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Our take —

Despite the urgent need for interventions to lower risks of SARS-CoV-2 transmission at public events, there has been surprisingly little evidence from randomized trials. This RCT took place at a large indoor concert in Paris, France in May of 2021, and evaluated a package of transmission control measures including rapid antigen testing within 3 days of the event, optimized ventilation, mask distribution and mandatory mask-wearing, and a closure of all bars with a ban on alcohol consumption. Eight of the 3,917 attendees were PCR-positive 7 days after the concert (five of the eight were already PCR-positive on the day of the concert), while three of 1,947 non-attendees were PCR-positive at the same time. The infection rate among concert attendees was deemed to be “non-inferior” to that among non-attendees, meaning that the intervention was successful in preventing excess SARS-CoV-2 transmission. Although many caveats apply (e.g., this intervention came before the Delta variant and was conducted only among young adults), this trial demonstrates that, under the right conditions, a package of control measures can prevent large public gatherings from becoming loci of transmission.

Study design

Randomized Controlled Trial

Study population and setting

This was a randomized controlled trial involving 6,678 adults to evaluate the effectiveness of a package of SARS-CoV-2 transmission mitigation strategies in the context of a large indoor concert in Paris, France on May 29, 2021. Infection rates among concert attendees (n=3,917) were compared to those among non-attendees (n=1,947), and the intervention was evaluated for non-inferiority. Participants were recruited from a variety of media and randomized (2:1) to either concert attendance or non-attendance. Both participants and investigators were aware of treatment assignment. Eligible participants were Paris area residents aged 18-45 years with no comorbidities, who were not living with older or at-risk individuals, and who tested negative via a rapid antigen test performed by healthcare workers within the 3 days prior to the concert. Patients reporting symptoms compatible with COVID-19 or who reported contact with a person with a positive SARS-CoV-2 test within the past 14 days were excluded. The intervention consisted of the following elements: 1) presentation of negative rapid antigen tests at the arena gate; 2) distribution of a surgical facemask to all attendees with a mask-wearing mandate for the duration of the event; 3) mandatory hand sanitization at entrance with hand sanitizer stations throughout the arena; 4) a water bottle distributed to all participants with mask removal allowed for drinking; 5) closure of all arena bars and a ban on consumption of alcohol; and 6) ventilation employing 8 units, using only outside air without recirculation, on the arena floor and in all areas open to the public. Only the floor of the arena was open to the public (area=1,900 square meters). The show (one DJ set and one live set) lasted 2.5 hours and the doors were open for 4 hours; all artists and staff members (n=525) were tested for SARS-CoV-2 in the 3 days preceding the concert. All participants returned two self-collected saliva samples for RT-PCR testing (at day 0 and during a window from day 6-15); whole-genome sequencing was performed for SARS-CoV-2 subtyping and transmission cluster analysis. Cameras were used to capture mask-wearing behavior and neural networks were used to classify faces as a) not wearing a mask, b) wearing a mask inadequately (i.e., not covering the nose), or c) wearing a mask adequately; the proportion of adequate mask-wearing was calculated in 5-minute intervals and averaged over the 4 hours. The primary outcome was the proportion of PCR-confirmed SARS-CoV-2 infections at day 7.

Summary of Main Findings

The median age of participants was 28 years, and 59% were female; 43% were vaccinated with one dose and 7% were vaccinated with two doses, with 6% having received the second dose at least 14 days before the concert. Eight concert attendees (0.20%) tested positive on day 7 for SARS-CoV-2 infection, compared with three of the non-attendees (0.15%), for an estimated IRR of 1.33 (95% CI: 0.38 to 4.60). The 95% confidence interval for the absolute difference in incidence was -0.26% to 0.28, and the upper limit of this interval was lower than the prespecified threshold of 0.35% for non-inferiority. Five of the 8 attendees who tested positive at day 7 had also tested positive at day 0 (indicating prior infection), and an additional 5 attendees only tested positive at day 0. It is unclear whether the three remaining cases among attendees at day 7 acquired infection during the concert. Viral subtyping and cluster analyses did not indicate any transmission clusters at the concert, but not all positive results could be sequenced. None of the study participants required hospitalization. A sensitivity analysis using an imputed intention-to-treat dataset also found non-inferiority. In the mask-wearing behavior analysis, 33,349 faces were detected by the algorithm, and 85% were classified. Median mask-wearing compliance was estimated to be 90.0% (95% CI: 76.5 to 94.8) on the arena floor and 97.4% (74.1 to 99.9) in the lobby and staircases.

Study Strengths

For an intervention of this size and complexity, there was a fairly low rate of protocol deviation (3.5% in the treatment arm and 12.6% in the control arm, in addition to 8.5% who were assigned to attend the concert but did not). Active follow-up ensured a high rate of sample collection. The camera-based mask compliance analysis was novel and permitted assessment of mask-wearing over multiple time periods.

Limitations

This study took place when the Alpha variant was dominant in France, and it is unclear how results would generalize to the Delta variant or to other, more transmissible variants. Antigen testing during the 3 days preceding the concert did not detect 10 PCR-positive cases among attendees. The authors excluded 3.5% of attendees and 12.6% of non-attendees from analyses due to protocol violations (e.g., not returning saliva samples during the appropriate time window); estimation of SARS-CoV-2 incidence in either group could therefore be biased. Depending on the severity of the possible bias, the result of non-inferiority observed could be invalid (sensitivity analyses using intention-to-treat imputed datasets also concluded non-inferiority; while this is reassuring, these results depend on the validity of imputation of the missing saliva samples). The study was conducted among young adults; transmission risks may differ in other populations. Participants were aware that cameras were recording their mask-wearing behavior, which may have led to higher rates of mask compliance than would otherwise have occurred.

Value added

This is one of only two randomized controlled trials of an intervention to lower SARS-CoV-2 transmission risk at a public event; in fact, it is one of the only randomized controlled trials to date of any non-pharmaceutical intervention aimed at reducing the risk of SARS-CoV-2 transmission.  

