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Potential health and economic impacts of dexamethasone treatment for patients with COVID-19

<jats:title>Abstract</jats:title><jats:p>Dexamethasone can reduce mortality in hospitalised COVID-19 patients needing oxygen and ventilation by 18% and 36%, respectively. Here, we estimate the potential number of lives saved and life years gained if this treatment were to be rolled out in the UK and globally, as well as the cost-effectiveness of implementing this intervention. Assuming SARS-CoV-2 exposure levels of 5% to 15%, we estimate that, for the UK, approximately 12,000 (4,250 - 27,000) lives could be saved between July and December 2020. Assuming that dexamethasone has a similar effect size in settings where access to oxygen therapies is limited, this would translate into approximately 650,000 (240,000 - 1,400,000) lives saved globally over the same time period. If dexamethasone acts differently in these settings, the impact could be less than half of this value. To estimate the full potential of dexamethasone in the global fight against COVID-19, it is essential to perform clinical research in settings with limited access to oxygen and/or ventilators, for example in low- and middle-income countries.</jats:p>

HLA-E-restricted, Gag-specific CD8+ T cells can suppress HIV-1 infection, offering vaccine opportunities.

Human leukocyte antigen-E (HLA-E) normally presents an HLA class Ia signal peptide to the NKG2A/C-CD94 regulatory receptors on natural killer (NK) cells and T cell subsets. Rhesus macaques immunized with a cytomegalovirus-vectored simian immunodeficiency virus (SIV) vaccine generated Mamu-E (HLA-E homolog)-restricted T cell responses that mediated post-challenge SIV replication arrest in >50% of animals. However, HIV-1-specific, HLA-E-restricted T cells have not been observed in HIV-1-infected individuals. Here, HLA-E-restricted, HIV-1-specific CD8 + T cells were primed in vitro. These T cell clones and allogeneic CD8 + T cells transduced with their T cell receptors suppressed HIV-1 replication in CD4 + T cells in vitro. Vaccine induction of efficacious HLA-E-restricted HIV-1-specific T cells should therefore be possible.

Perspectives on public health interventions in the management of the COVID-19 pandemic in Thailand

<ns3:p> <h4>Background: </h4> Any government needs to react quickly to a pandemic and make decisions on healthcare interventions locally and internationally with little information regarding the perceptions of people and the reactions they may receive during the implementation of restrictions.</ns3:p><ns3:p> <h4>Methods: </h4> We report an anonymous online survey in Thailand conducted in May 2020 to assess public perceptions of three interventions in the Thai context: isolation, quarantine and social distancing. A total of 1,020 participants, of whom 52% were women, responded to the survey.</ns3:p><ns3:p> <h4>Results: </h4></ns3:bold>: Loss of income was the main concern among respondents (>80% for all provinces in Thailand). Traditional media and social media were important channels for communication during the pandemic. A total of 92% of respondents reported that they changed their social behaviour even before the implementation of government policy with 94% reporting they performed social distancing, 97% reported using personal protective equipment such as masks and 95% reported using sanitizer products.</ns3:p><ns3:p> <h4>Conclusions: </h4> This study showed a high level of compliance from individuals with government enforced or voluntarily controls such as quarantine, isolation and social distancing in Thailand. The findings from this study can be used to inform future government measures to control the pandemic and to shape communication strategies.</ns3:p>

Antibody testing for COVID-19: A report from the National COVID Scientific Advisory Panel.

<b>Background:</b> The COVID-19 pandemic caused >1 million infections during January-March 2020. There is an urgent need for reliable antibody detection approaches to support diagnosis, vaccine development, safe release of individuals from quarantine, and population lock-down exit strategies. We set out to evaluate the performance of ELISA and lateral flow immunoassay (LFIA) devices. <b>Methods:</b> We tested plasma for COVID (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) IgM and IgG antibodies by ELISA and using nine different LFIA devices. We used a panel of plasma samples from individuals who have had confirmed COVID infection based on a PCR result (n=40), and pre-pandemic negative control samples banked in the UK prior to December-2019 (n=142). <b>Results:</b> ELISA detected IgM or IgG in 34/40 individuals with a confirmed history of COVID infection (sensitivity 85%, 95%CI 70-94%), vs. 0/50 pre-pandemic controls (specificity 100% [95%CI 93-100%]). IgG levels were detected in 31/31 COVID-positive individuals tested ≥10 days after symptom onset (sensitivity 100%, 95%CI 89-100%). IgG titres rose during the 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. Point estimates for the sensitivity of LFIA devices ranged from 55-70% versus RT-PCR and 65-85% versus ELISA, with specificity 95-100% and 93-100% respectively. Within the limits of the study size, the performance of most LFIA devices was similar. <b>Conclusions:</b> Currently available commercial LFIA devices do not perform sufficiently well for individual patient applications. However, ELISA can be calibrated to be specific for detecting and quantifying SARS-CoV-2 IgM and IgG and is highly sensitive for IgG from 10 days following first symptoms.

