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Our take —

Global vaccination against COVID-19 will continue for the remainder of 2021, overlapping with seasonal influenza vaccine administration. Provision of both vaccines in a single visit would help maximize vaccine compliance, but there have been concerns regarding the safety and efficacy of co-administered vaccines. This study, available as a preprint and thus not yet peer-reviewed, demonstrates that co-administration of vaccines for SARS-CoV-2 and influenza is both safe and effective. While further research is needed, particularly among those over 65 years of age, these data could be used to guide national vaccine policy decision making, since vaccine co-administration appears to be a viable and safe option.

Study design

Randomized Controlled Trial, Non-Randomized Trial

Study population and setting

Conducted as a substudy of the phase 3 trial for NVX-CoV2373 (Novavax; September-November 2020), this study assessed the safety and efficacy of open label influenza vaccine coadministration with the first dose of NVXCoV2373 (n= 217) vs. placebo (n=214). Rates of minor vaccine reactions (collected via electronic diary) and adverse events were compared to a reactogenicity cohort from the main study (n=2000). Immunogenicity against influenza was assessed using a hemagglutination inhibitor assay, while that against SARS-CoV-2 was assessed by quantifying anti-spike IgG with ELISA; results were compared to an immunogenicity cohort from the main study (n=900). The primary vaccine efficacy endpoint was based on PCR detection of symptomatic SARS-CoV-2 infection at least seven days after administration of the second vaccine dose in participants aged 18 to 64 years who had not been previously infected with SARS-CoV-2 (n=360). Results were compared to vaccine efficacy for the per-protocol population of the main study age 18 to 64 years (n= 10,129), as well as vaccine efficacy against the Alpha variant for the per-protocol population of the main study (n=14,040).

Summary of Main Findings

Participants who received both vaccines had an increased frequency of minor reactions, including pain at the injection site, muscle aches, and fatigue. True adverse events were infrequent and not associated with vaccine co-administration. There was no significant change in the immune response to the influenza vaccine as a function of co-administration. However, antibody responses generated to NVX-CoV2373 were reduced among participants who had received both vaccines, as compared to those who had received only NVX-CoV2373. Vaccine efficacy in the co-administration substudy was 87.5% (CI: -0.2 – 98.4%), as compared to 89.8% (95% CI: 79.7 – 95.5%) for the main study. All substudy breakthrough infections were due to the Alpha variant; vaccine efficacy in the main study against the Alpha variant was 86.3% (95% CI: 71.3 – 93.5%).

Study Strengths

This study employed a placebo-controlled design to assess the safety and efficacy of coadministration of vaccines for SARS-CoV-2 and influenza. Influenza vaccines were assigned based on the public health guidelines for each age group. The study included laboratory measures of immunogenicity, as well as vaccine efficacy based on breakthrough infection events.

Limitations

Participation in the co-administration substudy, the reactogenicity cohort, and the immunogenicity cohort was not randomized. Substudy participants were younger, more diverse, and had fewer comorbidities than those in the main study. Influenza vaccine was administered open label to allow participants to discriminate between vaccine sites for reaction documentation. NVX-CoV2373 immunogenicity was assessed based on total antibody titer to spike protein, not neutralizing antibody titer. Due to the small number of substudy endpoint cases, 95% confidence intervals for NVX-CoV2373 efficacy were quite broad and the lower bound contained zero. The small number of breakthrough infection events also prevented the assessment of co-administered vaccine efficacy in individuals age 65 or older.

Value added

This is the first study demonstrating the safety and efficacy of coadministration of vaccines for SARS-CoV-2 and influenza.

Our take —

This double-blind, multicenter, 1:1 randomized controlled trial was conducted between March and December 2020 among 4,488 non-hospitalized patients diagnosed with COVID-19 who were either aged 70+ years or aged >40 years with at least one risk factor for severe disease (i.e., common comorbidities, shortness of breath, fever > 38.4 degrees C, or lab abnormalities). Patients were enrolled within 24 hours of their diagnosis. Then, within 4 hours of their enrollment, patients received their treatment (colchicine or placebo) via home-delivery. The results suggest that treatment with oral colchicine (0.5 mg twice daily for 3 days and then once daily for 27 days) reduced the risk of hospitalization or death from COVID-19. While this result did not reach statistical significance because the trial was stopped early, additional trials showing similar effects would strengthen the case for considering colchicine to prevent adverse short-term outcomes from COVID-19.