Our take —

A two-dose regimen of the Pfizer vaccine (10 ug per dose, one third of the dose approved for individuals older than 11 years) was recently approved for emergency use in children aged 5-11 years in the United States. This study reported the results of related clinical trials that led to this emergency use authorization. In the initial dose-finding study, two 10-ug doses led to comparable neutralizing antibody levels with fewer adverse events than higher doses, and this was the dose carried forward into a larger randomized controlled trial of safety, immunogenicity, and efficacy. The two-dose regimen was 91% effective in preventing COVID-19, and provided a similar immune response to that observed in a cohort of 16-25 year olds who received the 30-ug dose approved for that age group. Adverse events associated with vaccination were generally mild and transient, with fever reported in 8% of vaccine recipients. There were no cases of myocarditis, though the study did not have enough participants to adequately assess the risks of this rare adverse event. Although the follow-up period was short (only about 2 months) and more data are forthcoming about longer-term safety and efficacy, these results provide strong justification for emergency use authorization of the vaccine among children aged 5-11 years.

Study design

Randomized Controlled Trial

Study population and setting

This publication reported the results from two related studies of the Pfizer COVID-19 vaccine among children aged 5-11 years: a Phase 1 dose-finding study and a Phase 2/3 randomized trial of safety, immunogenicity, and efficacy (ongoing, with results not yet available for children aged 6 months through 4 years). In the both studies, children with pre-existing conditions were eligible except those with immunocompromising conditions, those taking immunosuppressive therapy, or those with a history of MIS-C. For the Phase 1 study, entry criteria also included no prior COVID-19 diagnosis. The Phase 1 study (n=48, 50% male, mean age 7.9 years, 79% white) included 16 children assigned to each dosage arm (10 ug, 20 ug, and 30 ug), with blood samples collected at 7 days after the second dose for measurement of geometric mean SARS-CoV-2 neutralization titers (GMTs). In the Phase 2/3 study, 2,268 participants (52% male, mean age 8.2 years, 79% white) were assigned in a 2:1 ratio to two doses of either the vaccine (at a dose determined by Phase 1) or placebo. Immunogenicity was compared between a subset of study participants (n=485) and 350 16-25 year olds with respect to GMTs, increase in GMTs over one month, and the proportion of participants with seroresponse (defined by a 4-fold increase in titers from baseline). In this “immunobridging” analysis comparing the two age groups, success was defined by a point estimate of 0.8 or greater for the GMT ratio, with the lower limit of the 95% confidence interval greater than 0.67. For difference in seroresponse, immunobridging success was defined by the lower limit of the 95% confidence interval exceeding -10%. Efficacy was compared between those receiving the vaccine and placebo, starting 7 days after administration of the second dose, and was defined as 100 x (1-RR). Injections were administered in the Phase 1 study from March 24 to April 14, 2021. Randomization for the Phase 2/3 trial took place from June 7-19, 2021; median follow-up time was 2.3 months.

Summary of Main Findings

In the Phase 1 safety and immunogenicity dose-finding study, all local reactions were transient, with fever more common in the 30 ug group. There was one severe case of fever (39.7 degrees Celsius, resolving after one day) reported in a 10-year-old after the second dose of a 20 ug dose. The second dose was administered to the full group only for the 10 ug and 20 ug doses, and neutralizing GMTs 7 days after the second dose were 4163 for the 10 ug dose and 4583 for the 20 ug dose, and thus the 10 ug dose was selected for the Phase 2/3 trial. Among Phase 2/3 trial participants, adverse local reactions and systemic events were more common in the vaccine group (mostly mild to moderate, resolving in 1-2 days), with fatigue and headache as the most common systemic adverse events. Adverse events were more common after the second dose of vaccine, with fever occurring in 8.3% of vaccine recipients after either the first or second dose. One vaccine recipient experienced severe fever (40.0 degrees Celsius, resolving after one day). Severe adverse events were reported in 0.1% of vaccine recipients and 0.1% of placebo recipients; there were no deaths or adverse events leading to withdrawal. There were no reported cases of myocarditis or pericarditis. The geometric mean ratio of neutralizing GMTs (comparing 5-11 year olds receiving 10 ug to 16-25 year olds who received 30 ug) was 1.04 (95% CI: 0.93 to 1.18), which met the immunobridging criteria. The difference in percentage achieving seroresponse between age groups was 0.0% (-2.0% to 2.2%), which also met immunobridging criteria. Neutralizing GMTs 1 month after second dose were comparable between 5-11 year olds and 16-25 year olds (1198 vs. 1147), as were geometric mean fold rises from baseline to 1 month after second dose (118.2 vs. 111.4). Among participants with no prior evidence of SARS-CoV-2 infection, there were 3 cases of COVID-19 among vaccine recipients and 16 among placebo recipients (vaccine efficacy: 90.7%, 95% CI: 67.7% to 98.3%). There were no additional cases among participants with prior evidence of infection; the estimated vaccine efficacy among all participants was 90.7% (67.4% to 98.3%). There were no reported cases of severe COVID-19 or MIS-C.

Study Strengths

This was a randomized controlled trial. Immunogenicity was evaluated using a formal non-inferiority approach relative to serum neutralizing titers in an older age group. Detailed safety data on the vaccine was obtained and reported.

Limitations

Although neutralizing antibody titers currently represent the best known correlate of immunity, there are likely other important determinants of immunity (e.g., T-cell response) that were not measured. The mean duration of follow-up was only 2.3 months, so it is not possible to infer vaccine effectiveness or adverse event incidence over longer durations; however, the study is ongoing. The study was not powered to assess risks of rare adverse events (e.g., myocarditis) that have been observed in other age groups, though an expanded cohort is currently being followed. The age range of 5 to 11 years represents a wide developmental spectrum; although the study was not designed to have adequate power for age-stratified analyses, it would have been informative if immunogenicity data had been presented by age strata. This study was conducted before widespread transmission of the delta variant. 

