Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Changes in Colonic Bile Acid Composition following Fecal Microbiota Transplantation Are Sufficient to Control <i>Clostridium difficile</i> Germination and Growth

<div><p>Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent <i>Clostridium difficile</i> infection (R-CDI), but its mechanisms remain poorly understood. Emerging evidence suggests that gut bile acids have significant influence on the physiology of <i>C</i>. <i>difficile</i>, and therefore on patient susceptibility to recurrent infection. We analyzed spore germination of 10 clinical <i>C</i>. <i>difficile</i> isolates exposed to combinations of bile acids present in patient feces before and after FMT. Bile acids at concentrations found in patients’ feces prior to FMT induced germination of <i>C</i>. <i>difficile</i>, although with variable potency across different strains. However, bile acids at concentrations found in patients after FMT did not induce germination and inhibited vegetative growth of all <i>C</i>. <i>difficile</i> strains. Sequencing of the newly identified germinant receptor in <i>C</i>. <i>difficile</i>, CspC, revealed a possible correspondence of variation in germination responses across isolates with mutations in this receptor. This may be related to interstrain variability in spore germination and vegetative growth in response to bile acids seen in this and other studies. These results support the idea that intra-colonic bile acids play a key mechanistic role in the success of FMT, and suggests that novel therapeutic alternatives for treatment of R-CDI may be developed by targeted manipulation of bile acid composition in the colon.</p></div

<i>C</i>. <i>difficile</i> spores germinate in response to primary bile acids.

<p>A) (Left Panel) Relative OD₆₀₀ of NAP1 spores exposed to 0.5 mM (square) or 2 mM (triangle) TA versus BHIS alone (circle). (Right Panel) Relative OD₆₀₀ of spores from 10 isolates after 20 min exposure to 0.5 or 2 mM TA vs. BHIS alone. B) (Left Panel) Relative OD₆₀₀ of NAP1 spores exposed to 0.5 mM (square), 1 mM (diamond), or 2 mM (triangle) CA versus BHIS alone (circle). (Right Panel) Relative OD₆₀₀ of spores from 10 isolates after 20 min exposure to 0.5, 1, or 2 mM CA vs. BHIS alone. C) (Left) Relative OD₆₀₀ of NAP1 spores exposed to 0.25 mM (dashed line), 0.5 mM (square), 1 mM (diamond), or 2 mM (triangle) CDCA versus BHIS alone (circle). (Right Panel) Relative OD₆₀₀ of spores from 10 isolates after 20 min exposure to 0.25, 0.5, 1, or 2 mM CDCA vs. BHIS alone. OD₆₀₀(t)/OD₆₀₀(t₀) = OD₆₀₀ normalized to initial OD₆₀₀ (relative OD₆₀₀). Legends: *** = p < 0.001, ** = p < 0.01; * = p < 0.05, n.s. = non-significant. BHIS = BHI with yeast extract and L-cysteine; TA = taurocholate; CA = cholate; and CDCA = chenodeoxycholic acid. Data represent mean ± SEM.</p

Growth of vegetative <i>C</i>. <i>difficile</i> is inhibited by post-FMT bile acids.

<p>A) Hourly OD₆₀₀ measurements for NAP1 cells in BHIS alone (circle), BHIS with pre-FMT bile acids (triangle), and BHIS with post-FMT bile acids (square). B) OD₆₀₀ at 24 h for 10 isolates. Legend: BA = bile acids; and * = p <0.01. Data represent mean ± SEM.</p

<i>C</i>. <i>difficile</i> spores do not germinate in response to secondary bile acids.

<p>A) (Left Panel) Relative OD₆₀₀ of NAP1 spores exposed to 0.5 mM (square), 1 mM (diamond), or 2 mM (triangle) DCA versus BHIS alone (circle). (Right Panel) Relative OD₆₀₀ of spores from 10 isolates after 20 min exposure to 0.5, 1, or 2 mM DCA vs. BHIS alone. B) (Left Panel) Relative OD₆₀₀ of NAP1 spores exposed to 0.5 mM (square), 1 mM (diamond), or 2 mM (triangle) LCA versus BHIS alone (circle). (Right Panel) Relative OD₆₀₀ of spores from 10 isolates after 20 min exposure to 0.5, 1, or 2 mM LCA vs. BHIS alone. OD₆₀₀(t)/OD₆₀₀(t₀) = OD₆₀₀ normalized to initial OD₆₀₀ (relative OD₆₀₀). Legend: n.s. = non-significant. BHIS = BHI with yeast extract and L-cysteine; DCA = deoxycholate; and LCA = lithocholic acid. Data represent mean ± SEM.</p

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license Background: Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial. Methods: This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013–14 to 2017–18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov, NCT02287467. Findings: 313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79–1·97; p=0·33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0·94 (0·55–1·59) and was 3·19 (1·21–8·42) for those with influenza B (interaction p=0·023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1·06, 95% CI 0·70–1·60; p=0·79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment. Interpretation: When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted. Funding: NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation