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1.
Lancet (London, England) ; 2022.
Article in English | EuropePMC | ID: covidwho-1756137
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319221

ABSTRACT

Summary: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0·1-10·0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays.Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0·001), ranging from 8% to 61% in ELISA and 46% to 87% in the immunoblot assay.Concurrent anti-S IgG ranged from GM concentration (95% CI) 74 (45-119) at 0·1mg to 1023 (468-2236) ng/ml at 5·0mg (p<0·001) and was not higher at 10·0mg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15-48% depending on dose level received.Interpretation: Encapsulated saRNA is safe for clinical development and is immunogenic at low dose levels. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.Trial Registration: (ISRCTN17072692, EudraCT 2020-001646-20)Funding Statement: Medical Research Council UKRI (MC_PC_19076 and MC_UU_12023/23), National Institute for Health Research, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust.Declaration of Interests: P.F.M. and R.J.S. are co-inventors on a patent application covering this SARS-CoV-2 saRNA vaccine. All other authors have nothing to declare. Ethics Approval Statement: This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency and the North East - York Research Ethics Committee (reference 20/SC/0145).

4.
EClinicalMedicine ; 44: 101262, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1620636

ABSTRACT

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0µg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1µg) to 61% (14/23; 10.0µg) in ELISA and 46% (18/39; 0.3µg) to 87% (20/23; 5.0µg and 10.0µg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1µg to 1023 (468-2236) ng/mL at 5.0µg (p<0.001) and was not higher at 10.0µg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1µg) to 48% (11/23; 5.0µg) depending on dose level received. Interpretation: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. Funding: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.

5.
Lancet HIV ; 8(11): e661-e662, 2021 11.
Article in English | MEDLINE | ID: covidwho-1541052
7.
Open Forum Infect Dis ; 8(7): ofab278, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1317924

ABSTRACT

BACKGROUND: Remdesivir is approved by the US Food and Drug Administration for the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19) and has been shown to shorten time to recovery and improve clinical outcomes in randomized trials. METHODS: This was the final day 28 comparative analysis of data from a phase 3, randomized, open-label study comparing 2 remdesivir regimens (5 vs 10 days, combined for this analysis [remdesivir cohort]) and a real-world retrospective longitudinal cohort study of patients receiving standard-of-care treatment (nonremdesivir cohort). Eligible patients, aged ≥18 years, had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), oxygen saturation ≤94% on room air or required supplemental oxygen, with pulmonary infiltrates. Propensity score matching (up to 1:10 ratio) was used to ensure comparable populations. We assessed day 14 clinical recovery (determined using a 7-point ordinal scale) and day 28 all-cause mortality (coprimary endpoints). RESULTS: A total of 368 (remdesivir) and 1399 (nonremdesivir) patients were included in the matched analysis. The day 14 clinical recovery rate was significantly higher among the remdesivir versus the nonremdesivir cohort (65.2% vs 57.1%; odds ratio [OR], 1.49; 95% confidence interval [CI], 1.16-1.90; P = 0.002). The day 28 mortality rate was significantly lower in the remdesivir cohort versus the nonremdesivir cohort (12.0% vs 16.2%; OR, 0.67; 95% CI, 0.47-.95; P = .03). CONCLUSIONS: Remdesivir was associated with significantly higher rates of day 14 clinical recovery, and lower day 28 mortality, compared with standard-of-care treatment in hospitalized patients with COVID-19. These data, taken together, support the use of remdesivir to improve clinical recovery and decrease mortality from SARS-CoV-2 infection.