Value added

These results are the first from a randomized controlled trial of a COVID-19 vaccine among children aged 5-11 years.

Our take —

This study examined a sub-cohort of participants in the phase three Coronavirus Efficacy vaccine (COVE) trial to identify antibody immune markers as correlates of protection against COVID-19 in individuals who received two doses of Moderna’s mRNA-1273 vaccine. All of the immune markers assessed showed an inverse correlation with risk of COVID-19 disease and were positively correlated with vaccine efficacy providing possible immune marker endpoints for future vaccine trials.

Study design

Randomized Controlled Trial

Study population and setting

This study examined a sub-cohort of participants in the phase 3 Coronavirus Efficacy (COVE) clinical trial of the mRNA-1273 vaccine(Moderna) to assess neutralizing and binding antibodies as correlates of protection against COVID-19 disease. Antibody markers including IgG against the spike protein and receptor binding domain (RBD) proteins and ID50 and ID80 inhibitory dilution titers were assessed as possible correlates. The sub-cohort included 1010 vaccine and 137 placebo recipients. 34% of participants were age 65 or older, and 40% were considered to be at risk for severe COVID-19 illness. Correlates were measured on days 29 and 57 after the second vaccine dose

Summary of Main Findings

Nearly all vaccine recipients had detectable IgG antibody responses by day 29 and detectable responses for all four immune markers by day 57. Spike IgG and RBD IgG were tightly correlated with each other, as were the ID50 and ID80 inhibitory dilution titers. Additionally, each of the binding antibody markers were correlated with each of the neutralization markers at each time point. Among 1,010 vaccinated participants, 46 experienced COVID-19 by day 29 and 36 more developed COVID-19 by day 57. Vaccine recipients who contracted COVID-19 had lower levels of markers compared to vaccine recipient non-cases. As the antibody marker level increased, the risk of COVID-19 in vaccine recipients decreased; there were zero COVID-19 endpoints at ID50 titers above 1000 IU50/ml. That said, there was substantial overlap between markers in vaccinated individuals with COVID-19 and without, precluding any measurement at individual levels that could lead to specific recommendations about protection or the need for boosting.

Study Strengths

This study cohort was diverse, including 54% of participants from communities of color, and included many participants at risk of severe COVID-19 disease. The COVE study will continue follow up with participants for two years, allowing longer term data to be collected.

Limitations

This study has several limitations. First of all, the results could simply represent statistical correlates of protection rather than mechanistic correlates. The study did not assess immune correlates against severe COVID-19 outcomes, although preventing this outcome is the primary goal of vaccines. The study also did not assess the role of T cell immunity on prevention of infection. Almost all COVID-19 cases in this study resulted from COVID-19 strains with spike protein similar to the sequence found in the mRNA-1273 vaccine. Therefore, the data here do not address immune marker correlates relative to variants of concern. This study was also performed before booster doses of mRNA-1273 were approved, so the effects of a third dose were unable to be analyzed.

Value added

This study defined immune marker correlates of protection against COVID-19 in individuals who received two doses of Moderna’s mRNA-1273 vaccine, providing possible immune marker endpoints for future vaccine trials.

Our take —

This randomized, placebo-controlled, phase 3 clinical trial tested the safety, immunogenicity, and efficacy of the ChAdOx1 n-CoV-19 vaccine (Oxford/AstraZeneca) in adults ages 18 and older in the United States, Chile, and Peru from August 28, 2020 to January 15, 2021. The vaccine was found to be safe and effective, with an overall vaccine efficacy of 74%. The vaccine proved to be effective across all age groups studied.

Study design

Randomized Controlled Trial

Study population and setting

This paper describes a randomized, placebo-controlled, phase 3 clinical trial that took place across 88 sites in the United States, Chile, and Peru between August 28, 2020 and January 15, 2021. The trial aimed to study safety, efficacy, and immunogenicity of the ChAdOx1 n-CoV-19 vaccine (Oxford/AstraZeneca) in these countries. There were 32,451 participants, who were randomized in a 2:1 ratio to either receive two doses of vaccine (5^10 viral particles) administered four weeks apart (21,635 participants) or two doses of a saline placebo four weeks apart (10,816 participants). Participants were aged 18 or older, and the group randomization was stratified by age group (18-64 or 64 years+). Safety analysis was performed on all participants who received at least one dose of vaccine or placebo. Unsolicited adverse events were recorded for 28 days following each dose, while serious adverse events were recorded throughout the duration of the study. A sub-study to assess reactogenicity and immunogenicity was conducted, with reactogenicity being studied for 7 days following each dose. Immunogenicity was analyzed by measuring antibodies against the SARS-CoV-2 spike protein and neutralizing antibodies found in serum samples from sub-study participants. The primary efficacy endpoint was to see how well the vaccine could prevent the onset of symptomatic and severe RT-PCR confirmed COVID-19 infection 15 or more days following the second dose compared to second dose of placebo. Patients in efficacy analysis were seronegative at baseline.

Summary of Main Findings

The safety analysis found that the most common adverse events were generalized pain, headache, injection-site pain, and fatigue, at a rate of at least 5% in either vaccine and/or placebo groups. A similar and very small percentage (around 0.5%) of participants in both groups had a serious adverse event within 28 days after any dose. Zero vaccine or placebo related deaths occurred during the trial, and no COVID-19 related deaths were noted, either. Importantly, incidences of deep-vein thrombosis, pulmonary embolism, thrombocytopenia, and immune thrombocytopenia was very low and similar in both groups (generally < 0.1%). The sub-study on reactogenicity found that more participants in the vaccine group experienced local and systemic adverse events compared to the placebo group. Most (about 92%) of these adverse events were mild or moderate in degree and resolved 1-2 days after onset. There were fewer adverse events following the second dose in both the vaccine and placebo group. Overall vaccine efficacy (VE) was estimated to be 74% (95% CI, 65.3-80.5; P < 0.0001). Due to the clinical trial being put on hold, some patients received their second dose outside of the normal 28-day window, but VE was calculated to be similar in this group 78.1%, 95% CI, 49.2-90.6). When using the CDC’s definition of COVID-19, which can include mild disease, overall VE was estimated to be 70%. VE in participants ages 65 and older was estimated to be 83.5% (95% CI, 54.2-94.1). No severe or critical symptomatic cases of COVID-19 were observed in fully vaccinated participants, while 8 cases were noted in the placebo group. Then efficacy of the vaccine in preventing infection, assessed by measuring antibodies in patient serum, was 64.3% (95% CI, 56.1-71.0; P < 0.001). As for the exploratory endpoint measuring the vaccine’s efficacy in prevention against COVID-19 hospitalizations, VE was estimated to be 94.2% (95% CI, 53.2-99.3). Neutralizing antibodies against the COVID-19 spike protein were observed to increase after the first dose of vaccine and even more so when measured 28 days after second dose of vaccine, while levels remained low throughout the trial in the placebo group.

Study Strengths

This trial aimed to include a diverse population, studying the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine in three new countries across a wide age range. Participants also included those with coexisting conditions, as well as some participants with well-controlled HIV.

Limitations

While trying to include a diverse population, 79% of participants were still white. Due to small COVID-19 case numbers in Chile and Peru sites, vaccine efficacy could not be estimated for those locations. The level of neutralizing antibodies that correlates with protection is still unknown. Early unblinding of group assignment for more than one third of participants occurred in order to allow patients a choice in deciding whether they would like to become vaccinated after other vaccines received emergency use approval. Finally, the results included in this report encompass only a short duration of follow up.

Value added

This report describes the safety and efficacy of the Oxford/AstraZeneca vaccine in United States, Chile, and Peru.

Our take —

This randomized controlled trial of daily testing of contacts of SARS-CoV-2 cases (“test-to-stay”) vs. 10-day quarantine in secondary schools and colleges in England found that the test-to-stay approach did not increase virus transmission within schools and may have reduced COVID-19 related school absences by 20%. However, compliance with the test-to-stay intervention varied substantially across schools, suggesting that the feasibility of this intervention is setting-dependent. Overall, transmission from index cases to close contacts within schools was low (~2%).  

Study design

Randomized Controlled Trial

Study population and setting

This open-label cluster randomized controlled trial of daily testing of close contacts of SARS-CoV-2 cases was conducted in 201 secondary schools and further education colleges (students aged 11 years and older) in England between April and June 2021, during which time the Delta (B.1.617.2) variant was the predominant circulating strain, but community transmission rates were low to moderate. SARS-CoV-2 cases in intervention and control arms were routinely identified through twice weekly asymptomatic testing using lateral flow devices (LFD; i.e., rapid tests) and symptom screening. Schools were randomized such that asymptomatic close contacts of cases in schools were given either 10-day quarantine (control arm) or daily testing with LFD for seven days, excluding weekends (intervention arm). Contacts in the intervention arm could remain in school if they tested negative on the LFD that day (i.e., test-to-stay). LFD testing was done using Orient Gene (Huzhou, China) by school staff on anterior nasal swabs. All individuals with a positive LFD test or with symptoms indicative of SARS-CoV-2 infection were required to isolate and obtain a PCR confirmatory test. Randomization was done at the school level, and stratified based on school type (secondary vs. college), presence of residential students, presence of a 6th form, and the proportion of students eligible for school meals (>17% or ≤17%). Co-primary outcomes were assessed in students and staff at the school-level and included (1) rates of COVID-19 school-related absences and (2) PCR-confirmed COVID-19, adjusted for community case rates. Data on school-related absences were either directly reported by the schools or obtained through government databases, whereas data on PCR-confirmed COVID-19 were obtained solely through the National Health Services (NHS) Test and Trace Program database. The trial was designed as a non-inferiority trial, meaning that it was powered to identify whether the intervention and control arms had similar outcomes rather than, as is more typical, powered to find a difference in the outcomes across arms.  Primary analyses were intent-to-treat and done using quasi-Poisson regression. In secondary analyses, efficacy was assessed after adjustment for compliance with the LFD testing intervention, where compliance was defined for individuals as 3 or more LFD tests or an LFD positive test.  

Summary of Main Findings

2000 schools were notified of the study, and 201 schools were enrolled and assigned to either the intervention (n=102) or control (n=99) arm. Among these schools, 77% (n=76) in the control arm and 84% (n=86) in the intervention arm directly reported student and staff lists and attendance data. Overall, SARS-CoV-2 transmission from index cases to close contacts was low in intervention and control arms (~2%). Mean compliance with the intervention (i.e., daily LFD testing) was 42% (n=2432/5763 contacts), but compliance varied substantially across schools (median 63%: IQR=40-79%). In primary, intent-to-treat-analyses, COVID-19 school-related absences were non-significantly reduced by 20% in the intervention arm (adjusted incidence rate ratio [IRR] 0.80; 95%CI 0.54-1.19). After adjustment for compliance, there was a greater relative reduction in COVID-19 related school absences observed in the intervention arm (IRR 0.61; 0.30-1.23), but this difference was also not statistically significantly different. In a separate analysis of impact on all-cause school absence rates, there were no differences observed between study arms (0.97; 95%CI: 0.82-1.16). There were also no differences in rates of PCR-confirmed symptomatic infection between study arms (IRR 0.96; 95%CI:0.75-1.22). While cases were more commonly found among students in both arms, intervention efficacy for either of the two primary outcomes did not significantly differ between students and staff. Using data on a subset of PCR-confirmed infections, the LFD rapid was estimated to have 99.93% specificity and 53% sensitivity.

Study Strengths

The major strength of this study is that it was a randomized controlled trial. Multiple, independent databases were used to obtain information on the primary outcomes. Infection rates in schools were adjusted for background community transmission rates. Multiple policy relevant outcomes were assessed, and sensitivity analyses conducted. The non-inferiority design was appropriate given the study hypotheses, which were that there would be a reduction in COVID-19 related absences but that there would not be a difference in SARS-CoV-2 transmission across arms.

