Skip to main content

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.

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.

Our take —

Vaccines using the nanoparticle/Matrix-M1 adjuvant approach, like NVX-CoV2373 (Novavax), have been widely studied and have a very acceptable safety profile. This phase 2 trial report, available as a preprint and thus not yet peer-reveiwed, found that both the 5ug and 25ug doses of NVX-CoV2373 were effective at inducing production of IgG and neutralizing antibodies, while the 25ug dose had a higher incidence of local reactogenicity in both younger and older adults. Therefore, Novavax will move forward with a 2-dose regimen of 5ug NVX-CoV2373 administered 21 days apart in phase 3 trials. Trials are currently ongoing in South Africa, the UK, the US, and Mexico.

Study design

Randomized Controlled Trial

Study population and setting

This paper described the phase 2 trial of the Novavax vaccine, NVX-CoV2373, which is composed of trimeric full-length SARS-CoV-2 spike proteins and adjuvant. The trial took place between August 24 and September 25, 2020. 1283 participants in two age groups were studied: younger (18-59 years) and older (60-84 years) adults, at nine sites in Australia and eight sites in the US. Participants received either one or two doses of 5ug or 25ug NVX-CoV2373 or placebo 21 days apart. Immunogenicity and safety data were studied through day 35, including adverse events, reactogenicity within 7 days of receiving the vaccine, IgG response, and neutralizing antibody production.

Summary of Main Findings

The most commonly reported local adverse events were pain and tenderness at the injection site, while the most common systemic adverse events were muscle pain, fatigue, headache, and malaise. Fever was only reported in less than 2% of all participants. Reactogenicity occurred at higher frequency in younger participants compared to older participants, and the systemic reactions were also more common after the second dose. Seroconversion rates of IgG production were 99% and 100% (younger participants) and 97% and 99% (older participants) after 2 doses of 5ug or 25ug, respectively. Additionally, seroconversion of neutralizing antibodies were 100% and 100% (younger participants) and 100% and 96% (older participants) after 2 doses of 5ug or 25ug, respectively. Higher amounts of neutralizing antibodies were detected in both younger and older participants compared to convalescent sera.

Study Strengths

This vaccine uses a recombinant protein approach, which is different than the other already approved COVID-19 vaccines, making it novel. This trial studied multiple doses and dosing regimens for NVX-CoV2373, and also included both younger and older adults.

Limitations

The study included 87% white participants. Future trials for NVX-CoV2373 included a more diverse population in South Africa and Mexico, but these data are not reported here. No analysis of T-cells was included here, only study of antibodies, even though no true correlate of vaccine protection has been defined. Finally, data was only published here for observations through day 35, so no-long term data is provided yet.

Value added

First report of phase 2 results from the Novavax NVX-CoV2373 vaccine, with results in both younger and older adults

Our take —

This phase Ib/II clinical trial in South Africa, available as a preprint and thus not yet peer reviewed, estimated that the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca) was not shown to be effective against the B.1.351 South African strain, with an estimated efficacy of preventing symptomatic COVID-19 of 10.4% against the B.1.351 variant. Because this variant was highly prevalent among cases, the overall efficacy for symptomatic COVID-19 was 21.9%. The study could not determine if the vaccine was protective against severe disease due to insufficient numbers. No serious adverse events were reported in the sample. Further research is necessary, with larger sample sizes, including groups with comorbidities or immunocompromised individuals, to fully understand the effectiveness of the vaccine against this emergent variant.

After the NCRC reviewed this preprint, it was published in a scientific journal here.