Study design

Randomized Controlled Trial

Study population and setting

The COLCORONA trial was a phase 3, double-blind, multicenter randomized controlled trial that compared treatment with oral colchicine (0.5 mg twice a day for 3 days and subsequently once a day for 27 more days) against placebo. It enrolled 4488 participants (n=2235 colchicine arm, n=2253 placebo arm) between March 23 and December 22, 2020 in Brazil, Canada, Greece, South Africa, Spain, and the United States. Participants were eligible if they had been diagnosed with COVID-19 within 24 hours of enrollment but were not being considered for immediate hospitalization, and were either >70 years old or >40 years old with at least one of: BMI > 30 kg/m2, diabetes, systolic blood pressure > 150 mmHg, known respiratory or heart disease, fever > 38.4 deg C, dyspnea, had more than one low cell count, or a high neutrophil count with lymphocytopenia. Eligible participants were 1:1 randomized in block sizes of six to 0.5 mg of colchicine twice daily for three days and then daily for 27 days or a matching placebo. The primary endpoint was a composite of death or need for hospitalization due to COVID-19 within 30 days after randomization, and the one planned subgroup analysis included the participants (n=2075 colchicine, n=2084 placebo) who enrolled after a positive PCR test.

Summary of Main Findings

In an intention-to-treat analysis, 104/2235 (4.7%) patients treated with colchicine had a primary endpoint event (death and/or hospitalization due to COVID-19), compared to 131/2253 (5.8%) patients in the placebo group (OR 0.79; 95%CI 0.61,1.03). Subgroup analysis of only patients with PCR-confirmed COVID-19 (n=2075 colchicine arm, n=2084 placebo arm) revealed a reduction in primary endpoint event among patients treated with colchicine (4.6% vs. 6.0% placebo; OR 0.75; 95%CI 0.57,0.99). Post-hoc analyses reveal a significant reduction in the rate of hospitalization (OR 0.75; 95%CI 0.57,0.99) but not in the mortality rate (OR 0.56; 95%CI 0.19,1.66). Stratification of the patients by any of the aforementioned risk factors showed nonsignificant decreases in the primary endpoint rate. Participants in the colchicine arm were more likely to have gastrointestinal adverse effects than those in the placebo arm (23.9% vs 13.8%).

Study Strengths

The study population consisted of patients with above-average risk for severe COVID-19 but who were not immediately considered for hospitalization, which describes a sizeable proportion of COVID-19 cases. The double-blinded, randomized participant allocation reduced the risk of unmeasured confounding, selection bias, and analytical bias. Lastly, the enrolled patients were 53.9% women, which is more representative of the population at large, compared to trials with a heavy male-predominant population.

Limitations

The study only recruited 75% of the anticipated number of patients, which left the study slightly underpowered for the composite primary endpoint of death or hospitalization due to COVID-19. Furthermore, they did not utilize a stratified randomization scheme or condition on covariates associated with the outcome, both of which could have increased power and mitigated the fact that they ended the study early. Also, colchicine treatment was only assessed with a 30-day course, and endpoints were measured only up to 30 days from randomization, which limits the ability to make conclusions about shorter courses of treatment, longer-term outcomes of colchicine treatment, or the potential impact of colchicine on COVID-19 symptoms that linger beyond the initial infection. Finally, the majority of participants lived in Canada or the United States, potentially limiting generalizability to regions outside of North America.

Value added

This study suggests that oral colchicine can be used as an effective treatment in preventing death or hospitalization among individuals with an elevated risk profile for severe COVID-19 shortly after a diagnosis.

Our take —

This randomized controlled open-label trial assessed the difference in incidence of SARS-CoV-2 infection among 1,047 adults randomized to enter (experimental) or not enter (control) an indoor concert event in Spain. Nasopharyngeal swabs were tested using antigen-detecting rapid diagnostic tests (Ag-RDT), with follow-up reverse transcriptase polymerase chain reaction (RT-PCR) confirmation before the concert event and eight days after the event. Two control participants tested positive for SARS-CoV-2 during the follow-up visit, but this difference was not statistically significant. The results suggest mass indoor gatherings may be attended without increased risk of transmission, in a setting with low current transmission, if screening and other prevention measures are adopted, but additional studies are needed to confirm these findings and context related to vaccine coverage was missing.

