were non-Hispanic White. The rate of breakthrough infections was higher in PWH vs PWoH (55 [95% CI, 52-58] cases per 1000 person-years vs 43 [95% CI, 42-45] cases per 1000 person-years). Cumulative incidence of breakthroughs 9 months after full vaccination was low (3.8% [95% CI, 3.7%-3.9%]), albeit higher in PWH vs PWoH (4.4% vs 3.5%; log-rank P < .001; risk difference, 0.9% [95% CI, 0.6%-1.2%]) and within each vaccine type. Breakthrough infection risk was 28% higher in PWH vs PWoH (adjusted hazard ratio, 1.28 [95% CI, 1.19-1.37]). Among PWH, younger age (<45 y vs 45-54 y), history of COVID-19, and not receiving an additional dose (aHR, 0.71 [95% CI, 0.58-0.88]) were associated with increased risk of breakthrough infections. There was no association of breakthrough with HIV viral load suppression, but high CD4 count (ie, ≥500 cells/mm3) was associated with fewer breakthroughs among PWH. Conclusions and Relevance: In this study, COVID-19 vaccination, especially with an additional dose, was effective against infection with SARS-CoV-2 strains circulating through December 31, 2021. PWH had an increased risk of breakthrough infections compared with PWoH. Expansion of recommendations for additional vaccine doses to all PWH should be considered.


Subject(s)
Acquired Immunodeficiency Syndrome , COVID-19 , HIV Infections , Acquired Immunodeficiency Syndrome/complications , Adult , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Testing , COVID-19 Vaccines/therapeutic use , Cohort Studies , HIV Infections/complications , HIV Infections/epidemiology , Humans , Male , Prospective Studies , SARS-CoV-2 , United States/epidemiology
9.
PLoS One ; 17(4): e0265670, 2022.
Article in English | MEDLINE | ID: covidwho-1775445

ABSTRACT

Host biomarkers are increasingly being considered as tools for improved COVID-19 detection and prognosis. We recently profiled circulating host-encoded microRNA (miRNAs) during SARS-CoV-2 infection, revealing a signature that classified COVID-19 cases with 99.9% accuracy. Here we sought to develop a signature suited for clinical application by analyzing specimens collected using minimally invasive procedures. Eight miRNAs displayed altered expression in anterior nasal tissues from COVID-19 patients, with miR-142-3p, a negative regulator of interleukin-6 (IL-6) production, the most strongly upregulated. Supervised machine learning analysis revealed that a three-miRNA signature (miR-30c-2-3p, miR-628-3p and miR-93-5p) independently classifies COVID-19 cases with 100% accuracy. This study further defines the host miRNA response to SARS-CoV-2 infection and identifies candidate biomarkers for improved COVID-19 detection.


Subject(s)
COVID-19 , MicroRNAs , Biomarkers , COVID-19/diagnosis , Gene Expression Profiling , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Respiratory System/metabolism , SARS-CoV-2/genetics
10.
Cell ; 185(5): 872-880.e3, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1699915

ABSTRACT

Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.

11.
Science ; 375(6583): 864-868, 2022 02 25.
Article in English | MEDLINE | ID: covidwho-1650843

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antibodies, Viral/chemistry , Immune Evasion , Receptors, Coronavirus/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , Antigenic Drift and Shift , Broadly Neutralizing Antibodies/chemistry , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/metabolism , Cryoelectron Microscopy , Crystallography, X-Ray , Humans , Models, Molecular , Mutation , Protein Binding , Protein Conformation , Protein Domains/genetics , Protein Interaction Domains and Motifs/genetics , Receptors, Coronavirus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
12.
PLoS Pathog ; 17(7): e1009759, 2021 07.
Article in English | MEDLINE | ID: covidwho-1329138

ABSTRACT

The host response to SARS-CoV-2 infection provide insights into both viral pathogenesis and patient management. The host-encoded microRNA (miRNA) response to SARS-CoV-2 infection, however, remains poorly defined. Here we profiled circulating miRNAs from ten COVID-19 patients sampled longitudinally and ten age and gender matched healthy donors. We observed 55 miRNAs that were altered in COVID-19 patients during early-stage disease, with the inflammatory miR-31-5p the most strongly upregulated. Supervised machine learning analysis revealed that a three-miRNA signature (miR-423-5p, miR-23a-3p and miR-195-5p) independently classified COVID-19 cases with an accuracy of 99.9%. In a ferret COVID-19 model, the three-miRNA signature again detected SARS-CoV-2 infection with 99.7% accuracy, and distinguished SARS-CoV-2 infection from influenza A (H1N1) infection and healthy controls with 95% accuracy. Distinct miRNA profiles were also observed in COVID-19 patients requiring oxygenation. This study demonstrates that SARS-CoV-2 infection induces a robust host miRNA response that could improve COVID-19 detection and patient management.


Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , COVID-19/genetics , MicroRNAs/genetics , SARS-CoV-2 , Adult , Aged , Animals , COVID-19/blood , Case-Control Studies , Diagnosis, Differential , Disease Models, Animal , Female , Ferrets , Gene Expression , Host Microbial Interactions/genetics , Humans , Influenza A Virus, H1N1 Subtype , Longitudinal Studies , Male , MicroRNAs/blood , Middle Aged , Orthomyxoviridae Infections/diagnosis , Orthomyxoviridae Infections/genetics , Pandemics , Supervised Machine Learning
13.
J Virol ; 95(15): e0032721, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1305507

ABSTRACT

The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains; previously C6orf106) was identified as a proviral factor for Hendra virus infection and was recently characterized to function as an inhibitor of type I interferon expression. Here, we have utilized transcriptome sequencing (RNA-seq) to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of Caco-2 cells. We find that inhibition of ILRUN expression by RNA interference alters transcription profiles of numerous cellular pathways, including upregulation of the SARS-CoV-2 entry receptor ACE2 and several other members of the renin-angiotensin aldosterone system. In addition, transcripts of the SARS-CoV-2 coreceptors TMPRSS2 and CTSL were also upregulated. Inhibition of ILRUN also resulted in increased SARS-CoV-2 replication, while overexpression of ILRUN had the opposite effect, identifying ILRUN as a novel antiviral factor for SARS-CoV-2 replication. This represents, to our knowledge, the first report of ILRUN as a regulator of the renin-angiotensin-aldosterone system (RAAS). IMPORTANCE There is no doubt that the current rapid global spread of COVID-19 has had significant and far-reaching impacts on our health and economy and will continue to do so. Research in emerging infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is growing rapidly, with new breakthroughs in the understanding of host-virus interactions to assist with the development of innovative and exciting therapeutic strategies. Here, we present the first evidence that modulation of the human protein-coding gene ILRUN functions as an antiviral factor for SARS-CoV-2 infection, likely through its newly identified role in regulating the expression of SARS-CoV-2 entry receptors ACE2, TMPRSS2, and CTSL. These data improve our understanding of biological pathways that regulate host factors critical to SARS-CoV-2 infection, contributing to the development of antiviral strategies to deal with the current SARS-CoV-2 pandemic.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/metabolism , Down-Regulation , Gene Expression Regulation, Enzymologic , Neoplasm Proteins/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Caco-2 Cells , Cathepsin L/biosynthesis , Cathepsin L/genetics , Chlorocebus aethiops , Humans , Neoplasm Proteins/genetics , Renin-Angiotensin System , SARS-CoV-2/genetics , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Vero Cells
14.
NPJ Vaccines ; 6(1): 67, 2021 May 10.
Article in English | MEDLINE | ID: covidwho-1223093

ABSTRACT

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.

15.
Int J Mol Sci ; 22(7)2021 Mar 25.
Article in English | MEDLINE | ID: covidwho-1154425

ABSTRACT

The global COVID-19 pandemic caused by SARS-CoV-2 has resulted in over 2.2 million deaths. Disease outcomes range from asymptomatic to severe with, so far, minimal genotypic change to the virus so understanding the host response is paramount. Transcriptomics has become incredibly important in understanding host-pathogen interactions; however, post-transcriptional regulation plays an important role in infection and immunity through translation and mRNA stability, allowing tight control over potent host responses by both the host and the invading virus. Here, we apply ribosome profiling to assess post-transcriptional regulation of host genes during SARS-CoV-2 infection of a human lung epithelial cell line (Calu-3). We have identified numerous transcription factors (JUN, ZBTB20, ATF3, HIVEP2 and EGR1) as well as select antiviral cytokine genes, namely IFNB1, IFNL1,2 and 3, IL-6 and CCL5, that are restricted at the post-transcriptional level by SARS-CoV-2 infection and discuss the impact this would have on the host response to infection. This early phase restriction of antiviral transcripts in the lungs may allow high viral load and consequent immune dysregulation typically seen in SARS-CoV-2 infection.