Study design

Randomized Controlled Trial

Study population and setting

This was a Phase Ib/II randomized controlled trial across 7 study sites in South Africa. Participants were randomized to the vaccine (0.33 – 0.5mL ChAdOx1-nCoV19 AstaZeneca and Oxford vaccine) or placebo, with an additional booster dose administered 21 to 35 days later. A cohort of 70 HIV-negative people were initially enrolled for safety testing, and an additional 1956 HIV-negative individuals were enrolled for a total of 2021 in the safety study, 1010 received placebo, and 1011 received the vaccine. The safety study collected reactogenicity within 7 days of full vaccination and unsolicited adverse event reporting for 28 days following vaccination. Of these 2021 initial people, 1467 were included in the efficacy study (717 placebo and 750 vaccine), with sampling for SARS-CoV-2 infection occurring at routine visits and also if COVID-19 symptoms were reported. The primary endpoint for the efficacy study was symptomatic COVID-19 occurring >14 days after the second shot among participants seronegative at baseline. Serostatus at randomization was evaluated with IgG assays, and antibody neutralization studies were conducted within 2 weeks of the 2nd dose in 107 randomly selected vaccine recipients who were seronegative at enrolment.

Summary of Main Findings

In the safety study, adverse events (both mild and serious) were similar among vaccine and placebo groups with no statistically significant differences. For vaccine efficacy, there were 42 cases with either mild (15 received vaccine and 17 received placebo) or moderate (4 who received vaccine, 6 receiving placebo) COVID-19. There were no reported severe disease or hospitalization in placebo or vaccine groups. The incidence of COVID-19 for those who received the placebo >14 days after the booster was 93.6 cases per 1000 person-years, and 73.1 cases per 1000 person-years for the vaccinated group. In their neutralization study, there was a strong antibody response after the first dose, with 9 of 19 seronegative (47%) showing no detectable neutralization to an RBD triple-mutant pseudovirus, while 79% (15 of 19) showed no detectable neutralization response to the B.1.351 pseudovirus. 41 of 42 samples among endpoint cases were sequenced, of which 39 (95.1%) were B.1.351. The vaccine efficacy about patients with the B.1.351 variant was 10.4% (95% CI: -76.8 to 54.8%), and all COVID-19 (regardless of severity or variant) was 21.9% (95% CI: -49.9 to 59.8%).

Study Strengths

The study was a double-blind randomized controlled trial, which reduced selection and measurement bias in this sample. They were able to examine not only safety, but also efficacy, and immunogenicity through its neutralization study. Additionally, the study included a diverse range of people, including being 70.5% black African, which are often underrepresented in clinical trial studies.

Limitations

The primary limitation is the generalizability of the RCT results. The study had a diverse range of participants included in the study, however the age range was primarily <60 years of age, and may reflect individuals with stronger immune systems who can respond to the vaccine. Similarly, a small minority of the study population had respiratory disorders, and given that COVID-19 is expected to have pronounced severe disease among those with prior respiratory conditions, these results may not reflect certain immunocompromised or comorbid populations. Additionally, the follow-up of this study was from 140-171 days, and it is not clear if the same level of efficacy can be seen long-term beyond this. Finally, there were relatively few individuals in each arm of the study and larger sample sizes are needed for more precise estimates of efficacy.

Value added

The study is the first to explicitly interrogate the impact of the vaccine on the B.1.351 South African strain of COVID-19, as new strains become a growing concern. It found no significant efficacy against symptomatic COVID-19 caused by the B.1.351 variant, which has critical implications for vaccine rollout and planning in particularly in Southern Africa.

Our take —

Prior studies of tocilizumab were not sufficiently large enough to show a significant mortality improvement associated with tocilizumab. This interim report, available as a preprint and thus not yet peer-reviewed, showed that tocilizumab reduces mortality in hospitalized COVID-19 patients, taken both on its own and as part of a meta-analysis including prior studies. The mortality benefit conferred by tocilizumab is in addition to that which is conferred by systemic corticosteroids, which are now considered part of the usual standard of care. Finally, the absolute risk reductions for primary and secondary outcomes were small in this interim report: it is possible that the magnitude of improvement conferred by tocilizumab may diminish when all follow-up is complete for all participants.

