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1.
Sci Rep ; 12(1): 13207, 2022 Aug 01.
Article in English | MEDLINE | ID: covidwho-1967628

ABSTRACT

Sputnik-V (Gam-COVID-Vac) is a heterologous, recombinant adenoviral (rAdv) vector-based, COVID-19 vaccine now used in > 70 countries. Yet there is a shortage of data on this vaccine's performance in diverse populations. Here, we performed a prospective cohort study to assess the reactogenicity and immunologic outcomes of Sputnik-V vaccination in Kazakhstan. COVID-19-free participants (n = 82 at baseline) were followed at day 21 after Sputnik-V dose 1 (rAd5) and dose 2 (rAd26). Self-reported local and systemic adverse events were captured using questionnaires. Blood and nasopharyngeal swabs were collected to perform SARS-CoV-2 diagnostic and immunologic assays. We observed that most of the reported adverse events were mild-to-moderate injection site or systemic reactions, no severe or potentially life-threatening conditions were reported, and dose 1 appeared to be more reactogenic than dose 2. The seroconversion rate was 97% post-dose 1, remaining the same post-dose 2. The proportion of participants with detectable virus neutralization was 83% post-dose 1, increasing to 98% post-dose 2, with the largest relative increase observed in participants without prior COVID-19 exposure. Dose 1 boosted nasal S-IgG and S-IgA, while the boosting effect of dose 2 on mucosal S-IgG, but not S-IgA, was only observed in subjects without prior COVID-19. Systemically, vaccination reduced serum levels of growth regulated oncogene (GRO), which correlated with an elevation in blood platelet count. Overall, Sputnik-V dose 1 elicited both blood and mucosal SARS-CoV-2 immunity, while the immune boosting effect of dose 2 was minimal. Thus, adjustments to the current vaccine dosing regimen are necessary to optimize immunization efficacy and cost-effectiveness. While Sputnik-V reactogenicity is similar to that of other COVID-19 vaccines, the induced alterations to the GRO/platelet axis warrant investigation of the vaccine's effects on systemic immunology.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunogenicity, Vaccine , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunoglobulin A , Immunoglobulin G , Mucous Membrane , Prospective Studies , SARS-CoV-2
2.
PLoS One ; 17(7): e0272008, 2022.
Article in English | MEDLINE | ID: covidwho-1963042

ABSTRACT

COVID-19 exposure in Central Asia appears underestimated and SARS-CoV-2 seroprevalence data are urgently needed to inform ongoing vaccination efforts and other strategies to mitigate the regional pandemic. Here, in a pilot serologic study we assessed the prevalence of SARS-CoV-2 antibody-mediated immunity in a multi-ethnic cohort of public university employees in Karaganda, Kazakhstan. Asymptomatic subjects (n = 100) were recruited prior to their first COVID-19 vaccination. Questionnaires were administered to capture a range of demographic and clinical characteristics. Nasopharyngeal swabs were collected for SARS-CoV-2 RT-qPCR testing. Serological assays were performed to detect spike (S)-reactive IgG and IgA and to assess virus neutralization. Pre-pandemic samples were used to validate the assay positivity thresholds. S-IgG and -IgA seropositivity rates among SARS-CoV-2 PCR-negative participants (n = 100) were 42% (95% CI [32.2-52.3]) and 59% (95% CI [48.8-69.0]), respectively, and 64% (95% CI [53.4-73.1]) of the cohort tested positive for at least one of the antibodies. S-IgG titres correlated with virus neutralization activity, detectable in 49% of the tested subset with prior COVID-19 history. Serologically confirmed history of COVID-19 was associated with Kazakh ethnicity, but not with other ethnic minorities present in the cohort, and self-reported history of respiratory illness since March 2020. Overall, SARS-CoV-2 exposure in this cohort was ~15-fold higher compared to the reported all-time national and regional COVID-19 prevalence, consistent with recent studies of excess infection and death in Kazakhstan. Continuous serological surveillance provides important insights into COVID-19 transmission dynamics and may be used to better inform the regional public health response.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Testing , COVID-19 Vaccines , Clinical Laboratory Techniques , Humans , Immunoglobulin A , Immunoglobulin G , Kazakhstan/epidemiology , Seroepidemiologic Studies , Vaccination
5.
J Inorg Biochem ; 234: 111899, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1882225