Limitations

Compliance with routine asymptomatic testing and symptom screening to identify index cases was reportedly poor, but not quantified in either study arm. Not all schools directly reported data to the study teams, and so intervention compliance could only be assessed from a subset of schools, which likely had higher compliance rates. This study was conducted over a relatively short time frame (~10 weeks), during periods of low/moderate SARS-CoV-2 transmission, and was underpowered to detect modest differences in outcomes between arms. Variability in other transmission control measures (e.g., masking protocols, air circulation protocols, spacing of students in classrooms) across schools was not reported, and so it is possible that there was unmeasured confounding by these measures due to chance imbalances. Given that this study only included secondary schools or higher, the findings may not be applicable to children in primary schools, pre-school, or day care.

Value added

This is the first randomized controlled trial to study an intervention to reduce SARS-CoV-2 transmission in an educational setting. Detailed, high quality information on the epidemiology of virus transmission within schools is also provided.

Our take —

COVID-19 convalescent plasma has been widely employed in the US through an Extended Access Program. However, the results of this randomized clinical trial of 938 hospitalized patients needing oxygen support, which took place between May 2020 and January 2021, show that convalescent plasma does not reduce mortality or the need for intubation at 30 days post enrollment. Furthermore, the risk of serious adverse effects (worsening hypoxemia, respiratory failure) was significantly increased in patients who received convalescent plasma treatment (33.4% vs 26.4%, RR 1.27). The results of this study provide further evidence against the use of convalescent plasma for patients hospitalized with COVID-19.

Study design

Randomized Controlled Trial

Study population and setting

The study described in this article is a multi-center, open-label randomized controlled trial of 938 patients hospitalized within 12 days of onset with COVID-19 needing oxygen support. The study was conducted between May 14, 2020 and January 29, 2021, across 72 hospitals in the US, Canada, and Brazil. The study compared the proportion of patients who died or who required intubation within 30 days of enrollment between those receiving standard of care (n = 307) and those receiving COVID-19 convalescent plasma (n = 614). Secondary analyses of note include that of safety of convalescent plasma, as well as the role of antibodies in modifying the effect of convalescent plasma.

Summary of Main Findings

The trial was stopped at 78% of planned enrollment after an interim analysis suggested no benefit to the intervention group. In an intention-to-treat analysis, 199/614 (32.4%) of patients in the convalescent plasma group died or were intubated within 30 days, versus 86/307 (28.0%) in the standard of care group, a nonsignificant difference (RR 1.16, 95% CI: 0.94 – 1.43, p 0.18). Subgroup analysis found that patients receiving plasma from supplier 3, as well as patients not on corticosteroids, had worse outcomes when receiving convalescent plasma compared to standard of care. However, there were no significant differences in outcomes of any other subgroup analyses, including age, sex, ethnicity, blood type, smoking history, comorbidities, disease timeline, or level of oxygen dependency. Serious adverse events, typically worsening hypoxemia and respiratory failure, were significantly more likely in the convalescent plasma group (33.4%) compared to the standard of care group (26.4%; RR 1.27, 95% CI: 1.02 – 1.57, p 0.034).

Study Strengths

A major strength of this study was the additional serological testing of the plasma, which identifies factors that change and may explain variations in the treatment effect. Specifically, the study found plasma with higher capability for antibody-dependent cell cytotoxicity reduced the odds ratio by 24% per unit (95% CI 0.62 – 0.92). Similarly, plasma with higher capability for neutralization reduced the odds ratio by 23% per unit (95% C1 0.63 – 0.94). Another strength of the study was the accompanying meta-analysis, which summarized evidence both from studies that evaluated exclusively high-titer convalescent plasma therapy and those that evaluated  convalescent plasma of indiscriminate titer but found no evidence of benefit from either approach.

Limitations

This is an open-label study, which can introduce bias into the observation and reporting of adverse effects, as well as the planning of treatment strategies and potentially skew the data.

Value added

This study corroborates previous randomized controlled trials in finding that treatment with COVID-19 convalescent plasma does not reduce mortality or need for intubation at 30 days. In addition, this study found that convalescent plasma treatment was significantly more likely to lead to serious adverse effects, including worsening hypoxemia and respiratory failure, compared to usual standard of care.

Our take —

This was a very large and well-designed cluster-randomized controlled trial of a multi-pronged intervention program to encourage mask-wearing in rural and peri-urban Bangladesh from November 2020 to April 2021; it was available as a preprint and is thus not yet peer reviewed. The study found that the intervention package (which included mask distribution, public role-modeling, and encouragement to non-mask-wearers in public settings) more than tripled public mask usage behaviors (from 13% to 42%) without diminishing observed physical distancing. Most importantly, villages with the intervention had a 10% relative reduction in symptomatic seroprevalence (reported COVID-19 symptoms with presence of SARS-CoV-2 antibodies) compared to control villages. Surgical masks were apparently more effective than cloth masks. This study did not measure whether mask wearing was associated with COVID-19 at an individual level, and there are potential problems with the outcome measure of symptomatic seroprevalence. However, the study provides evidence that interventions promoting mask use can reduce community SARS-CoV-2 transmission even when fewer than half of community members wear masks. If the results are valid, they imply that near-universal mask wearing would be associated with much larger reductions in transmission.

