IMPORTANCE Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit. OBJECTIVE To determine whether ivermectin is an efficacious treatment for mild COVID-19. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state's health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020. INTERVENTION Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200). MAIN OUTCOMES AND MEASURES Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected. RESULTS Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group). CONCLUSION AND RELEVANCE Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

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Background A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. Methods This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0•5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1•50 mg CpG-1018 and 0•75 mg alum) or placebo (0•9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). Findings 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44•4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67•2% (95•72% CI 54•3-76•8), 83•7% (97•86% CI 55•9-95•4) against moderateto-severe COVID-19, and 100% (97•86% CI 25•3-100•0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78•7% (95% CI 57•3-90•4) for delta, 91•8% (44•9-99•8) for gamma, and 58•6% (13•3-81•5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35•7% [287 of 803] vs 10•3% [81 of 786]) and second (26•9% [189 of 702] vs 7•4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. Interpretation Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. Funding Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Background Takeda’s live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across eight dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year post-vaccination. This exploratory analysis provides an update with cumulative and third year data. Methods Healthy 4–16 year-olds (n=20,099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific RT-PCR. Results Cumulative efficacy after three years was 62.0% (95% confidence interval: 56.6%, 66.7%) against virologically-confirmed dengue (VCD) and 83.6% (76.8%, 88.4%) against hospitalized VCD. Efficacy was 54.3% (41.9%, 64.1%) against VCD and 77.1% (58.6%, 87.3%) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9%, 70.1%) against VCD and 86.0% (78.4%, 91.0%) against hospitalized VCD in seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5%, 54.7%), while efficacy against hospitalized VCD was sustained at 70.8% (49.6%, 83.0%). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (i.e. second half of the three years following vaccination), but none were related. No important safety risks were identified. Conclusions TAK-003 was efficacious against symptomatic dengue over three years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.