Study design

Randomized Controlled Trial

Study population and setting

Using a randomized controlled open-label trial, authors assessed the incidence of RT-PCR-confirmed SARS-CoV-2 among 1,047 participants aged 18-59 years attending an indoor concert in Sala Apolo, Barcelona, Spain. Participants were tested for SARS-CoV-2 using the Panbio COVID-19 Rapid Test (an antigen-detecting rapid diagnostic test [Ag-RDT]) and a transcription-mediated amplification (TMA) test within 12 hours of the concert. Participants with a positive Ag-RDT result were excluded and positive TMA results were retested using RT-PCR. Among those with a negative Ag-RDT result, participants were block-randomized 1:1 to either enter the concert (experimental) or not enter the event and return home (control). Block randomization is a type of randomization that divides potential participants into n blocks of a predetermined size, and randomly allocates participants within blocks to the experimental or control group. Participants randomized to enter the event were required to wear an N95 mask for the duration of the event, except when in a socially distanced outdoor smoking area or when eating or drinking in defined locations. Eight days after the concert, all participants (those who entered and those who did not) were visited for a nasopharyngeal swab collection for Ag-RDT, TMA, and PCR testing. Authors also estimated the negative predictive value (NPV) of the Ag-RDT.

Summary of Main Findings

No participants tested positive for SARS-CoV-2 prior to the event via Ag-RDT; 465 participants entered the event and had a follow up visit and 495 participants who did not enter the event had a follow up visit, resulting in 960 total participants included in the analysis. Of those included, the mean age was 33.6 years and 82% were male. At baseline, 13 (3%) participants in the experimental group and 15 (3%) in the control group had a positive TMA test; of which one experimental and one control participant had a positive RT-PCR result with CT values = 37, indicating levels of viral detection. All individuals with a positive baseline TMA result had a documented prior case of infection in the recent past (median 50 days). Nine experimental and 11 control participants who were TMA-negative at baseline had a positive TMA test eight days after the concert; two of these controls (0.4% of total) were positive via Ag-RDT and RT-PCR. Incidence of SARS-CoV-2 infection did not differ significantly (-0.15% [-0.72 to 0.44]) between the two groups. The NPV of the Ag-RDT for a positive RT-PCR was 99.9% (99.5-100).

Study Strengths

Randomized trials are considered the gold standard for evaluating the effectiveness of an intervention and is the most rigorous study design for hypothesis testing. The study used three separate tests for SARS-CoV-2 infection and the use of RT-PCR likely eliminated the risk of false negative results among participants.

Limitations

Clinical trials are often limited by the modification of behavior by participants who know they are being observed; however, post-event questionnaire results suggest this was not a major concern in this study. The analytic sensitivity of Ag-RDTs is lower than RT-PCR and likely only reliable for ruling out virus transmission within a few hours following the test (i.e., cannot be used to rule out longer term transmission). Overall, despite apparent effectiveness of mass screening prior to the event, such measures may not be sustainable on a larger scale. Transmission of SARS-CoV-2 was low in the population from which study participants were drawn – study results may differ in populations with higher disease burden. Finally, due to the time of the study (mid-December 2020) and the availability of COVID-19 vaccines in Spain (late December 2020), the effect of vaccination – an important factor needed to properly contextualize results – can not be assessed.

Value added

This randomized controlled open-label trial demonstrated the effectiveness of mass screening for SARS-CoV-2 and mask wearing in a densely populated indoor concert space. It is the first randomized clinical trial to assess risk of SARS-CoV-2 transmission under these settings and using these preventative measures.

Our take —

This study presents interim analyses from a randomized double-blinded trial of 40,111 participants randomized to one of either two inactivated SARS-CoV-2 vaccines from Sinopharm pharmaceutical company (HB02 or WIV04) or placebo (aluminum adjuvant only) in 1:1:1 ratio. The study was conducted in multiple clinical sites in the United Arab Emirates and Bahrain. The interim results demonstrated an efficacy of 78.1% and 72.8% for the HB02 and WIV04 vaccines respectively against symptomatic COVID-19 disease a median of 3 months following the second dose, with no significant adverse events reported. The study, however, included only a small number of participants over the age of 60 or women, lacked data on comorbid conditions, and was conducted only in a few sites in the Middle East, which may limit the generalizability of results. Finally, the study was not designed to evaluate asymptomatic SARS-CoV-2 infection or symptomatic COVID-19 illness after the first dose.