Study design

Randomized Controlled Trial

Study population and setting

This was a cluster-randomized trial of community-level promotion of mask-wearing, designed to estimate the impact of interventions on SARS-CoV-2 symptomatic seroprevalence in Bangladesh from November 2020 to April 2021. Secondary outcomes included mask-wearing behavior, physical distancing behavior, and COVID-19 symptom prevalence. The study was conducted in 600 rural and peri-urban villages containing 341,830 adults throughout Bangladesh. From an initial sampling frame of 1,000 rural and peri-urban unions (a union is a rural administrative unit in Bangladesh, consisting of ~80,000 people), the authors used pairwise randomization to select 300 intervention and 300 control unions, and selected one village (containing the largest regional market) in each union. The intervention was rolled out in waves from November 2020 to January 2021, and lasted for 8 weeks. Control group villages received no intervention. Intervention group villages received a multi-pronged mask promotion strategy, designed in conjunction with local leaders. The intervention had five elements: 1) one-time mask distribution and promotion to households, 2) mask distribution in markets 3-6 days per week, 3) mask distribution at mosques on three Fridays, 4) mask promotion in public spaces and markets, during which non-mask-wearers were encouraged to wear masks, and 5) role-modeling and active promotion of masks by religious and other community leaders. In addition, intervention villages were cross-randomized to four additional interventions: 1) cloth vs. surgical masks, 2) village-level incentives if a given level of mask-wearing was achieved vs. no incentives, 3) public commitments via provision of signs to households vs. no public commitments, and 4) additional text message reminders vs. no reminders. There were also three additional household-level cross randomizations: 1) messages focused on community protection vs. self-protection, 2) twice-weekly text message reminders, and 3) asking households to make a verbal commitment to mask-wearing. The households received differently colored masks depending on the sub-arm to which they were randomized, and the color schemes themselves were randomized village-by-village. The behavioral outcomes for this study were measured by an enumerator who recorded behaviors in a public space in each village. The enumerator noted whether people were wearing masks, the colors of those masks, whether both mouth and nose were covered, and whether people were keeping physical distance from each other. Behavioral data was measured up to 10 weeks following the start of the intervention, and additionally 20-27 weeks after baseline. One member per household completed phone surveys at weeks 5 and 9 to assess SARS-CoV-2 symptom prevalence (consistent with the WHO COVID-19 case definition for suspected or probable cases with an epidemiologic link) in the previous month. Participants who reported symptoms were tested for IgG antibodies against SARS-COV-2 during weeks 10-12.

Summary of Main Findings

Symptomatic seroprevalence: Symptom data was collected from 98% of the study population; 8.6% of participants in control villages reported having COVID-19 symptoms, while the figure for intervention villages was 7.6%. Of all 13,893 symptomatic participants, 40% consented to providing blood, and 37% were tested for SARS-CoV-2 antibodies. The adjusted prevalence ratio for symptomatic seroprevalence was 0.907 (95% CI: 0.817 to 0.997), implying a 9% relative reduction in symptomatic seroprevalence comparing intervention villages to control villages. When considering only symptoms, the adjusted prevalence ratio was 0.88 (0.83 to 0.93), implying a 12% reduction in self-reported COVID-19 symptoms during the study period for intervention villages relative to control villages. Subgroup analyses suggested greater reductions in symptomatic seroprevalence for surgical masks compared to cloth masks, and for older participants relative to younger participants. Among participants aged 60 years and older, the adjusted prevalence ratio was 0.65 (0.46 to 0.85), implying a 35% reduction in symptomatic seroprevalence in intervention villages.

Mask-wearing behavior: The estimated prevalence of mask-wearing behavior was 13% in the control group and 42% in the intervention villages, implying that the intervention increased mask-wearing behavior by 29 percentage points. Models controlling for baseline characteristics of villages (baseline mask-wearing, baseline SARS-CoV-2 symptom prevalence) produced the same result. Physical distancing behavior also increased from 24% in the control arms to 29% in the intervention arms, suggesting that increased mask wearing did not cause net risk-compensating behaviors. Mask wearing behavior effects persisted for the full 10-week period of the study; however, by weeks 20-27, mask-wearing in intervention villages declined to 22% while mask-wearing in control villages declined to 14%. None of the cross-randomized interventions (e.g. changes in messaging, monetary incentives, etc.) had any substantial effects on mask-wearing behavior. Evidence from pilot studies indicated that the primary mechanism of the intervention’s effectiveness was promotion of mask-wearing in public spaces.

Study Strengths

This study was a very large and well-designed cluster randomized controlled trial of a realistic intervention. Outcome measures included directly observed behavior, rather than self-reported behavior. Symptom data was measured in a very high proportion of participating households. Analyses were pre-specified.

Limitations

The outcome measure– the proportion of individuals who reported symptoms and who tested positive for antibodies– is a poor proxy for actual SARS-CoV-2 infections during the study period. Moreover, only 40% of those reporting SARS-CoV-2 symptoms consented to providing a blood sample for antibody testing. If there were systematic differences between intervention and control villages in the proportion of antibody-positive individuals among the >60% of symptomatic individuals who were not tested, the results would be biased. As this was a cluster randomized trial, the study could not link individual mask-wearing behavior with incident SARS-CoV-2 infection, and could only measure putative effects on community-level transmission. It is unclear whether the serological assay used to assess the primary outcome was validated in the population under study, or when serological measurements were taken relative to symptom onset. Furthermore, using symptomatic seroprevalence as an outcome means that authors could not distinguish between effects on infections and on symptom severity. Another key limitation is that the persons recording the behavior data could not be blinded to whether the village was a control or intervention arm, leaving open the possibility that data recorders could have been influenced by knowledge of the study arm. People from control villages may have acquired masks or encountered mask promotion in nearby intervention villages, which would dilute the apparent effectiveness of the intervention on behavior. Finally, it is unclear whether or how the intervention would need to be modified to obtain similar results outside the setting of Bangladesh.

Value added

This study is the largest and best-designed randomized controlled trial to date of a realistic non-pharmaceutical intervention on SARS-CoV-2 transmission.

