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ImportanceEvidence suggests that early, robust type 1 interferon responses to SARS-CoV-2 are critical determinants for COVID-19 disease outcomes, accelerating viral clearance and limiting viral shedding. ObjectiveWe undertook a ring prophylaxis study to determine whether pegylated IFN{beta}-1 could reduce SARS-CoV-2 household transmission. DesignA cluster randomized clinical trial of pegylated IFN{beta}-1 conducted in Santiago, Chile. Recruitment was conducted between December 4th 2020, and 31st May 2021, with the last follow-up completed June 29th 2021. SettingThe study was conducted across 341 households in the metropolitan area of Santiago, Chile. ParticipantsIndex cases were identified from databases of those with confirmed SARS-CoV-2 from COVID-19 clinics and emergency room visits in Santiago, Chile. 5,154 index cases were assessed for eligibility, 1,372 index cases were invited to participate, and 341 index cases and their household contacts (n = 831) were enrolled in the study. InterventionHouseholds were cluster randomized to receive 125{micro}g subcutaneous pegylated IFN{beta}-1 (n = 172 households, 607 participants), or standard care (n = 169 households, 565 participants). Main Outcome(s) and Measure(s)Frequentist and Bayesian analyses were undertaken to determine the effects of treatment on (i) reducing viral shedding in index cases and (ii) reducing viral transmission to treatment-eligible household contacts. Four secondary outcomes were assessed including duration of viral shedding, effects on viral transmission and seroconversion, incidence of hospitalization, and incidence and severity of reported adverse events. A post-hoc at risk population was defined as households where the index case was positive at the start of the study and there was at least one treatment eligible contact in a household who tested negative for SARS-CoV-2. ResultsIn total, 1172 participants in 341 households underwent randomization, with 607 assigned to receive IFN{beta}-1 and 565 to standard care. Based on intention to treat and per protocol analyses, IFN{beta}-1 treatment was ineffective. However, in the at risk population, the relative risk of infection was reduced by 23% in treated individuals and that there was a 95% probability that IFN{beta}-1 reduced household transmission Conclusions and RelevanceRing prophylaxis with IFN{beta}-1 reduces the probability of SARS-CoV-2 transmission within a household. Trial RegistrationClinicaltrials.gov identifier: NCT04552379
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ObjectivesTo assess the overall effect of vitamin D supplementation on risk of acute respiratory infection (ARI), and to identify factors modifying this effect. DesignWe conducted a systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. Data SourcesMEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard RCT Number (ISRCTN) registry from inception to May 2020. Eligibility Criteria for Selecting StudiesDouble-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. ResultsWe identified 40 eligible RCTs (total 30,956 participants, aged 0 to 95 years). Data were obtained for 29,841 (96.5%) of 30,909 participants in 39 studies. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.89, 95% CI 0.81 to 0.98; P for heterogeneity 0.009). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of [≤]12 months (OR 0.82, 95% CI 0.72 to 0.94). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.94, 95% CI 0.81 to 1.08). Risk of bias within individual studies was assessed as being low for all but two trials. A funnel plot showed asymmetry, suggesting that small trials showing non-protective effects of vitamin D may have been omitted from the meta-analysis. ConclusionsVitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. The overall effect size may have been over-estimated due to publication bias. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation. Systematic Review RegistrationCRD42020190633 O_TEXTBOXSummary Box What is already known on this subject?O_LIA previous individual participant data meta-analysis from 10,933 participants in 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infection (ARI) demonstrated an overall protective effect (number needed to treat to prevent one ARI [NNT]=33).Sub-group analysis revealed most benefit in those with the lowest vitamin D status at baseline and not receiving bolus doses. C_LI What this study addsO_LIWe updated this meta-analysis with trial-level data from an additional 14 placebo-controlled RCTs published since December 2015 (i.e. new total of 39 studies with 29,841 participants). C_LIO_LIAn overall protective effect of vitamin D supplementation against ARI was seen (NNT=36). C_LIO_LIA funnel plot revealed evidence of publication bias, which could have led to an over-estimate of the protective effect. C_LIO_LINo statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. C_LIO_LIStrongest protective effects were associated with administration of daily doses of 400-1000 IU vitamin D for [≤]12 months (NNT=8). C_LI C_TEXTBOX