Study design

Randomized Controlled Trial

Study population and setting

This multicenter parallel randomized double-blinded study randomized participants to either placebo (aluminum adjuvant alone), WIV04 vaccine, or HB02 vaccine (both are inactivated SARS-CoV-2 vaccine with aluminum adjuvant from Sinopharm pharmaceutical company) in 1:1:1 ratio with two doses 21 days apart. The study included participants from the United Arab Emirates, Bahrain, Egypt, and Jordan. Randomization was stratified by study site using a block size of 15. Patients with confirmed SARS, MERS infection or positive SARS-CoV-2 PCR, acute respiratory illness, HIV, leukemia, lymphoma, an autoimmune disease, history of bleeding disorders or were on anti-tuberculosis treatments and pregnant women were excluded. The primary outcome was laboratory-confirmed symptomatic COVID-19 at least 14 days after the second dose. Cases were defined as mild, moderate, severe or critical according to the definition of National Health Commission of China. Vaccine efficacy was assessed using different population sets as follows: 1) participants who were PCR negative at enrollment, were randomized, received at least one treatment dose and had at least one follow up visit; 2) participants who were randomized, received at least one treatment dose and had least one follow up visit regardless of baseline PCR; 3) all participants who were PCR negative at baseline who received two treatment doses and at least one follow up visit; and 4) all participants who received two treatment doses and at least one follow up visit, regardless of baseline PCR. Subsequent analysis limited to those who were compliant to their protocol assignments were also conducted. The results presented are from the second interim analysis after a data lock on Dec 20,2021 when 142 cases of SARS-CoV-2 infection were identified in two of the study sites (UAE and Bahrain).

Summary of Main Findings

A total of 40,111 participants were randomized into the three arms. The mean age of study participants was 36.2 years (more than 97 percent below the age of 60 years), 84-85 % male, and the mean body mass index was 26-27 kg/m2. Only 5% had evidence of SARS-CoV-2 infection at study enrollment. The median duration of follow-up was 77 days (1-121 days) after two weeks of the second dose. A total of 142 cases of symptomatic COVID-19 were identified 2 weeks after the second dose (95 in the placebo arm; 26 in the WIV04 arm; 21 in the HB02 arm), representing the following incidence rates per 1,000 person-years: 44.4, 95%CI 36.6-54.6 (placebo), 12.1, 95%CI 8.3-17.8 (WIV04) and 9.8, 95%CI 6.4-15 (Hb02). Vaccine efficacy was 78.1% (95%CI 64.8-86.3) for HB02 and 72.8% (95%CI 58.1-82.4) for WIV04. Two cases of severe infection were identified in the placebo group compared to zero cases in both vaccine groups. . There were no differences in solicited or unsolicited adverse events reported among the three groups.

Study Strengths

Since this is a randomized double-blinded study, biases due to selection or outcome ascertainment were unlikely to impact the study results. Symptomatic cases were adjudicated by two independent masked committees, further minimizing the risk of ascertainment bias. The study included more than 40,000 participants with multiple racial backgrounds, which strengthens the study’s external validity.

Limitations

The mean age of the study participants was 36.1 years and the majority of participants were male, with no symptomatic COVID-19 infection in people over age 60 years, which limits generalizability. No data pertaining to comorbidities were reported in the main manuscript or in the supplementary material. While balance between the study groups in regard to medical conditions is expected due to randomization and the large sample size, generalizing the study results to other settings might be limited if the study population was generally free of comorbidities. While the study included participants with multiple racial backgrounds, it included three sites in only two countries (UAE and Bahrain) which may limit generalizing results to settings where the SARS-CoV-2 transmission rates could be different. The median duration of the follow up was 3 months after the second dose, which limits inferences on vaccine efficacy beyond this period. The study didn’t address the efficacy of the WIV04 or HB02 vaccines against any of the new variant strains.

Value added

This study presents interim analyses from the first trial to evaluate the efficacy of two inactivated SARS-CoV-2 vaccines against symptomatic COVID-19 disease.

Our take —

This study, available as a preprint and thus not yet peer-reviewed, was a phase 3 trial of the Novavax NVX-CoV2373 recombinant SARS-CoV-2 nanoparticle vaccine. Findings demonstrated that the two-dose vaccine regimen of NVX-CoV2373 had a favorable safety profile and high efficacy against a blend of viral strains as well as against the UK variant, specifically. This is the first evidence of a protein-based, adjuvanted vaccine being able to provide protection against both the prototype strain and UK variant of SARS-CoV-2. The study population was overwhelming white (94%), and the study was underpowered to assess vaccine efficacy against individual specific strains of SARS-CoV-2.

Study design

Randomized Controlled Trial

Study population and setting

This study was a phase 3 trial of the Novavax NVX-CoV2373 recombinant SARS-CoV-2 nanoparticle vaccine. NVX-CoV2373 is comprised of a trimeric full-length SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant. The trial assessed safety and efficacy of NVX-CoC2373 in preventing COVID-19 in participants in the UK, at a time when the UK variant (B.1.1.7) was beginning to circulate more widely. Individuals with a history of documented COVID-19 were excluded from participation. 14,039 participants meeting criteria for the per-protocol efficacy population, were randomized 1:1, with 7020 in the vaccine group and 7019 in the placebo group. Participants at the 33 sites across the UK were between the ages of 18-84 years, and received two 5 ug intramuscular doses, 21 days apart. Solicited adverse events were recorded for 8 days after each dose, and unsolicited adverse events were recorded through 28 days after the second dose. The primary endpoint was symptomatic COVID-19 confirmed by qPCR, with onset at least 7 days after the second vaccination in serologically negative patients. At symptom onset, respiratory specimens were collected daily f or 3 days in order to confirm infection.