COVID-19 Vaccines: Global Challenges and Prospects Forum Recommendations.

Perspective On November 4 and 5, 2020 the 11th Annual KAIMRC Global Forum was organized as a G20 related event entitled COVID-19 Vaccines: Global Challenges and Prospects, https://globalcovid19vaccines.com. It was a vital event that provided a hub for leading COVID-19 scientists, regulators, pharmaceutical representative, funders and charities to learn about COVID-19 vaccines in development, discuss different vaccine candidates, make recommendations, highlight lessons learned and address appropriate plans for global distribution and pricing. Over 10,000 people from 94 countries attended the forum. The leading COVID-19 vaccines presented use different technologies including: (a) Non-replicating viral vector based vaccines, ChAdOx1 nCoV-19/AZD1222 vaccine developed by Oxford-AstraZeneca (van Doremalen et al., 2020), the Sputnik V developed by the Russian Gamaleya Institute consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector (Logunov et al., 2020), and the Ad26.COV2.S developed by Center for Virology and Vaccine Research, at Harvard Medical School in collaboration with Janssen Vaccines and Prevention BV, Leiden (Mercado et al., 2020). (b) Nucleic Acid, DNA- or RNA- based Vaccines that include the mRNA-1273 vaccine that is being developed by Moderna (Anderson et al., 2020), and a self-amplifying (saRNA) vaccine termed VGHsa111 developed by Imperial College, London as well as another co-developed by Pfizer and Biontech. An example of a DNA based vaccine against COVID19 is INO-4800 that is being developed by Inovio Pharmaceuticals Inc. (Smith et al., 2020). (c) Protein based vaccines, CoV RBD219-N1 Vaccine from Baylor College of Medicine, Texas that is based on a yeast-derived (Pichia pastoris) protein (Hotez and Bottazzi, 2020) and from Anhui Zhifei Longcom Biopharmaceutical Co. Ltd (Dai et al., 2020). Representatives from the Bill & Melinda Gates Foundation, the Bring Hope Humanitarian Foundation (BHHF), and the Coalition for Epidemic Preparedness Innovations (CEPI), presented their plans for distributing the vaccines to people in need around the world including the low-income countries. They are also developing educational programs to train health workers in immunization procedures.

Chemogenomics for drug discovery: clinical molecules from open access chemical probes

<p>Chemical probes are of great use for investigating target safety, viability, and translation. Alongside this, they act as useful structural templates to inspire drug discovery.</p>

Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo-erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen-specific CD8+ T-cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced effector CD8+ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen-specific CD8+ T-cell killing, which has wide-ranging implications on antigen prioritisation for next-generation pre-erythrocytic malaria vaccines.

Theory of change: Drama and arts-based community engagement for malaria research and elimination in Cambodia

<ns3:p><ns3:bold>Background</ns3:bold>: Across the Greater Mekong Sub-region, malaria persists in isolated communities along international borders. Arts and drama have been used to reach to communities in Cambodia to engage them in malaria research, prevention and control. The “Village Drama Against Malaria” (VDAM) project was conducted in north eastern and western Cambodia: Stung Treng; Battambang and Pailin provinces during 2016 to 2019.  In total, VDAM reached 55 rural villages, 2,378 student participants and 43,502 audience members.</ns3:p><ns3:p> <ns3:bold>Methods</ns3:bold>: This article presents the results of two stakeholder-led evaluation workshops in which participants collaboratively developed theories of change to better understand the potential and actual impact of arts and drama-based activities on malaria in these communities. The workshops had a particular focus on identifying areas for monitoring and evaluation so that impact can be measured. Workshop participants included village malaria workers, community leaders, professional and student drama performers, and representatives from the local health authorities and the national malaria control programme.</ns3:p><ns3:p> <ns3:bold>Results</ns3:bold>: Five broad areas were identified as relevant for monitoring and evaluation: logistical and practical challenges; embeddedness and reach of engagement; health knowledge and confidence of young people; community-level malaria outcomes; impact on malaria. These areas align well with the monitoring and evaluation conducted to date and point to additional opportunities for data collection.</ns3:p><ns3:p> <ns3:bold>Conclusions</ns3:bold>: The findings from these workshops will inform future engagement strategies, for example, we may engage a smaller number of young people but over a longer period and more in-depth.</ns3:p>

Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria

<jats:title>ABSTRACT</jats:title> <jats:p>Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for <jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content> malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated with 1,800 blood-stage <jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content> parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by quantitative PCR (qPCR), and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semimechanistic parasite dynamics model was developed to explain the maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with <jats:named-content content-type="genus-species">P. falciparum</jats:named-content> malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (<jats:italic>E</jats:italic><jats:sub>max</jats:sub>) function. Treatment simulations (i.e., 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug-resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥10<jats:sup>2</jats:sup> per life cycle (38.8 h) with a duration of action of ≥2 weeks. The semimechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool for assessing and optimizing current and new antimalarial drug combination therapies containing piperaquine and the impact of these therapies on killing multidrug-resistant infections. (This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741.)</jats:p>

Within-host genomics of SARS-CoV-2

<jats:title>Abstract</jats:title><jats:p>Extensive global sampling and whole genome sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to characterise its spread, and to identify mutations that may increase transmission or enable the virus to escape therapies or vaccines. Two important components of viral spread are how frequently variants arise within individuals, and how likely they are to be transmitted. Here, we characterise the within-host diversity of SARS-CoV-2, and the extent to which genetic diversity is transmitted, by quantifying variant frequencies in 1390 clinical samples from the UK, many from individuals in known epidemiological clusters. We show that SARS-CoV-2 infections are characterised by low levels of within-host diversity across the entire viral genome, with evidence of strong evolutionary constraint in Spike, a key target of vaccines and antibody-based therapies. Although within-host variants can be observed in multiple individuals in the same phylogenetic or epidemiological cluster, highly infectious individuals with high viral load carry only a limited repertoire of viral diversity. Most viral variants are either lost, or occasionally fixed, at the point of transmission, consistent with a narrow transmission bottleneck. These results suggest potential vaccine-escape mutations are likely to be rare in infectious individuals. Nonetheless, we identified Spike variants present in multiple individuals that may affect receptor binding or neutralisation by antibodies. Since the fitness advantage of escape mutations in highly-vaccinated populations is likely to be substantial, resulting in rapid spread if and when they do emerge, these findings underline the need for continued vigilance and monitoring.</jats:p>

An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples

<ns3:p>MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 <ns3:italic>Plasmodium falciparum</ns3:italic> samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.</ns3:p>

Flavivirus maturation leads to the formation of an occupied lipid pocket in the surface glycoproteins

<jats:title>Abstract</jats:title><jats:p>Flaviviruses such as Dengue (DENV) or Zika virus (ZIKV) assemble into an immature form within the endoplasmatic reticulum (ER), and are then processed by furin protease in the trans-Golgi. To better grasp maturation, we carry out cryo-EM reconstructions of immature Spondweni virus (SPOV), a human flavivirus of the same serogroup as ZIKV. By employing asymmetric localised reconstruction we push the resolution to 3.8 Å, enabling us to refine an atomic model which includes the crucial furin protease recognition site and a conserved Histidine pH-sensor. For direct comparison, we also solve structures of the mature forms of SPONV and DENV to 2.6 Å and 3.1 Å, respectively. We identify an ordered lipid that is present in only the mature forms of ZIKV, SPOV, and DENV and can bind as a consequence of rearranging amphipathic stem-helices of E during maturation. We propose a structural role for the pocket and suggest it stabilizes mature E.</jats:p>

Pharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in Africa

<jats:title>ABSTRACT</jats:title> <jats:p>When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 82 Congolese children with severe <jats:italic>falciparum</jats:italic> malaria to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg of body weight) followed 12 h later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at 11 fixed intervals, following 0- and 12-h drug administrations. Clinical, laboratory, and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large interindividual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients, however, reached previously suggested <jats:italic>in vivo</jats:italic> IC<jats:sub>50</jats:sub> and IC<jats:sub>90</jats:sub> values (98.7% and 92.5%, respectively) of combined concentrations of artesunate and dihydroartemisinin between 15 and 30 min after drug administration. The median (interquartile range [IQR]) time above IC<jats:sub>50</jats:sub> and IC<jats:sub>90</jats:sub> was 5.68 h (2.90 to 6.08) and 2.74 h (1.52 to 3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7 to 54.5) for artesunate and 19.8% (10.3 to 35.3) for dihydroartemisinin. The initial 12-h parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR), 84.3% (50.0 to 95.4) versus 69.2% (45.7 to 93.6), respectively (<jats:italic>P</jats:italic> = 0.49). Despite large interindividual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe <jats:italic>falciparum</jats:italic> malaria while they are transferred to a facility where parenteral artesunate is available. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.)</jats:p>