ABSTRACT

Polyoxidometalates (POMs) exhibit a range of biological properties that can be exploited for a variety of therapeutic applications. However, their potential utility as antivirals has been largely overlooked in the ongoing efforts to identify safe, effective and robust therapeutic agents to combat COVID-19. We focus on decavanadate (V10), a paradigmatic member of the POM family, to highlight the utility of electrostatic forces as a means of disrupting molecular processes underlying the SARS-CoV-2 entry into the host cell. While the departure from the traditional lock-and-key approach to the rational drug design relies on less-specific and longer-range interactions, it may enhance the robustness of therapeutic agents by making them less sensitive to the viral mutations. Native mass spectrometry (MS) not only demonstrates the ability of V10 to associate with the receptor-binding domain of the SARS-CoV-2 spike protein, but also provides evidence that this association disrupts the protein binding to its host cell-surface receptor. Furthermore, V10 is also shown to be capable of binding to the polybasic furin cleavage site within the spike protein, which is likely to decrease the effectiveness of the proteolytic processing of the latter (a pre-requisite for the viral fusion with the host cell membrane). Although in vitro studies carried out with SARS-CoV-2 infected cells identify V10 cytotoxicity as a major factor limiting its utility as an antiviral agent, the collected data provide a compelling stimulus for continuing the search for effective, robust and safe therapeutics targeting the novel coronavirus among members of the POM family.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Vanadates/pharmacology , Virus Internalization
6.
J Med Chem ; 65(11): 7818-7832, 2022 06 09.
Article in English | MEDLINE | ID: covidwho-1873394

ABSTRACT

The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Humans , Pandemics , Peptide Hydrolases , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
7.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337705

ABSTRACT

It has been previously reported that chronic infection with human cytomegalovirus (CMV) may contribute to poor vaccine responses against de novo antigens in older adults. We assessed effects of CMV serostatus on antibody quantity and quality, as well as cellular memory responses, after 2 and 3 SARS-CoV-2 mRNA vaccine doses, in older adults in congregate living facilities. CMV serostatus did not affect anti-Spike and anti-RBD IgG antibody levels, nor neutralization capacity against wildtype or beta variants of SARS-CoV-2. CMV seropositivity altered T cell expression of senescence-associated markers and increased T EMRA cell numbers, as has been previously reported;however, this did not impact the Spike-specific CD4 + T cell memory responses. CMV seropositive individuals did not have a higher incidence of COVID-19, though prior infection influenced humoral immunity. Therefore, CMV seropositivity may alter T cell composition but does not impede humoral or cellular memory responses after SARS-CoV-2 mRNA vaccination in older adults.

8.
Chemistry (Weinheim an der Bergstrasse, Germany) ; 28(15), 2022.
Article in English | EuropePMC | ID: covidwho-1837001

ABSTRACT

A unique DNA aptamer, denoted MSA52, displays universally high affinity for the spike proteins of the wild‐type SARS‐CoV‐2 as well as its Alpha, Beta, Gamma, Epsilon, Kappa, Delta and Omicron variants. This aptamer also recognizes pseudotyped lentiviruses expressing eight different spike proteins of SARS‐CoV‐2 with very high affinity, exhibiting dissociation constants (Kd) of 20–50 pM for these viruses. More information can be found in the Research Article by J. D. Brennan, Y. Li et al. (DOI: 10.1002/chem.202200078).

9.
PLoS Pathog ; 18(5): e1010471, 2022 05.
Article in English | MEDLINE | ID: covidwho-1833668

ABSTRACT

The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28-2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.