Summary of Main Findings

The most commonly reported adverse events were injection site pain, headache, muscle pain, and fatigue. These were all mild and of short duration. Adverse events were more commonly reported in the vaccine group compared to the placebo group, and more common after the second dose compared to the first dose. Additionally, they were more common among younger vaccine recipients (18-64 years) compared to older recipients (>64 years). Fever was only reported in 2% and 4.8% of participants after the first and second dose of vaccine, respectively. Out of 14,039 participants, there were few cases of virologically confirmed, symptomatic, mild, moderate or severe COVID-19 with onset at least 7 days after the second dose. There were 10 cases in the vaccinated group and 96 cases in the placebo group, resulting in an estimated 89.7% vaccine efficiency. Vaccine efficacy among patients >64 years was 88.9%. Post-hoc analysis of patient respiratory swab samples collected identified 29 cases of COVID-19 where the isolated strain was the prototype strain, 66 cases where it was the UK variant, and 11 cases where the strain was unknown, respectively. Based on these identifications, vaccine efficacy against the prototype strain was 96.4%, while efficacy against UK variant was 86.3%.

Study Strengths

6% of participants in the study had at least one co-morbid condition, which is an important variable to include in SARS-CoV-2 vaccine trials due to the fact that COVID-19 can be particularly dangerous for individuals with co-morbidities.

Limitations

Over 94% of participants in this trial where white, and this vaccine should be tested in a more diverse population of individuals in future trials. Next, the viral strains from patient samples were sequenced and identified post-hoc, so the trial was not powered to assess efficacy of the vaccine against individual strains of SARS-CoV-2. The trial began in September 2020, while the UK (B.1.1.7) variant was not identified and sequenced until October 2020. Also, vaccine efficacy estimates were derived from a short duration of observation time (~ 3 months). Therefore, this study requires ongoing follow-up to determine the durability of the effectiveness. Interestingly, in a previous analysis in South Africa from the same group, serologically positive individuals were excluded from analysis, but that was not done here.

Value added

This was a report of a recombinant vaccine that demonstrated high efficacy against the UK variant in a phase 3 clinical trial.

Our take —

In this randomized controlled trial involving over 15,000 adults in the UK, participants were initially classified by general COVID-19 vaccine hesitancy (willing, doubtful, and strongly hesitant), and then were provided with a standard statement of COVID-19 vaccine safety and effectiveness. Participants then read a randomly assigned package of information related to COVID-19 vaccines, and responded to survey questions designed to measure their level of vaccine hesitancy. Among those who were strongly hesitant, information focused on personal benefits of COVID-19 vaccination was the most effective in lowering hesitancy relative to the control group (standard statement only). This finding may be useful in planning public health messaging to improve vaccine coverage, though the results may not be applicable in other contexts.

Study design

Randomized Controlled Trial

Study population and setting

This was a randomized controlled trial that tested whether the provision of specific types of information content related to COVID-19 vaccination, beyond a standard statement of safety and effectiveness, would increase the acceptance of vaccines. The study enrolled 15,014 adults in the UK from January 19 to February 5, 2021; participants were quota-sampled to be nationally representative of the UK with respect to gender, age, region, education, and ethnicity. An additional 3,841 vaccine-hesitant adults were recruited through February 19, 2021. Participants were recruited via a wide variety of online platforms (e.g., social networks, advertisements, and mobile games) and offline methods (television and radio ads, mail) through a market research firm. Participants were stratified into three levels of vaccine hesitancy (willing, doubtful, and strongly hesitant) by their response to a single initial question about vaccine intentions, and then were randomized within strata to one of ten “information conditions.” The control condition was a safety and effectiveness statement from the National Health Service; the others added more information to this statement addressing personal benefits, collective benefits, pandemic seriousness, and safety concerns in various combinations. Participants then read text corresponding to each information condition (without being aware that other conditions existed) and completed a mediation measure of COVID-19 complacency and confidence beliefs and an outcome measure of COVID-19 vaccine hesitancy (the 7-item Oxford Vaccine Hesitancy Scale, with scores ranging from 7 to 35). The authors performed linear regression on the vaccine hesitancy score to test for differences by information condition, with interaction terms for baseline vaccine hesitancy.