8.
N Engl J Med ; 385(13): 1172-1183, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1287849

ABSTRACT

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Immunogenicity, Vaccine , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Humans , Injections, Intramuscular/adverse effects , Middle Aged , SARS-CoV-2 , Single-Blind Method , Vaccines, Synthetic/immunology , Young Adult
10.
Clin Pharmacol Ther ; 110(1): 64-68, 2021 07.
Article in English | MEDLINE | ID: covidwho-938406

ABSTRACT

The urgent global public health need presented by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has brought scientists from diverse backgrounds together in an unprecedented international effort to rapidly identify interventions. There is a pressing need to apply clinical pharmacology principles and this has already been recognized by several other groups. However, one area that warrants additional specific consideration relates to plasma and tissue protein binding that broadly influences pharmacokinetics and pharmacodynamics. The principles of free drug theory have been forged and applied across drug development but are not currently being routinely applied for SARS-CoV-2 antiviral drugs. Consideration of protein binding is of critical importance to candidate selection but requires correct interpretation, in a drug-specific manner, to avoid either underinterpretation or overinterpretation of its consequences. This paper represents a consensus from international researchers seeking to apply historical knowledge, which has underpinned highly successful antiviral drug development for other viruses, such as HIV and hepatitis C virus for decades.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19 , Drug Design , Drug Development , COVID-19/drug therapy , COVID-19/metabolism , Consensus , Humans , Protein Binding , SARS-CoV-2
11.
Br J Clin Pharmacol ; 87(4): 2078-2088, 2021 04.
Article in English | MEDLINE | ID: covidwho-883246

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC90 . METHODS: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. RESULTS: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. CONCLUSION: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/prevention & control , Drug Repositioning , Models, Biological , Nitro Compounds/administration & dosage , Thiazoles/administration & dosage , Adult , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , COVID-19/blood , Computer Simulation , Drug Dosage Calculations , Female , Humans , Lung/metabolism , Male , Middle Aged , Nitro Compounds/blood , Nitro Compounds/pharmacokinetics , Reproducibility of Results , Thiazoles/blood , Thiazoles/pharmacokinetics , Tissue Distribution , Young Adult
12.
AIDS ; 34(12): 1795-1800, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-860218

ABSTRACT

OBJECTIVE: To determine comorbidity indices in people with HIV (PWH) and lifestyle-similar HIV-negative controls. DESIGN: Cross-sectional analysis of the Pharmacokinetic and clinical Observations in PeoPle over fiftY cohort study in the United Kingdom and Ireland. METHODS: The Elixhauser Comorbidity Index (ECI), Charlson Comorbidity Index and the Comorbidity Burden Index were compared between older PWH and HIV-negative controls using the Mann-Whitney U test; the magnitude of the difference between groups was quantified using the r effect size. RESULTS: The 699 PWH and 304 HIV-negative controls were predominantly male (87.5% vs. 64.0%), white (86.3% vs. 90.0%) and had median ages of 57 and 58 years, respectively. Among PWH, the median (interquartile range) CD4 T-cell count was 624 (475, 811) cells/µl; 98.7% were on antiretroviral therapy. The median (interquartile range) ECI was 0 (0, 8) and 0 (-3, 1), Charlson Comorbidity Index was 2 (1, 5) and 1 (0, 1) and Comorbidity Burden Index 8.6 (2.2, 16.8) and 5.9 (0.6, 10.8), respectively. While all three indices were significantly higher in PWH than in controls (P < 0.001 for each), the magnitude of the differences between the two groups were small to medium, with effect sizes (95% confidence interval) of 0.21 (0.16, 0.27), 0.38 (0.32, 0.42) and 0.18 (0.11, 0.23), respectively. CONCLUSION: These three comorbidity indices are higher in PWH compared with HIV-negative controls, although the magnitude of differences between groups were small. Differences in the ECI, reportedly associated with poorer coronavirus disease 2019 outcomes, were driven by more individuals with HIV being within the higher end of the range.


Subject(s)
Coronavirus Infections/epidemiology , HIV Infections/epidemiology , Pneumonia, Viral/epidemiology , Anti-Retroviral Agents/therapeutic use , CD4 Lymphocyte Count , COVID-19 , Cohort Studies , Comorbidity , Cross-Sectional Studies , Female , HIV Infections/drug therapy , Humans , Ireland/epidemiology , Male , Middle Aged , Pandemics , Severity of Illness Index , United Kingdom/epidemiology
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