Subject(s)
COVID-19 , Interferon Type I , Orthomyxoviridae Infections , Humans , Interleukin-6/metabolism , Macrophages/metabolism , Proteolysis
10.
Int J Environ Res Public Health ; 19(9)2022 05 05.
Article in English | MEDLINE | ID: covidwho-1820287

ABSTRACT

INTRODUCTION: This study evaluated the impact of the Build Our Kids' Success (BOKS) after-school program on children's physical activity (PA) and well-being during the COVID-19 pandemic. METHODS: Program leaders, children, and their parents were recruited from after-school programs in Nova Scotia, Canada, that delivered BOKS programming in Fall 2020. After participating, Grade 4-6 children (n = 14) completed the Physical Literacy Assessment for Youth Self (PLAYself), Physical Activity Questionnaire for Older Children (PAQ-C), the Physical Activity Enjoyment Scale (PACES), and 5 National Institutes of Health (NIH) Patient-Reported Outcomes Measures Information System (PROMIS) scales. Children (n = 7), parents (n = 5), and program leaders (n = 3) completed interviews, which were analyzed for themes inductively. RESULTS: The average PAQ-C score was 2.70 ± 0.48, PLAYself was 68.23 ± 13.12, and PACES was 4.22 ± 0.59 (mean ± SD). NIH PROMIS scores were below standard means (cognitive function, family relationships) or within normal limits (peer relationships, positive affect, and life satisfaction). A thematic analysis of interviews revealed that children's PA levels were impacted by the pandemic and that BOKS positively impacted children's physical well-being and integrated well with school-based activities. CONCLUSIONS: Participation in BOKS provided an overall positive experience and may have mitigated COVID-19-related declines in PA in well-being. The results of this evaluation can inform future physically-active after-school programming.


Subject(s)
COVID-19 , Adolescent , COVID-19/epidemiology , Child , Exercise , Humans , Nova Scotia , Pandemics , Schools
11.
BMJ Open ; 12(4): e054061, 2022 04 04.
Article in English | MEDLINE | ID: covidwho-1774957

ABSTRACT

INTRODUCTION: Pesticide self-poisoning kills an estimated 110 000-168 000 people worldwide annually. Data from South Asia indicate that in 15%-20% of attempted suicides and 30%-50% of completed suicides involving pesticides these are purchased shortly beforehand for this purpose. Individuals who are intoxicated with alcohol and/or non-farmers represent 72% of such customers. We have developed a 'gatekeeper' training programme for vendors to enable them to identify individuals at high risk of self-poisoning (gatekeeper function) and prevent such individuals from accessing pesticides (means restriction). The primary aim of the study is to evaluate the effectiveness of the gatekeeper intervention in preventing pesticide self-poisoning in Sri Lanka. Other aims are to identify method substitution and to assess the cost and cost-effectiveness of the intervention. METHODS AND ANALYSIS: A stepped-wedge cluster randomised trial of a gatekeeper intervention is being conducted in rural Sri Lanka with a population of approximately 2.7 million. The gatekeeper intervention is being introduced into 70 administrative divisions in random order at each of 30 steps over a 40-month period. The primary outcome is the number of pesticide self-poisoning cases identified from surveillance of hospitals and police stations. Secondary outcomes include: number of self-poisoning cases using pesticides purchased within the previous 24 hours, total number of all forms of self-harm and suicides. Intervention effectiveness will be estimated by comparing outcome measures between the pretraining and post-training periods across the divisions in the study area. The original study protocol has been adapted as necessary in light of the impact of the COVID-19. ETHICS AND DISSEMINATION: The Ethical Review Committee of the Faculty of Medicine and Allied Sciences, Rajarata University, Sri Lanka (ERC/2018/30), and the ACCORD Medical Research Ethics Committee, Edinburgh University (18-HV-053) approved the study. Results will be disseminated in scientific peer-reviewed journals. TRIAL REGISTRATION NUMBER: SLCTR/2019/006, U1111-1220-8046.


