Adaptive immunity to SARS-CoV-2 and COVID-19.

Clinical question What is the role of drug interventions in the treatment of patients with covid-19? New recommendation Increased attention on ivermectin as a potential treatment for covid-19 triggered this recommendation. The panel made a recommendation against ivermectin in patients with covid-19 regardless of disease severity, except in the context of a clinical trial. Prior recommendations (a) a strong recommendation against the use of hydroxychloroquine in patients with covid-19, regardless of disease severity; (b) a strong recommendation against the use of lopinavir-ritonavir in patients with covid-19, regardless of disease severity; (c) a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19; (d) a conditional recommendation against systemic corticosteroids in patients with non-severe covid-19, and (e) a conditional recommendation against remdesivir in hospitalised patients with covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation There is insufficient evidence to be clear to what extent, if any, ivermectin is helpful or harmful in treating covid-19. There was a large degree of uncertainty in the evidence about ivermectin on mortality, need for mechanical ventilation, need for hospital admission, time to clinical improvement, and other patient-important outcomes. There is potential for harm with an increased risk of adverse events leading to study drug discontinuation. Applying pre-determined values and preferences, the panel inferred that almost all well informed patients would want to receive ivermectin only in the context of a randomised trial, given that the evidence left a very high degree of uncertainty on important effects. Updates This is a living guideline. It replaces earlier versions (4 September, 20 November, and 17 December 2020) and supersedes the BMJ Rapid Recommendations on remdesivir published on 2 July 2020. The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline. Readers note This is the fourth version (update 3) of the living guideline (BMJ 2020;370:m3379). When citing this article, please consider adding the update number and date of access for clarity.

https://www.bmj.com/content/bmj/370/bmj.m3379.full.pdf

A living WHO guideline on drugs for covid-19

Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization.

Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.

/pdf/neutralizing-monoclonal-antibodies-for-treatment-of-covid-19-26zbfts2zk.pdf

Neutralizing monoclonal antibodies for treatment of COVID-19.

Tackling COVID-19 with neutralizing monoclonal antibodies

Background LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. Methods In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. Results On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). Conclusions Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

/pdf/a-neutralizing-monoclonal-antibody-for-hospitalized-patients-41tbqrnnuq.pdf

T. Benfield

Papers

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.