Study design

Randomized Controlled Trial

Study population and setting

This study was a subset of the broader Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, which compares various therapies for the treatment of hospitalized COVID-19 patients. The study described in this article was an open label randomized controlled trial that recruited 4116 patients (out of 21550) hospitalized with suspected or confirmed COVID-19 infection across 131 hospitals in the United Kingdom. The study compared the 28-day mortality of patients receiving usual care (n = 2094) to patients receiving the anti-IL-6R antibody tocilizumab in addition to usual care (n = 2022). Tocilizumab was given via 60 minute IV infusion of approximately 8 mg/kg, with a second infusion given 12-24 hours later if the patient’s condition was not deemed to be improving by their attending physician. In addition to the primary outcome of 28-day mortality, the study measured secondary outcomes including time to discharge, and among patients not receiving invasive ventilation, progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death.

Summary of Main Findings

This was an interim analysis as follow-up is only complete for 79% of participants in the tocilizumab group, and 79% in the usual care group: >95% follow-up forms are expected at the conclusion of the study. Among the restricted group of people with completed follow-up forms, 83% of people assigned to receive tocilizumab received at least one dose, while 3% of persons assigned to usual care received at least one dose of tocilizumab. Intention to treat with tocilizumab was associated with a significant reduction in 28-day mortality compared to usual care alone (29% in the tocilizumab group vs. 33% in the control group; rate ratio 0.86; 95%CI = 0.77-0.96; p 0.007). Of the patients enrolled in the study, 94% of them had a lab-confirmed positive test for COVID-19; in a post hoc analysis of exclusively these patients, the rate ratio was similar (0.86; 95%CI 0.78 to 0.98; p 0.02). Patients who were allocated tocilizumab were significantly more likely to be discharged alive within 28 days (54% vs. 47%; rate ratio 1.22; 95%CI 1.12-1.34; p < 0.0001) and significantly less likely to progress to needing invasive ventilation if they did not need it at baseline (33% vs. 38%; risk ratio 0.95; 95%CI 0.78-0.93; p 0.0005). The need for hemodialysis or hemofiltration was lower in the tocilizumab group (5% vs. 7%; risk ratio 0.75; 95%CI 0.59-0.96; p 0.02). Rates of cardiac arrythmias were comparable between the two groups. There was one case each of otitis externa, S. aureus bacteremia, and lung abscess documented as adverse reactions to tocilizumab, all of which resolved with the appropriate respective treatments. In a subgroup analysis, persons who received corticosteroids and tocilizumab appeared to benefit more than persons who received tocilizumab alone.

Study Strengths

The study as reported in this article enrolled 4,116 patients, but this selection was part of the larger RECOVERY trial which recruited 21,550 total patients across 131 hospitals. This scale allows for a reasonable balance of patients between most randomized treatments. The ethnic backgrounds of participants appeared representative: 17% of the patients in the study had a Black, Asian, or other minority ethnic background, although the specific breakdown between minority background is not explicitly provided. In addition, persons with comorbidities (such as HIV and severe liver disease) were permitted in this trial. Although the double randomization design was complicated, persons who received tocilizumab were comparable with regards to several other randomized treatments to persons who received usual care.

Limitations

The study was open label and not blinded. As a result, bias may be imparted by providers, who may consciously or subconsciously change the way care is provided to patients in different arms of the trial. No children were enrolled in the study, which limits the generalizability of the findings to adult patients. 17% of the patients who were allocated to the tocilizumab group did not end up receiving the treatment, for reasons that were not documented in the study. Since this was an open-label study, treating physicians could overrule the randomization assignment, limiting the effects of randomization. Thus, a per protocol analysis is also warranted for this study. Furthermore, this data is still preliminary, as 8% of the patients have not yet reached the 28-day checkpoint, and 21% of participants in both arms did not have complete follow-up forms. In addition, the median hospital stay for the enrolled patients is longer than 28-days, meaning the results of a planned six-month follow up should provide more information. There are no details on the receipt of antivirals such as monoclonal antibodies, convalescent plasma, or remdesivir, and whether this was balanced between groups.