Subject(s)
COVID-19 , Pesticides , Commerce , Humans , Randomized Controlled Trials as Topic , Rural Population , Sri Lanka/epidemiology
12.
Cell Rep Methods ; 1(6): 100069, 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1763677

ABSTRACT

The compounding challenges of low signal, high background, and uncertain targets plague many metagenomic sequencing efforts. One solution has been DNA capture, wherein probes are designed to hybridize with target sequences, enriching them in relation to their background. However, balancing probe depth with breadth of capture is challenging for diverse targets. To find this balance, we have developed the HUBDesign pipeline, which makes use of sequence homology to design probes at multiple taxonomic levels. This creates an efficient probe set capable of simultaneously and specifically capturing known and related sequences. We validated HUBDesign by generating probe sets targeting the breadth of coronavirus diversity, as well as a suite of bacterial pathogens often underlying sepsis. In separate experiments demonstrating significant, simultaneous enrichment, we captured SARS-CoV-2 and HCoV-NL63 in a human RNA background and seven bacterial strains in human blood. HUBDesign (https://github.com/zacherydickson/HUBDesign) has broad applicability wherever there are multiple organisms of interest.

13.
Chemistry ; 28(15): e202200524, 2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1750335

ABSTRACT

Invited for the cover of this issue are John Brennan, Yingfu Li, and co-workers at McMaster University. The image depicts MSA52 as a universal DNA aptamer that recognizes spike proteins of diverse SARS-CoV-2 variants of concern. Read the full text of the article at 10.1002/chem.202200078.

16.
mSphere ; 7(2): e0099821, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1714366

ABSTRACT

SARS-CoV-2 coronavirus is a recently identified novel coronavirus that is the causative agent of the COVID-19 pandemic that began in 2020. An intense research effort has been undertaken by the research community in order to better understand the molecular etiology of this virus and its mechanisms of host cell subjugation and immune system evasion. To facilitate further research into the SARS-CoV-2 coronavirus we have generated adenovirus 5-based viral vectors that express SARS-CoV-2 proteins-S, N, E, NSP7, NSP8, and NSP12 as hemagglutinin (HA)-tagged and untagged variants. We have also engineered two additional viruses that express the S protein receptor binding domain and a fusion of the receptor binding domain to the N protein. We show that these vectors are expressed in several different cell lines by Western blotting and real-time quantitative reverse transcriptase (qRT-PCR), we evaluate the subcellular localization of these viral proteins, and we show that these coronavirus proteins bind to a variety of cellular targets. The flexibility of adenovirus vectors allows them to be used in a variety of cell models and, importantly, in animal models as well. IMPORTANCE The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus has brought untold personal and economic suffering to the world. Intense research has made tremendous progress in understanding how this virus works, yet much research remains to be done as new variants and continued evolution of the virus keep shifting the rules of engagement on the pandemic battlefield. Therefore, wide availability of resources and reagents to study SARS-CoV-2 is essential in overcoming the pandemic and for the prevention of future outbreaks. Our viral vectors provide additional tools for researchers to use in order to better understand the molecular biology of virus-host interactions and other aspects of SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenoviridae/genetics , Animals , Humans , Pandemics , SARS-CoV-2/genetics , Viral Proteins
17.
Int J Environ Res Public Health ; 19(4)2022 02 19.
Article in English | MEDLINE | ID: covidwho-1708249