Summary of Main Findings

In the unstratified population, none of the information conditions were associated with differences in the vaccine hesitancy score compared to the control. However, within the strongly hesitant group, three conditions were associated with lower vaccine hesitancy: one addressing personal benefit (difference in vaccine hesitancy score: -1.49 (95% CI: -2.16 to -0.82)), one addressing safety concerns in relation to the speed of vaccine development (-0.91 (-1.58 to -0.23), and a full combination of all forms of information (-0.86 (-1.53 to -0.18)). In this group, provision of information related to personal benefits of vaccination was associated with lower vaccine hesitancy relative to either a) provision of information related to collective benefit, or b) a combination of the two. There were no statistically significant differences in vaccine hesitancy for any information condition relative to control in the willing or doubtful groups. No evidence was seen for mediation by COVID-19 vaccine views.

Study Strengths

This was a randomized controlled trial, and as such was less susceptible to confounding bias than other study designs. The sample size was large and participants were sampled to be representative of the UK population with respect to several demographic variables. The vaccine hesitancy score was developed in consultation with members of the general public, was validated against other scores, and had high internal consistency.

Limitations

Self-reported intentions regarding COVID-19 vaccination may not correspond well with actual behavior. Even if the study findings are valid, it is not clear how the vaccine information designed to reduce hesitancy could be best delivered; participants received the information in the context of a study into which they had voluntarily enrolled, and this dynamic may not be replicable in the wider population. This was not a probability-based sample; those who participated in the study may have been systematically different from the general population in unpredictable ways. The representativeness of the study population was diminished by the inclusion of the second group of vaccine-hesitant individuals. Finally, because participants were classified at baseline by a single question (as opposed to the full outcome measure), no change in vaccine hesitancy scores could be calculated for participants.

Value added

This is the only randomized controlled trial to date of information-based interventions to decrease COVID-19 vaccine hesitancy.

Our take —

This interim analysis from a phase 3 randomized, double-blinded, placebo-controlled clinical trial of the Johnson & Johnson/Janssen Pharmaceuticals Ad26.COV2.S COVID-19 vaccine demonstrated that it is effective, particularly at preventing severe-critical COVID-19. The authors noted that, compared to many of the other vaccines currently available, this COVID-19 vaccine can be stored under a broader range of temperatures and requires only a single dose – both of which are important considerations. Given the initial safety concerns raised, ongoing monitoring and transparency in the post-marketing setting will be crucial.

Study design

Randomized Controlled Trial

Study population and setting

This study reports the findings from the phase 3 randomized, double-blinded, placebo-controlled clinical trial of the Johnson & Johnson/Janssen Pharmaceuticals Ad26.COV2.S COVID-19 vaccine. The single-dose vaccine utilizes recombinant, non-replicating adenovirus type 26 as a vector to deliver double-stranded DNA encoding the full-length SARS-CoV-2 spike (S) protein. The trial, which is still ongoing, is underway in multiple Latin American countries, South Africa, and the United States (this study reports data from September 21, 2020 to January 22, 2021). Approximately 40,000 per-protocol participants were included, with half receiving placebo. Vaccine efficacy against moderate to severe-critical COVID-19 was assessed following at least 14 days and at least 28 days after injection.

Summary of Main Findings

468 confirmed symptomatic cases of COVID-19 were recorded overall: 116 in the vaccine group and 348 in the placebo group. This provided estimated vaccine efficacy at least 14 days following injection of 66.9% (76.7% for severe-critical disease). Vaccine efficacy at least 28 days following injection was 66.1% (85.4% for severe-critical disease). Overall vaccine efficacy against asymptomatic infection with SARS-CoV-2 was estimated at 65.5% based on serological testing throughout the study.

Study Strengths

The study population was large, diverse, and included many patients with comorbidities. Inclusion of estimates for vaccine efficacy against asymptomatic SARS-CoV-2 infection is extremely helpful.

Limitations

The estimated vaccine efficacy against asymptomatic SARS-CoV-2 infection was based on serological testing of participants 71 days after injection to assess for antibodies against the nucleocapsid (N) protein (which would only be present following natural infection, since the vaccine would only induce antibodies against S). However, those with ‘unknown’ baseline serostatus were also included. Ideally only participants with proven seroconversion (negative to positive) should have been utilized for analysis.

Value added

This is the first peer-reviewed report of the phase 3 clinical trial results for the Johnson & Johnson/Janssen Pharmaceuticals Ad26.COV2.S COVID-19 vaccine.

Our take —

This was a very large, well-designed, and well-conducted cluster-randomized controlled trial of a multi-pronged intervention program to encourage mask-wearing in Bangladesh from November 2020 to January 2021. The trial 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. The study is the largest and best-designed trial to date of a non-pharmaceutical intervention to combat SARS-CoV-2. The second half of the study, which will assess whether the intervention affected SARS-CoV-2 transmission and COVID-19 outcomes, is in progress as of June 2021.