Structure-switching aptamer sensors for the specific detection of piperaquine and mefloquine

<jats:p>Tracking antimalarial drug use and efficacy is essential for monitoring the current spread of antimalarial drug resistance. However, available methods for determining tablet quality and patient drug use are often inaccessible, requiring well-equipped laboratories capable of performing liquid chromatography–mass spectrometry (LC-MS). Here, we report the development of aptamer-based fluorescent sensors for the rapid, specific detection of the antimalarial compounds piperaquine and mefloquine—two slow-clearing partner drugs in current first-line artemisinin-based combination therapies (ACTs). Highly selective DNA aptamers were identified that bind piperaquine and mefloquine with dissociation constants (<jats:italic>K</jats:italic><jats:sub>d</jats:sub>’s) measured in the low nanomolar range via two independent methods. The aptamers were isolated from a library of single-stranded DNA molecules using a capture–systematic evolution of ligands by exponential enrichment (SELEX) technique and then adapted into structure-switching aptamer fluorescent sensors. Sensor performance was optimized for the detection of drug from human serum and crushed tablets, resulting in two sensing platforms. The patient sample platform was validated against an LC-MS standard drug detection method in samples from healthy volunteers and patients with malaria. This assay provides a rapid and inexpensive method for tracking antimalarial drug use and quality for the containment and study of parasite resistance, a major priority for malaria elimination campaigns. This sensor platform allows for flexibility of sample matrix and can be easily adapted to detect other small-molecule drugs.</jats:p>

A haemagglutination test for rapid detection of antibodies to SARS-CoV-2.

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.

Evaluating the potential impact of interruptions to neglected tropical disease programmes due to COVID-19

Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera

T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.

Vulnerability, Agency, and the Research Encounter: Family Members' Experiences and Perceptions of Participating in an Observational Clinical Study in Kenya.

Pediatric clinical research in low-resourced countries involves individuals defined as "vulnerable" in research ethics guidance. Insights from research participants can strengthen the design and oversight of studies. We share family members' perspectives and experiences of an observational clinical study conducted in one Kenyan hospital as part of an integrated empirical ethics study. Employing qualitative methods, we explored how research encounters featured in family members' care-seeking journeys. Our data reveals that children's vulnerability is intricately interwoven with that of their families, and that research processes and procedures can inadvertently add to hidden burdens for families. In research, the potential for layered and intersecting situational and structural vulnerability should be considered, and participants' agency in constrained research contexts actively recognized and protected.

Convalescent plasma therapy for the treatment of patients with COVID-19: Assessment of methods available for antibody detection and their correlation with neutralising antibody levels

<h4>Introduction: </h4> The lack of approved specific therapeutic agents to treat COVID-19 associated with SARS coronavirus 2 (SARS-CoV-2) infection has led to the rapid implementation and/or randomised controlled trials of convalescent plasma therapy (CPT) in many countries including the UK. Effective CPT is likely to require high titres of neutralising antibody levels in convalescent donations. Understanding the relationship between functional neutralising antibodies and antibody levels to specific SARS-CoV-2 proteins in scalable assays will be crucial for the success of large-scale collection and use of convalescent plasma. We assessed whether neutralising antibody titres correlated with reactivity in a range of ELISA assays targeting the spike (S) protein, the main target for human immune response. Methods. Blood samples were collected from 52 individuals with a previous laboratory confirmed SARS-CoV-2 infection at least 28 days after symptom resolution. These were assayed for SARS-CoV-2 neutralising antibodies by microneutralisation and pseudotype assays, and for antibodies by four different ELISAs. ROC analysis was used to further identify sensitivity and specificity of selected assays to identify samples containing high neutralising antibody levels suitable for clinical use of convalescent plasma. Results. All samples contained SARS-CoV-2 antibodies, whereas neutralising antibody titres of greater than 1:20 were detected in 43 samples (83% of those tested) and >1:100 in 22 samples (42%). The best correlations were observed with EUROimmun IgG ELISA S/CO reactivity (Spearman Rho correlation co-efficient 0.88; p<0.001). Based on ROC analysis, EUROimmun would detect 60% of samples with titres of >1:100 with 100% specificity using a reactivity index of 9.1 (13/22). Discussion. Robust associations between virus neutralising antibody titres and reactivity in several ELISA-based antibody tests demonstrate their possible utility for scaled-up production of convalescent plasma containing potentially therapeutic levels of anti-SARS-CoV-2 neutralising antibodies.