10 research outputs found
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK
Background
A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.
Methods
This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5âĂâ1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1â-ârelative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.
Findings
Between April 23 and Nov 4, 2020, 23â848 participants were enrolled and 11â636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0â75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4â97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8â80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74â341 person-months of safety follow-up (median 3·4 months, IQR 1·3â4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.
Interpretation
ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.
BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5âĂâ1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1â-ârelative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23â848 participants were enrolled and 11â636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74â341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca
Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein
Association of plasma exosomal mRNA changes with long-term durable response to ipilimumab (IPI) in metastatic melanoma (MM) patients.
Identification of recombinant Fabs for structural and functional characterization of HIV-host factor complexes.
Viral infection and pathogenesis is mediated by host protein-viral protein complexes that are important targets for therapeutic intervention as they are potentially less prone to development of drug resistance. We have identified human, recombinant antibodies (Fabs) from a phage display library that bind to three HIV-host complexes. We used these Fabs to 1) stabilize the complexes for structural studies; and 2) facilitate characterization of the function of these complexes. Specifically, we generated recombinant Fabs to Vif-CBF-ÎČ-ELOB-ELOC (VCBC); ESCRT-I complex and AP2-complex. For each complex we measured binding affinities with KD values of Fabs ranging from 12-419 nM and performed negative stain electron microscopy (nsEM) to obtain low-resolution structures of the HIV-Fab complexes. Select Fabs were converted to scFvs to allow them to fold intracellularly and perturb HIV-host protein complex assembly without affecting other pathways. To identify these recombinant Fabs, we developed a rapid screening pipeline that uses quantitative ELISAs and nsEM to establish whether the Fabs have overlapping or independent epitopes. This pipeline approach is generally applicable to other particularly challenging antigens that are refractory to immunization strategies for antibody generation including multi-protein complexes providing specific, reproducible, and renewable antibody reagents for research and clinical applications. The curated antibodies described here are available to the scientific community for further structural and functional studies on these critical HIV host-factor proteins
Identification of recombinant Fabs for structural and functional characterization of HIV-host factor complexes.
Viral infection and pathogenesis is mediated by host protein-viral protein complexes that are important targets for therapeutic intervention as they are potentially less prone to development of drug resistance. We have identified human, recombinant antibodies (Fabs) from a phage display library that bind to three HIV-host complexes. We used these Fabs to 1) stabilize the complexes for structural studies; and 2) facilitate characterization of the function of these complexes. Specifically, we generated recombinant Fabs to Vif-CBF-ÎČ-ELOB-ELOC (VCBC); ESCRT-I complex and AP2-complex. For each complex we measured binding affinities with KD values of Fabs ranging from 12-419 nM and performed negative stain electron microscopy (nsEM) to obtain low-resolution structures of the HIV-Fab complexes. Select Fabs were converted to scFvs to allow them to fold intracellularly and perturb HIV-host protein complex assembly without affecting other pathways. To identify these recombinant Fabs, we developed a rapid screening pipeline that uses quantitative ELISAs and nsEM to establish whether the Fabs have overlapping or independent epitopes. This pipeline approach is generally applicable to other particularly challenging antigens that are refractory to immunization strategies for antibody generation including multi-protein complexes providing specific, reproducible, and renewable antibody reagents for research and clinical applications. The curated antibodies described here are available to the scientific community for further structural and functional studies on these critical HIV host-factor proteins
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Identification of recombinant Fabs for structural and functional characterization of HIV-host factor complexes.
Viral infection and pathogenesis is mediated by host protein-viral protein complexes that are important targets for therapeutic intervention as they are potentially less prone to development of drug resistance. We have identified human, recombinant antibodies (Fabs) from a phage display library that bind to three HIV-host complexes. We used these Fabs to 1) stabilize the complexes for structural studies; and 2) facilitate characterization of the function of these complexes. Specifically, we generated recombinant Fabs to Vif-CBF-ÎČ-ELOB-ELOC (VCBC); ESCRT-I complex and AP2-complex. For each complex we measured binding affinities with KD values of Fabs ranging from 12-419 nM and performed negative stain electron microscopy (nsEM) to obtain low-resolution structures of the HIV-Fab complexes. Select Fabs were converted to scFvs to allow them to fold intracellularly and perturb HIV-host protein complex assembly without affecting other pathways. To identify these recombinant Fabs, we developed a rapid screening pipeline that uses quantitative ELISAs and nsEM to establish whether the Fabs have overlapping or independent epitopes. This pipeline approach is generally applicable to other particularly challenging antigens that are refractory to immunization strategies for antibody generation including multi-protein complexes providing specific, reproducible, and renewable antibody reagents for research and clinical applications. The curated antibodies described here are available to the scientific community for further structural and functional studies on these critical HIV host-factor proteins
Communication to promote and support physical distancing for COVID-19 prevention and control
Background
This review is an update of a rapid review undertaken in 2020 to identify relevant, feasible and effective communication approaches to promote acceptance, uptake and adherence to physical distancing measures for COVIDâ19 prevention and control. The rapid review was published when little was known about transmission, treatment or future vaccination, and when physical distancing measures (isolation, quarantine, contact tracing, crowd avoidance, work and school measures) were the cornerstone of public health responses globally.