Value added

The preliminary findings of this RCT provide supportive evidence that the use of the anti-IL-6R antibody tocilizumab reduces 28-day mortality in hospitalized COVID-19 patients.

Our take —

Clinical efficacy of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca) preventing symptomatic COVID-19 was similar between the UK variant (B.1.1.7) and other viral lineages even though the vaccine induced neutralizing antibodies were less effective against the B.1.1.7 variant. This suggests that a lower level of neutralizing antibodies may be needed to prevent symptomatic infection than previously thought, and/or other immune mechanisms may contribute to protection. Results also suggested that vaccine recipients appear less likely to transmit virus compared to unvaccinated individuals. Overall, these data support the ongoing use of this vaccine in areas that contain variant B.1.1.7 or the original strain.

Study design

Randomized Controlled Trial

Study population and setting

This study used samples collected from participants in a phase II/III trial testing the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca) in adults age 18 years and older at 20 centers across the UK. Symptomatic patients had nasopharyngeal and oral swabs taken, while all patients provided a weekly self-administered nose and throat swab for NAAT testing beginning 1 week after their first vaccination. Samples were processed by nucleic acid amplification testing (NAAT). Cases were excluded if they came up positive before 15 days post-second vaccination. PCR cycle threshold (Ct) values served as a proxy for measuring viral load (lower values equate to higher viral loads). Positive samples were sequenced (SARS-CoV-2 in samples) and viral lineages were assigned. Sera from vaccinated participants was tested for neutralization against the UK variant (B.1.1.7) and a canonical non-B.1.1.7 Victoria lineage from Australia.

Summary of Main Findings

Out of 499 participants that developed COVID-19 between October 1, 2020 and January 14, 2021, investigators were able to obtain sequences from 256 participants (a total of 322 swabs). Of these, 179 were in the primary efficacy cohort (120 symptomatic, 44 were asymptomatic/unknown, and 15 “other”). About 2/3 of infections were due to non-UK lineages while about 1/3 were caused by the UK variant (B.1.1.7). Overall vaccine efficacy against the B.1.1.7 variant was lower but similar to that against other variants (66.5% vs. 80.7%, respectively). Symptomatic cases had a higher viral load compared to asymptomatic cases and were PCR positive for a longer time period, with vaccination reducing that length of time by 1 week. The length of time participants tested positive for virus did not differ between the UK variant and other variants. Participants in the vaccinated group exhibited lower viral loads compared to those in the control group. Neutralizing antibody titers were 9 times lower  (i.e., less effective) against the UK lineage compared to the Victoria lineage of the SARS-CoV-2 virus.

Study Strengths

Swabs were collected from patients at several time points in order to track viral load over time, and sequencing was performed in order to determine viral lineages in actual COVID-19 cases. Clinical efficacy was tested in participants who had received varying vaccine dosing strategies. Viral load in addition to neutralizing antibody efficacy were studied.

Limitations

New viral variants are beginning to appear as the virus begins to evolve within the population. Additionally, positive PCR results may not truly indicate live, transmissible virus, and a true correlate of immune protection has still not been established. Samples with Ct values greater than 30 were not sequenced, so the lineages of virus in patients with low viral load were unable to be assessed. Additionally, sequences from all positive swab samples were unable to be obtained due to logistical constraints. Finally, false positive samples could not be sequenced since they did not contain virus, and therefore fell into a category of negative clinical efficacy, possibly skewing results.

Value added

This study provides the first data on clinical efficacy of the ChAdOx1 nCoV-19 vaccine against the UK variant of SARS-CoV-2 compared to other lineages.

Our take —

CoronaVac (developed by Sinovac) was demonstrated in the phase 1/2 trial in Heibei, China, to be safe in older adults ages 60 years and older, and was successfully able to induce neutralizing antibody responses. A 3ug two-dose immunization schedule will move forward into phase 3 trials because it is similarly effective to the 6ug dose and more effective than the 1.5ug dose in inducing production of neutralizing antibodies.