Our take —

Although awake prone positioning has gained favor in clinical practice for treatment of COVID-19 patients requiring high-flow oxygen supplementation, no clinical trials to date had assessed its efficacy. This large meta-trial of 1,121 patients (including six individual randomized trials from Canada, France, Ireland, Mexico, Spain, and the USA) evaluated the efficacy of awake prone positioning, in addition to standard high-flow nasal cannula, for preventing intubation or death among COVID-19 patients with acute hypoxemic respiratory failure. Patients in the intervention arm were 14% less likely to have treatment failure (intubation or death by 28 days after enrollment) and more likely to be weaned off high-flow nasal cannula compared to the standard of care. On the other hand, among those who survived, the two groups spent a similar amount of time in the hospital (16.4 vs. 16.5 days in intervention vs. control groups, respectively) and, among those intubated, on invasive mechanical ventilation (12.4 vs. 12.4 days). Despite some possible sources of bias, this study provides strong evidence of the benefits for awake prone positioning among patients with severe COVID-19 pneumonia in six upper-middle and high-income settings.

Study design

Randomized Controlled Trial

Study population and setting

This collaborative, prospective meta-trial combined individual-level data from six randomized clinical trials in hospitals from six countries (Ireland, USA, Mexico, Spain, Canada and France) to evaluate the efficacy of awake prone positioning for COVID-19 patients between April 2, 2020 and January 26, 2021. The study included patients with acute hypoxemic respiratory failure (requiring respiratory support with high-flow nasal cannula and with a ratio of peripheral arterial oxygen saturation to the fraction of expired oxygen (SpO2: FiO2) of 315 or lower) due to clinically confirmed or suspected COVID-19 pneumonia. The study excluded those with body mass index above 40 kg/m2, pregnant women, hemodynamically unstable patients, those unable to provide consent, and those with a contraindication to awake prone positioning. The primary outcome was treatment failure, defined as intubation or death. Secondary outcomes included intubation, death, use of noninvasive mechanical ventilation, time to weaning off high-flow nasal cannula, time to treatment failure, time to intubation, and time to death. The relative risk for the primary outcome was estimated with a mixed effect log-binomial model. Proportional hazards models were used to estimate differences in times to events. For intubation, mortality was considered as a competing risk. Analyses were pre-specified, including a subgroup analysis among patients who had SpO2/FiO2 less than 190.

Summary of Main Findings

Among the 1,126 patients in the study, 564 were randomized to the awake prone positioning arm and 557 to the standard of care arm. The median duration of awake prone positioning was 5 hours. In intention-to-treat analysis, 40% of the patients assigned to the intervention arm had been intubated or died by day 28 of enrollment compared to 46% in the standard of care arm (RR=0.86, 95% CI: 0.75 to 0.98). The estimated number of patients who need to be treated with awake prone positioning to prevent one intubation or death was 15 (95%CI: 8 to 156).  Regarding secondary outcomes, patients in the intervention arm were less likely to be intubated (33% vs. 40%) and were more likely to be weaned off high-flow nasal cannula. There were no differences in 28-day mortality, time to death, length of hospital stay, or time for weaning off mechanical ventilation. In the intervention arm, those who were able to maintain prone positioning daily for at least 8 hours were less likely to be intubated or die compared to those who had less than 8 hours of daily prone position (17% vs. 48%).  There was no difference in the incidence of central or arterial line dislodgement between the two groups, and none of the patients had cardiac arrest due to prone positioning.

Study Strengths

This was a large meta-trial including six randomized clinical trials, with a large sample size, coordination across study protocols, and pre-specified analytical plans. The study included trials from six different countries with wide variation in their health care systems, allowing greater confidence in the generalizability of the findings.

Limitations

There was significant variability in the median duration of awake prone positioning across trials, with a total median duration of only 5 hours. It is possible that longer durations could have led to better outcomes. Also, one in ten patients in the control group were treated with awake prone positioning. This, combined with the intention-to-treat analysis, could have resulted in underestimating the true effect of prone positioning in preventing intubation or death. Also, no stratification for the duration of prone positioning was done at study enrollment, which limits the interpretation of lower rates of intubation and death among patients who had eight hours or more of awake prone positioning. The trial could not be blinded, and treatment assignment may have affected clinical decision-making. For example, mechanical ventilation may have been delayed in the intervention arm due to temporary improvement of respiratory parameters during prone positioning. Finally, despite coordination, there were variations across trials in inclusion criteria that may have had unpredictable effects on results.

Value added

This is the first prospective randomized study to evaluate the efficacy of awake prone positioning for COVID-19 patients requiring high flow oxygen supplementation.

Our take —

Moderna’s mRNA-1273 vaccine against COVID-19 was determined to be safe in adolescents ages 12-17. The immune response generated by the vaccine was similar to those in young adults ages 18-25 years that were included in the larger phase 3 trial of adults. The vaccine was estimated to be over 90% effective at preventing COVID-19 in this age group, and therefore there was an overall favorable benefit-risk ratio. The success of this vaccine is important since there are few vaccine options for people in the adolescent age group.

Study design

Randomized Controlled Trial

Study population and setting

This phase 2-3, randomized, placebo-controlled trial tested Moderna’s mRNA-1273 vaccine in healthy male and female adolescents ages 12-17 years old. The trial took place between December 9, 2020 and February 28, 2021 at 26 sites in the United States and included 3,732 participants. Participants were randomized 2:1 to either receive two doses of 100ug of mRNA-1273 or two doses of placebo 28 days apart. Primary objectives were safety of the vaccine, which was tracked through adverse events and data on multi-inflammatory syndrome in children (MIS-C) throughout the trial, and noninferiority of the immune response in the adolescent age group compared to the young adult (18-25) age group. Noninferiority was assessed by measuring neutralizing antibody titers 28 days after the second dose and comparing these values to those of the young adult group. A secondary aim of the study was to gain a preliminary assessment of vaccine efficacy against preventing COVID-19 or asymptomatic SARS-CoV-2, evaluated by PCR testing and clinical symptoms.