Subject(s)
Cytokines/genetics , RNA Processing, Post-Transcriptional , Ribosomes/metabolism , Ribosomes/virology , SARS-CoV-2/immunology , Transcription Factors/genetics , Animals , Antiviral Agents/antagonists & inhibitors , Cell Line, Tumor , Chlorocebus aethiops , Computational Biology , Cytokines/metabolism , Epithelial Cells/immunology , Epithelial Cells/virology , Gene Expression Profiling , Host Microbial Interactions , Humans , Immunity, Innate/genetics , Lung/immunology , Lung/virology , RNA, Messenger/metabolism , RNA-Seq , Ribosomes/genetics , SARS-CoV-2/metabolism , Transcription Factors/metabolism , Transcriptome , Vero Cells
16.
J Bioeth Inq ; 17(4): 803-808, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-917154

ABSTRACT

The doctrine of consent (or informed consent, as it is called in North America) is built upon presumptions of mental capacity. Those presumptions must be tested according to legal rules that may be difficult to apply to COVID-19 patients during emergency presentations. We examine the principles of mental capacity and make recommendations on how to assess the capacity of COVID-19 patients to consent to emergency medical treatment. We term this the CARD approach (Comprehend, Appreciate, Reason, and Decide).


Subject(s)
COVID-19 , Critical Care , Informed Consent , Mental Competency , Patient Admission , Humans , Pandemics , SARS-CoV-2
17.
J Bioeth Inq ; 17(4): 663-667, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-917153

ABSTRACT

Australian prisons are overpopulated with people suffering from numerous health problems. COVID-19 presents a significant threat to prisoner health. This article examines the current regulatory responses from Australian state and territory governments to COVID-19 and a recent case which tested the human rights of prisoners during a pandemic.


Subject(s)
COVID-19/epidemiology , Communicable Disease Control/organization & administration , Human Rights , Prisons , Australia/epidemiology , Crowding , Health Status , Humans , Pandemics , Prevalence , SARS-CoV-2
18.
J Virol Methods ; 286: 113977, 2020 12.
Article in English | MEDLINE | ID: covidwho-800505

ABSTRACT

The development of medical countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires robust viral assays. Here we have adapted a protocol for polyethylene glycol (PEG)-mediated precipitation of SARS-CoV-2 stocks without the need for ultracentrifugation. Virus precipitation resulted in a ∼1.5 log10 increase in SARS-CoV-2 titres of virus prepared in VeroE6 cells and enabled the infection of several immortalized human cell lines (Caco-2 and Calu-3) at a high multiplicity of infection not practically achievable without virus concentration. This protocol underscores the utility of PEG-mediated precipitation for SARS-CoV-2 and provides a resource for a range of coronavirus research areas.


Subject(s)
Betacoronavirus/isolation & purification , Clinical Laboratory Techniques/methods , Coronavirus Infections/virology , Pneumonia, Viral/virology , Polyethylene Glycols/chemistry , Animals , COVID-19 , COVID-19 Testing , Caco-2 Cells , Chlorocebus aethiops , Coronavirus Infections/diagnosis , Humans , Pandemics , Pneumonia, Viral/diagnosis , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Ultracentrifugation/methods , Vero Cells
19.
J Bioeth Inq ; 17(4): 555-561, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-728244

ABSTRACT

In response to the COVID-19 pandemic, there has been a rapid growth in research focused on developing vaccines and therapies. In this context, the need for speed is taken for granted, and the scientific process has adapted to accommodate this. On the surface, attempts to speed up the research enterprise appear to be a good thing. It is, however, important to consider what, if anything, might be lost when biomedical innovation is sped up. In this article we use the case of a study recently retracted from the Lancet to illustrate the potential risks and harms associated with speeding up science. We then argue that, with appropriate governance mechanisms in place (and adequately resourced), it should be quite possible to both speed up science and remain attentive to scientific quality and integrity.


Subject(s)
Biomedical Research/ethics , COVID-19/prevention & control , Pandemics , Publications , Biomedical Research/standards , COVID-19/epidemiology , COVID-19/virology , Ethics, Research , Health Resources , Humans , Risk , SARS-CoV-2 , Science , Translational Research, Biomedical/ethics , Translational Research, Biomedical/standards , Vaccines , COVID-19 Drug Treatment
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