This updated review includes more recent evidence to extend what we know about effective pandemic public health communication. This includes considerations of changes needed over time to maintain responsiveness to pandemic transmission waves, the (in)equities and variable needs of groups within communities due to the pandemic, and highlights again the critical role of effective communication as integral to the public health response.
Objectives
To update the evidence on the question 'What are relevant, feasible and effective communication approaches to promote acceptance, uptake and adherence to physical distancing measures for COVIDâ19 prevention and control?', our primary focus was communication approaches to promote and support acceptance, uptake and adherence to physical distancing.
Secondary objective: to explore and identify key elements of effective communication for physical distancing measures for different (diverse) populations and groups.
Search methods
We searched MEDLINE, Embase and Cochrane Library databases from inception, with searches for this update including the period 1 January 2020 to 18 August 2021. Systematic review and study repositories and grey literature sources were searched in August 2021 and guidelines identified for the eCOVID19 Recommendations Map were screened (November 2021).
Selection criteria
Guidelines or reviews focusing on communication (information, education, reminders, facilitating decisionâmaking, skills acquisition, supporting behaviour change, support, involvement in decisionâmaking) related to physical distancing measures for prevention and/or control of COVIDâ19 or selected other diseases (sudden acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, Ebola virus disease (EVD) or tuberculosis (TB)) were included. New evidence was added to guidelines, reviews and primary studies included in the 2020 review.
Data collection and analysis
Methods were based on the original rapid review, using methods developed by McMaster University and informed by Cochrane rapid review guidance.
Screening, data extraction, quality assessment and synthesis were conducted by one author and checked by a second author. Synthesis of results was conducted using modified framework analysis, with themes from the original review used as an initial framework.
Main results
This review update includes 68 studies, with 17 guidelines and 20 reviews added to the original 31 studies.
Synthesis identified six major themes, which can be used to inform policy and decisionâmaking related to planning and implementing communication about a public health emergency and measures to protect the community.
Theme 1: Strengthening public trust and countering misinformation: essential foundations for effective public health communication
Recognising the key role of public trust is essential. Working to build and maintain trust over time underpins the success of public health communications and, therefore, the effectiveness of public health prevention measures.
Theme 2: Twoâway communication: involving communities to improve the dissemination, accessibility and acceptability of information
Twoâway communication (engagement) with the public is needed over the course of a public health emergency: at first, recognition of a health threat (despite uncertainties), and regularly as public health measures are introduced or adjusted. Engagement needs to be embedded at all stages of the response and inform tailoring of communications and implementation of public health measures over time.
Theme 3: Development of and preparation for public communication: target audience, equity and tailoring
Communication and information must be tailored to reach all groups within populations, and explicitly consider existing inequities and the needs of disadvantaged groups, including those who are underserved, vulnerable, from diverse cultural or language groups, or who have lower educational attainment. Awareness that implementing public health measures may magnify existing or emerging inequities is also needed in response planning, enactment and adjustment over time.
Theme 4: Public communication features: content, timing and duration, delivery
Public communication needs to be based on clear, consistent, actionable and timely (upâtoâdate) information about preventive measures, including the benefits (whether for individual, social groupings or wider society), harms (likewise) and rationale for use, and include information about supports available to help follow recommended measures. Communication needs to occur through multiple channels and/or formats to build public trust and reach more of the community.
Theme 5: Supporting behaviour change at individual and population levels
Supporting implementation of public health measures with practical supports and services (e.g. essential supplies, financial support) is critical. Information about available supports must be widely disseminated and well understood. Supports and communication related to them require flexibility and tailoring to explicitly consider community needs, including those of vulnerable groups. Proactively monitoring and countering stigma related to preventive measures (e.g. quarantine) is also necessary to support adherence.
Theme 6: Fostering and sustaining receptiveness and responsiveness to public health communication
Efforts to foster and sustain public receptiveness and responsiveness to public health communication are needed throughout a public health emergency. Trust, acceptance and behaviours change over time, and communication needs to be adaptive and responsive to these changing needs. Ongoing community engagement efforts should inform communication and public health response measures.
Authors' conclusions
Implications for practice
Evidence highlights the critical role of communication throughout a public health emergency. Like any intervention, communication can be done well or poorly, but the consequences of poor communication during a pandemic may mean the difference between life and death.
The approaches to effective communication identified in this review can be used by policymakers and decisionâmakers, working closely with communication teams, to plan, implement and adjust public communications over the course of a public health emergency like the COVIDâ19 pandemic.
Implications for research
Despite massive growth in research during the COVIDâ19 period, gaps in the evidence persist and require highâquality, meaningful research. This includes investigating the experiences of people at heightened COVIDâ19 risk, and identifying barriers to implementing public communication and protective health measures particular to lowerâ and middleâincome countries, and how to overcome these