Summary of Main Findings

In the safety assessment, the most common solicited reaction was injection site pain after first dose. Other common systemic reactions included fatigue, headache, muscle pain, and chills. There was a higher incidence of adverse events in the vaccine group compared to the placebo group. Additionally, incidence of erythema, or skin redness, was higher in the adolescent group compared to young adults. No deaths, MIS-C or adverse events occurred in either group. The criteria for noninferiority of the immunogenicity were met for both objectives, and it was determined that the vaccine worked as well in adolescents as it does in young adults. Vaccine efficacy was estimated to be 93.3% using the CDC’s definition of COVID-19 with onset at least 14 days after the 2nd dose. For asymptomatic infection, vaccine efficacy was estimated to be 39.2% for the per protocol population, but this is consistent with other age groups in that efficacy against asymptomatic infection is lower than efficacy against symptomatic COVID-19.

Study Strengths

This trial included a modest number of participants in an age group that has been sparsely studied in the realm of COVID-19 vaccines. The data from the adolescents in this study was compared to results from young adults in the phase 3 trial. Also, the young adults had similar demographic characteristics to the adolescents in this trial.

Limitations

The trial population was less diverse, and therefore less representative of the US population, compared to the participants in the phase 3 trial. Over 80% of participants were white. Next, efficacy was difficult to assess here due to a very low incidence of COVID-19 in the participants, with only 4 cases in the placebo group and 0 cases in the vaccine group, therefore the authors used the CDC’s less stringent definition of COVID-19. There was also a relatively low number of asymptomatic cases, resulting in a negative lower boundary of the 95% confidence interval. Finally, safety data was based on assessments for a median of 83 days of follow-up, and therefore any longer-term effects cannot be determined from this study. Although it should be noted that there have been no long-term effects of the vaccine reported in previous trials suggesting this is not a concern.

Value added

First report of safety, immunogenicity, and efficacy results for Moderna’s mRNA-1273 vaccine in adolescents.

Our take —

Given evidence of COVID-related thrombosis (blood clots), these two randomized controlled trials (first, second) assessed whether heparin was better than usual-care blood clot prevention (i.e., thromboprophylaxis) for patients hospitalized with COVID-19. For patients with noncritical COVID-19, therapeutic-dose heparin reduced the need for organ support significantly (19.8% vs. 23.6%) and reduced death (7.3% v 8.2%), albeit non-significantly. In contrast, patients with critical COVID-19 received no benefit from therapeutic-heparin; in fact, patients with critical COVID-19 likely had an increased risk of in-hospital mortality (37.3% vs. 35.5%) and the need for organ support (1 vs. 4 organ support-free days) as compared to standard thromboprophylaxis. Additionally, critically and non-critically ill patients receiving therapeutic heparin were both slightly more likely to have major bleeds. Overall, these studies can inform clinical decision-making regarding blood clot prevention and provide evidence that therapeutic-dose heparin may be beneficial, but only for patients with mild to moderate COVID-19 symptoms.

Study design

Randomized Controlled Trial

Study population and setting

These were two international open-label, multiplatform, randomized controlled trials published concurrently comparing therapeutic dosing of heparin to usual standard thromboprophylaxis in patients hospitalized with Covid-19. The patients were determined to be critically ill based on the need for critical-care organ support (high-flow nasal cannula, mechanical ventilation, extracorporeal life support, vasopressors, or inotropes) at time of enrollment, or noncritically ill otherwise. The primary outcome was number of days free of organ support in the first 21 days, with patients who did not survive to discharge being automatically scored -1.

Summary of Main Findings

Enrollment began in April 2020 for both studies. For critically ill patients, the study enrolled 1207 patients through December 2020, when an interim analysis showed futility. Patients who received therapeutic dose heparin had a median of 1 organ support-free day (IQR -1 to 16) versus 4 (IQR -1 to 16) in the usual standard of care group (OR = 0.93; 95%CI 0.67 – 1.03; posterior probability of futility = 99.9%; posterior probability of inferiority = 95%). 62.7% of patients in the heparin group survived to hospital discharge, versus 64.5% in the usual standard of care group (OR = 0.85; 95%CI = 0.64 – 1.11; posterior probability of inferiority = 89.2%).

For noncritically ill patients, the study enrolled 2244 patients through January 2021, when an interim analysis showed superiority. The median number of organ support-free days was 22 in both groups; 80.2% of noncritically ill patients who received therapeutic dose heparin survived until hospital discharge without needing organ support, versus 76.4% in the standard of care group (absolute difference 4.0%, 95%CI = 0.5 – 7.2). The odds ratio of organ-support free days was 1.27 (95%CI 1.03 – 1.58; posterior probability of superiority 98.6%) and was similarly high after stratification by D-dimer level. Major bleeding occurred in 1.9% of patients in the treatment group, versus 0.9% in the standard of care group, with 3 cases of fatal bleeding in the treatment group, versus 1 in the standard of care group.

Study Strengths

As the studies were paired, the results between the two can be readily controlled and compared. The sample size of both studies was large, allowing for stratified analyses. By using Bayesian analyses, the authors were able to set and use cutoffs to determine when the study was sufficiently powered. The multiplatform nature of the studies also suggests that these findings are generally reproducible in broad clinical contexts.

Limitations

This was a pair of open-label studies, so participants were not blinded to treatment group. This introduced the risk of ascertainment bias, in which a patient on a higher dose of heparin may have been more aggressively monitored for bleeds. The study excluded patients with an increased risk of bleeding, which was important for study balance but excluded a nontrivial amount of people at risk for moderate to severe COVID-19. Standard-of-care thromboprophylaxis varied between sites; most critically ill participants were enrolled in the UK, where standard treatment guidelines included intermediate-level heparin treatment for all COVID-19 patients, which may have impacted between-group comparisons and study generalizability. Early trial conclusion prevented researchers from identifying long-term secondary benefits of treatment.

Value added

These paired studies provide strong evidence that treatment with therapeutic dose heparin (as if the patient had a known venous thromboembolism) is beneficial for reducing in-hospital mortality and the need for organ support among patients with noncritical COVID-19. However, this approach provides no benefit to patients with critical illness (patients needing ICU-level care at time of enrollment), and is likely inferior to standard thromboprophylaxis treatment.