ABSTRACT

Children's physical activity participation declined during the COVID-19 pandemic, and these negative changes could lead to longer-term impacts on children's cognitive, social, and emotional health. PURPOSE: To determine parent/caregivers' perceptions of their children's cognitive function, peer and family relationships, life satisfaction, physical activity, sleep, positive affect, and global health, before and after participating in the Build Our Kids' Success (BOKS) programming at after-school programs in Fall 2020. METHODS: Parents of children participating in the BOKS programming at after-school programs in Nova Scotia, Canada, were recruited. At baseline, 159 parents completed the National Institutes of Health (NIH) Patient-Reported Outcomes Measures Information System (PROMIS) parent-proxy questionnaire, and 75 parents completed the measures at follow-up. Independent t-tests were used to determine if there were differences between baseline and follow-up Parent Proxy Questionnaire data. RESULTS: All NIH PROMIS outcome variables at baseline and follow-up were within normal limits (Adjusted T-Scores: 46.67 ± 7.15 to 50.04 ± 7.13). There were no significant differences in life satisfaction (t(188) = -1.05, p = 0.30), family relationships (t(189) = 0.31, p = 0.76), cognitive function (t(199) = -1.16, p = 0.25), peer relationships (t(192) = -1.86, p = 0.06), positive affect (t(195) = 0.25, p = 0.81), global health (t(216) = -0.43, p = 0.67), physical activity (t(202) = 0.787, p = 0.732), sleep disturbance (t(193) = 1.72, p = 0.087), or psychological stress (t(196) = 1.896, p = 0.059), from baseline to follow-up. CONCLUSIONS: Parent-proxy questionnaires suggested that the BOKS programming had a protective effect on children's health behaviours and cognitive, social, and emotional health as values remained within normal limits and were not impacted by the public health restrictions during the second wave of the COVID-19 pandemic in Nova Scotia.


Subject(s)
COVID-19 , COVID-19/epidemiology , Child , Cognition , Exercise , Humans , Nova Scotia/epidemiology , Pandemics , SARS-CoV-2
18.
Ann Intern Med ; 175(4): 556-565, 2022 04.
Article in English | MEDLINE | ID: covidwho-1702163

ABSTRACT

DESCRIPTION: The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2. This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021. These practice points do not evaluate vaccine-acquired immunity or cellular immunity. METHODS: The SMPC developed this version of the living, rapid practice points based on an updated living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. PRACTICE POINT 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. PRACTICE POINT 2: Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants. RETIREMENT FROM LIVING STATUS: Although natural immunity remains a topic of scientific interest, this topic is being retired from living status given the availability of effective vaccines for SARS-CoV-2 and widespread recommendations for and prevalence of their use. Currently, vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.


Subject(s)
COVID-19 , Physicians , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , Humans , Immunity, Innate , Reinfection , SARS-CoV-2
19.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-319945

ABSTRACT

The scientific rigor and computational methods of causal inference have had great impacts on many disciplines, but have only recently begun to take hold in spatial applications. Spatial casual inference poses analytic challenges due to complex correlation structures and interference between the treatment at one location and the outcomes at others. In this paper, we review the current literature on spatial causal inference and identify areas of future work. We first discuss methods that exploit spatial structure to account for unmeasured confounding variables. We then discuss causal analysis in the presence of spatial interference including several common assumptions used to reduce the complexity of the interference patterns under consideration. These methods are extended to the spatiotemporal case where we compare and contrast the potential outcomes framework with Granger causality, and to geostatistical analyses involving spatial random fields of treatments and responses. The methods are introduced in the context of observational environmental and epidemiological studies, and are compared using both a simulation study and analysis of the effect of ambient air pollution on COVID-19 mortality rate. Code to implement many of the methods using the popular Bayesian software OpenBUGS is provided.

20.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-317770

ABSTRACT

SARS-CoV-2 is a novel betacoronavirus and the aetiological agent of the current COVID-19 outbreak that originated in Hubei Province, China. While polymerase chain reaction is the front-line tool for SARS-CoV-2 surveillance, application of amplification-free and culture-free methods for isolation of SARS-CoV-2 RNA, partnered with next-generation sequencing, would provide a useful tool for both surveillance and research of SARS-CoV-2. We here release into the public domain a set of bait capture hybridization probe sequences for enrichment of SARS-CoV-2 RNA from complex biological samples. These probe sequences have been designed using rigorous bioinformatics methods to provide sensitivity, accuracy, and minimal off-target hybridization. Probe design was based on existing, validated approaches for detecting antimicrobial resistance genes in complex samples and it is our hope that this SARS-CoV-2 bait capture platform, once validated by those with samples in hand, will be of aid in combating the current outbreak.

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