Study design

Randomized Controlled Trial

Study population and setting

This study, designed to estimate the impact of public health interventions on mask-wearing behavior, took place 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 (each union consists of ~80,000 people), the authors used pairwise randomization to select 300 intervention and 300 control unions, and selected one village (containing the largest market in the region) in each union. The intervention was rolled out in waves starting from November 2020 to January 2021, and lasted for 8 weeks with 10 weeks of surveillance. The intervention group villages received a multi-pronged set of interventions, designed in conjunction with local leaders. The basic 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 main 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 (indicating randomization group), whether both mouth and nose were covered, and whether people were keeping physical distance from each other. Finally, the authors conducted an economic evaluation to estimate the degree to which this intervention was cost-effective in preventing deaths. This was the first stage of a larger study designed to estimate the effectiveness of mask-wearing in preventing SARS-CoV-2 transmission.

Summary of Main Findings

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%. 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. 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. A preliminary cost-effectiveness analysis suggested that this intervention was relatively cost-effective.

Study Strengths

This study benefited from being a very large, well-designed, and well-conducted cluster randomized controlled trial of a realistic intervention. The large-scale cluster randomization allowed the study to robustly examine the impact of this non-pharmaceutical intervention on directly observed behavior, rather than on self-reported behavior.

Limitations

One 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. Additionally, the cost-effectiveness analysis employed large and unrealistic assumptions about the translation of mask-wearing behavior to health outcomes. This study, the first stage of a larger trial, only assessed behavioral results and did not assess the impact of the intervention on SARS-CoV-2 transmission or COVID-19 outcomes. 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. The design and scale of this study allows for extremely high confidence in the utility and robustness of its results; it is likely that these results may apply to interventions outside this setting.

Our take —

This study presented data from a phase 1 and 2 trials of BBV152 (developed by Bharat Biotech), a whole virion inactivated SARS-CoV-2 vaccine. The study took place in 9 hospitals throughout India. The vaccine proved safe in phase 1 and 2 trials, with the ability to induce neutralizing antibodies and seroconversion, and the potential for a durable immune response. The 6ug dose with Algel-IMDG formulation of the BBV152 vaccine has been selected for phase 3 efficacy trials due to its ability to elicit superior cell-mediated responses, and comparable levels of adverse events to the 3ug dose.

Study design

Randomized Controlled Trial

Study population and setting

This paper describes the use of BBV152 (developed by Bharat Biotech), a whole virion inactivated SARS-CoV-2 vaccine. The vaccine formulation also uses a TLR 7/8 agonist called IMDG adsorbed to alum (Algel) as an adjuvant and to increase cell-mediated responses. The phase 1 trial tested a 3ug dose with Algel-IMDG, a 6ug dose with Algel-IMDG, 6ug with Algel, and Algel only, administered on days 0 and 14. The 3ug dose with Algel-IMDG and 6ug dose with Algel-IMDG formulations were selected for further testing in phase 2. 380 participants between the ages of 12 and 65 years were selected for phase 2, randomized 1:1 to receive either a 3ug dose with Algel-IMDG or a 6ug dose with Algel-IMDG on days 0 and 28. The trial took place in 9 hospitals across 9 states in India, with phase 2 participants enrolled between September 5 and 12, 2020. The primary outcomes were neutralizing antibody titers and seroconversion rates, with cell mediated responses being a secondary outcome. Safety was also assessed.

Summary of Main Findings

Neutralizing antibodies were increased by day 56 in both the 3 and 6ug dose groups, with levels significantly higher in the 6ug dose group. Levels of neutralizing antibodies in the 6ug dose group were also comparable to those found in convalescent serum. Seroconversion also occurred in 92.9% of participants in the 3ug dose group and 98.3% of participants in the 6ug dose group by day 56. A Th1-biased cell response was detected at day 42, with a significant increase in Th1-associated cytokines. The most common adverse events were injection site pain, followed by headache, fatigue, and fever. These occurred in only a small percentage of participants, were mostly mild, and resolved within 24 hours of onset. There was no significant difference in adverse events between the two dose groups, and no serious adverse events were reported. When following up with phase 1 participants 3 months after their second dose, participants still had detectable neutralizing antibody levels comparable to convalescent serum samples, as well as memory T-cells.

Study Strengths

This study included a small number of young adults between the ages of 12 and 18 years, which is an age not included in many other trials. There was a diverse range of geographic locations across India included in the trial. The BBV152 vaccine was also successfully able to neutralize variant of concern B.1.1.7, also known as the UK variant. Additionally, the vaccine has the potential to provide a durable immune response based on the follow-up results from the phase 1 trial participants.