Study design

Randomized Controlled Trial

Study population and setting

This study includes results of a phase 1/2 clinical trial testing the safety, tolerability, and immunogenicity of the CoronaVac vaccine (developed by Sinovac), which contains whole inactivated SARS-CoV-2, in adults age 60 years and older in Hebei, China. Phase 1 included 72 participants testing 3ug and 6ug doses, as well as placebo, in a two-dose schedule administered on days 0 and 28. In phase 2, there were 350 participants receiving either 1.5ug, 3ug, 6ug, or placebo also in the same two-dose regimen. The trial studied adverse reactions and seroconversion to production of neutralizing antibodies within 28 days after each injection.

Summary of Main Findings

Mild to moderate adverse reactions occurred in about 20% of participants regardless of dose, with the most common reactions being injection site pain (9%) and fever (3%). No vaccine-related serious-adverse events have been reported. Phase 1 data showed that seroconversion rates after only one dose of CoronaVac were low, underscoring the need for a two-dose regimen. In phase 2, seroconversion was seen in 90% participants in the 1.5ug group, 98% of the 3ug group, and 99% of the 6ug group. Seroconversion rates by 28 days after the second dose were higher than 94% in both 3ug and 6ug groups for all participant age groups studied (60-64, 65-69, and 70+ years old).

Study Strengths

This trial tested multiple doses to determine the smallest dose possible with the greatest immunogenicity, and studied the effects of a two-dose immunization schedule. It also tested the CoronaVac vaccine in older individuals, who are among the most susceptible to severe COVID-19 disease.

Limitations

The phase 1 and 2 results presented here were based off of small sample sizes, so p-values shown cannot support powerful conclusions. While neutralizing antibody titer were used as a correlate of protection here, no true correlate of protection against SARS-CoV-2 has yet been defined. A neutralizing antibody assay was used here instead of a live virus neutralization assay due to logistical constraints, and no study of T-cell immunity was performed. The trial participants were quite a homogenous population, mostly of Han ethnicity. Further analysis will need to be performed on a more diverse population. Finally, only short-term safety and immunogenicity data is presented here, with further results to come.

Value added

First results published on phase 1/2 trial data regarding the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in a population of older adults.

Our take —

This is an interim report of phase 3 data from the Russian Gam-COVD-Vac vaccine. This study demonstrated that Gam-COVID Vac was well tolerated and highly efficacious (91.6%). These data suggest a single dose could provide sufficient protection and that the vaccine was equally efficacious in elderly populations. While the promise of a single dose vaccine is encouraging, this study was designed to test a prime-boost regimen. As such, further studies will be necessary to completely verify the efficacy of a single dose vaccine.

Study design

Randomized Controlled Trial

Study population and setting

This study reports on findings from an interim analysis of the randomized, double-blind, placebo-controlled phase 3 trial of Gam-COVID-Vac in Russia. Gam-COVID-Vac is an adenoviral based vaccine using both rAd5 and rAd26. The vaccine is given in a prime boost regimen: the first dose is with rAd26 encoding the SARS-CoV-2 glycoprotein S and the second dose is 21 days later with rAd5 encoding the SARS-CoV-2 glycoprotein S. The study included 977 healthy participants aged 18-87 years old. The primary outcome of the study was the number of patients with PCR-confirmed COVID-19 at 21 days after the first dose. Secondary outcomes included antibody levels, neutralizing antibody titers, and T-cell immunity. Adverse events were documented.

Summary of Main Findings

From 15 to 21 days following the first dose, the vaccine efficacy was 73.6%. At 21 days following the first dose, vaccine efficacy was 91.6%. There was no decrease in efficacy among participants over 60 years old. There were also no cases of severe confirmed COVID-19 in the vaccine group at least 21 days after the first dose. Antibody levels were measured at day 42 after the first dose. There was a statistically significant difference in antibody levels between participants aged 18-30 years and all other age groups. Neutralizing antibody levels were also measured at day 42 and no significant differences were noted based on age or sex of the participants. The most common adverse events were flu-like illness, headache, injection site reactions, and lethargy. No vaccine-related serious adverse events were noted.