Limitations

Binding antibodies and cell mediated responses in convalescent serum were unable to be assessed here due to the low quantity of those samples available. This trial lacked ethnic, racial, and gender diversity, with about 3/4 of participants being male. Finally, long-term follow-up data from the phase 2 participants may look different than the results from phase 1 participants due to different dosing schedules (days 0 and 28 as opposed to days 0 and 14).

Value added

First report of phase 2 and phase 1 follow-up results from the Indian BBV152 inactivated whole virion vaccine.

Our take —

This preprint, which had not yet been peer reviewed, offered evidence that the Novavax NVX-CoV2373 is well tolerated and provides protection against symptomatic SARS-CoV-2 infection from the B.1.351 variant. Claims that prior infection with pre-B.1.351 viruses did not reduce the risk of COVID-19 due to re-infection with B.1.351 variants are unsupported.

This preprint was later published in a scientific journal here.

Study design

Randomized Controlled Trial

Study population and setting

This study, available as a preprint thus not yet been peer-reviewed, summarized the results of a phase IIa/b multicenter randomized placebo-controlled trial of Novavax’s NVX-CoV2737 conducted in South Africa. The NVX-CoV2737 vaccine contains full-length, pre-fusion SARS-CoV-2 spike protein (AA sequence from the original Wuhan isolate) and a saponin-based adjuvant.

The primary study population included 2,684 predominantly (95%) Black-African participants aged 18-84 years (18-64 years for a subset of medically stable people living with HIV [PLWH]) who were randomized in an approximately 1:1 ratio to receive two injections spaced 21 days apart of either NVX-CoV2737 or saline placebo. The primary endpoint assessed was vaccine efficacy (defined as prevention of diagnostically confirmed symptomatic mild, moderate, or severe COVID-19 in initially seronegative participants) seven or more days after receiving the second vaccine dose. Various separate analyses were also conducted on seropositive participants who received either vaccine or placebo. Monitoring for safety was conducted throughout the study, and is planned to continue for a year.

Summary of Main Findings

Fifteen cases of COVID-19 were detected amongst the 1,357 two-dose vaccine recipients, and 29 cases of COVID-19 were detected amongst the 1,327 two-dose placebo recipients, producing an overall estimated vaccine efficacy of 49.4% (95% CI 6.1 to 72.8%).

The majority (38/41) of available SARS-CoV-2 full-genome sequences obtained from positive, symptomatic participants (n = 44) in this trial belonged to the B.1.351 lineage, suggesting that viruses of this lineage were predominant in overall circulation.

No vaccine-related serious adverse events were recorded at the time of writing, although adverse events overall were slightly more common amongst the vaccine recipients versus the placebo recipients.

Study Strengths

Participants with an appropriate range of ages were included, and some had preexisting comorbidities (e.g. hypertension, diabetes mellitus, etc).

Limitations

As these are phase IIa/b trials, sample sizes are small, and any finding will need to be confirmed in larger phase III trials. Small sample sizes resulted in very large confidence intervals for the vaccine efficacy calculations (e.g., vaccine efficacy of 49.4% [95% CI 6.1 to 72.8%]).

The authors’ claim that prior infection with pre-B.1.351 viruses did not reduce the risk of COVID-19 due to re-infection with B.1.351 variants is based solely on the initial serological status of the participants as determined by an in-house IgG ELISA. This is insufficient evidence for such claims. As history of prior or current symptomatic COVID-19 excluded participation in the study, these recorded seropositive cases likely represent either asymptomatic infection or false positives from their in-house ELISA. However, it is unclear as the time since infection, severity of infection, and variant causing infection are all unknown or unreported for these cases. Additionally, the authors report approximately 30% of the total study population was seropositive at the start of the study. This is questionably high given that South Africa has currently reported about 1.5 million total infections out of a population of 59 million, which equates to about 2.5% of the population known to have been infected overall. To more convincingly demonstrate that previous infection with pre-B.1.351 SARS-CoV-2 provides no protection from infection with B.1.351, prior natural infection would need to be demonstrated by more than serology (e.g., a history of diagnostic nucleic acid amplification testing [NAAT], symptoms, etc.).

Finally, while inclusion of the PLWH participants was advantageous and various attempts are made to evaluate the efficacy amongst this subgroup, the study was underpowered for these purposes (as acknowledged by the authors) and thus inclusion of these participants adds very little meaningful data.

Value added

This study provides the first efficacy data for Novavax’s NVX-CoV2373 vaccine.