Study Strengths

This study included a separate analysis of elderly populations, which is important as this is a high risk population in which immune responses are often decreased compared to younger populations.

Limitations

This is an interim analysis. Full reporting of phase 3 data will be needed to fully understand the efficacy of this vaccine. No efficacy data were reported following the booster dose, though these data should be forthcoming. Antibody levels are not compared to convalescent plasma and so the meaning of the levels detected is difficult to interpret. The full adverse event report is not included, but should be forthcoming. The study population was also not ethnically diverse, and it is not clear that further studies are planned in more diverse populations. While participants 60 years and older were included, these were small numbers (1,611 in the vaccine group and 533 in the placebo group). Further studies may be necessary to fully understand the vaccine effects in this population. The authors state that storage is approved at 2-8C. However, it was designed to be stored at -18C, and no data supporting a new storage protocol are provided. Duration of protection is unclear, but this will be analyzed further as the trial continues.

Value added

This study demonstrates that the Gam-COVID-Vac was well tolerated and highly efficacious. While this trial was set up to study a prime-boost regime, the data suggest a single dose could be sufficient. Trials to study this directly are underway.

Our take —

This prospective cohort study was nested in a randomized controlled trial, and found that among 314 index patients with COVID-19, there were 753 contacts across 282 potential transmission clusters of which 32% had a transmission case. Increased viral load amongst the index case, household contacts, and age of contacts were associated with transmission; notably, respiratory symptoms of the index case were not associated with transmission. Additionally, among infected contacts testing positive but asymptomatic at first assessment, higher viral load within the contact was associated with their eventual onset of symptoms and time-to-symptom onset (higher viral load resulted in symptom onset in fewer days). A key limitation is that no asymptomatic index cases were included, however the study yielded important insights into the impact of viral load on transmission. Findings suggest that viral load, and not respiratory symptoms among index cases, predicts transmission, and that viral load amongst secondary infections impacts symptom onset.

Study design

Randomized Controlled Trial, Prospective Cohort

Study population and setting

The study objective was to identify transmission factors and clusters of COVID-19 in the Catalonia region of Spain using data from a randomized controlled trial conducted between March 17 and April 28, 2020 for hydroxychloroquine to reduce transmission of SARS-CoV-2. Eligibility criteria for cases included aged 18 years or older, not hospitalized, positive PCR results at baseline, an onset of mild symptoms within 5 days preceding enrollment, and no reported symptoms of COVID-19 at the home or workplace. Participants were identified using the Epidemiological Surveillance Emergency Service registry and their contacts were traced. Adult contacts were household members, nursing home residents, or healthcare worker contacts who had direct exposure to the index case for 15 or more minutes and no reported symptoms in the 7 days prior to index case enrollment. Contacts were followed for 14 days with visits on Day 1 and 14. The study used symptom questionnaires and collected age and sex information on cases and contacts. Authors assessed the relationship of viral load from PCR results and SARS-CoV-2 transmission.

Summary of Main Findings

From 314 patients with COVID-19, investigators identified 753 contacts from 282 (90%) of patients. Of these 282 potential connections across individuals, 90 (32%) had at least one transmission event documented by the study. Among the 125 index cases with viral load data available, viral load among the index case was associated with fever in the index case and was negatively associated with days since onset of symptoms (reinforcing that viral load is highest around timing of symptom onset). In terms of transmission, the viral load of the index case, being a household contact, and age of the contact were all positively associated with transmission. Age and sex of the index case, respiratory symptoms of the index case, and mask use of contacts were not associated with transmission. Further, among 421 contacts testing positive at their first visit and asymptomatic, viral load amongst contacts at first infection detection was associated with eventual development of symptoms and time to symptom onset.

Study Strengths

The study had viral load data available to understand differences in transmission related to viral load. It also had longitudinal follow-up for all contacts to track symptoms and positive tests. The study used epidemiologic surveillance systems that were coupled with mandated contact tracing to ensure a large sample size, though it was nested in a randomized controlled trial (RCT).

Limitations

By nesting this analysis in an RCT, investigators had stringent eligibility requirements for index cases that may not be representative of all or most cases in Catalonia at large. In particular, asymptomatic individuals were not enrolled as index cases. Finally, total time of exposure was not included in the analysis, which may have underestimated the protective nature of masks if household contacts used masks but also had a longer time period of exposure; further, mask use of the index cases was not factored into the analysis.

Value added

This is one of the largest studies investigating viral load, as opposed to just COVID-19 infection status. It has important insights into the impact viral load has on transmission.

Our take —

This study, available as a preprint and thus not yet peer reviewed, presents further data on the efficacy of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine. The authors demonstrated that a single dose is efficacious against symptomatic COVID-19 for at least 90 days. Higher vaccine efficacy was observed when the time between the first and second doses was longer (12+ weeks vs. <6 weeks). Additionally, asymptomatic cases decreased with vaccination suggesting a potential impact on transmission.

After the NCRC reviewed this preprint, it was published in a scientific journal here.

Study design

Randomized Controlled Trial

Study population and setting

Data is presented from phase III (conducted in the United Kingdom and Brazil) and phase I/II trials (conducted in the United Kingdom and South Africa) including 17,177 participants of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine. Previous findings and protocol descriptions can be found here. Importantly, participants were swabbed weekly, regardless of symptoms, to assess incidence of asymptomatic infection. ChAdOx1 nCoV-19 vaccine is a chimpanzee adenoviral vectored vaccine encoding the full-length SARS-CoV-2 S protein. Vaccine was administered in either a Standard Dose-Standard Dose (SDSD) regimen or Low Dose-Standard Dose (LDSD) regimen. The vaccine has been authorized for emergency use for adults over 18 years old in the UK and other countries using a 2-dose regimen administered 4-12 weeks apart. This report presents data from an additional month of follow-up from ongoing trials as well as analysis of a self-selected single dose cohort, and a cohort who received their second dose at an increased time interval.

Summary of Main Findings

Overall efficacy of the ChAdOx1 nCoV-19 vaccine was 66.7%. For the LDSD regimen, vaccine efficacy was 80.7%. For the SDSD regimen, overall vaccine efficacy was 63.1%. However, when vaccine doses were spaced more than 12 weeks apart, efficacy rose to 82.4%. Anti-spike antibodies and neutralizing antibody titers were also higher at 6 months post-vaccination in groups with longer time between doses. This suggests that the difference in efficacy between the SDSD and LDSD groups that was previously noted may be due to the timing of vaccination, rather than dosage, as the LDSD group had much more incidence of delayed second doses. In these studies, 130 cases of asymptomatic cases were observed 14 days after the booster. There was 47.2% efficacy against asymptomatic cases in the LDSD and SDSD combined data. A single dose did not show protection against asymptomatic infection. However, this was only tracked to 60 days post vaccination, and only 11 total cases were observed in this group.

Study Strengths

This study included weekly swabs of participants to assess asymptomatic infection. This is very important to understanding the full efficacy of this vaccine.

Limitations

This analysis was all performed post-hoc, and therefore has room for bias. These studies were not originally designed to assess differences in dosing intervals or to assess a single dose. Additionally, the 95% confidence intervals for much of the estimates were very large, making distinctions between some of the groups difficult to interpret. While efficacy observed against asymptomatic cases suggests that transmission might be reduced with this vaccine, this has not been directly demonstrated. The duration of protection from a single dose vaccine is not clear. Further follow-up of all groups is needed.

Value added

These studies showed that a single dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine was efficacious for at least 90 days. A booster shot did significantly increase the efficacy of the vaccine. These studies also indicated that previous differences in efficacy noted with different dosing amount of ChAdOx1 nCoV-19 vaccine were likely due to the amount of time between doses, not difference in dose amounts. This supports continued use of the SDSD regimen.