The Lancet: Study reports preliminary efficacy and safety results from interim analysis of Russian COVID-19 phase 3 vaccine trial

February 02, 2021

An interim analysis of data from the phase 3 trial of the COVID-19 vaccine from Russia (Gam-COVID-Vac) suggests that a two-dose regimen of the adenovirus-based vaccine offers 91.6% efficacy against symptomatic COVID-19. The preliminary findings, published in The Lancet, are based on analysis of data from nearly 20,000 participants, three-quarters of whom received the vaccine and one quarter received a placebo.

Serious adverse events (those requiring hospital admission) were rare in both the placebo (0.4% [23/5,435]) and vaccine (0.2% [45/16,427]) groups and none were considered associated with vaccination. Four deaths were reported in the trial, none of which were considered related to the vaccine. Most reported adverse events were mild, including flu-like symptoms, pain at injection site and weakness or low energy.

The Gam-COVID-Vac is a two-part vaccine that includes two adenovirus vectors - recombinant human adenovirus type 26 (rAd26-S) and recombinant human adenovirus type 5 (rAd5-S) - which have been modified to express the SARS-CoV-2 spike protein. The adenoviruses are also weakened so that they cannot replicate in human cells and cannot cause disease. Adenoviral vector vaccines have been previously used, and their safety has been confirmed in several clinical studies.

In this trial, participants were given one dose of rAd26-S, followed by a booster dose of rAd5-S 21 days later. The authors explain that using a different adenovirus vector for the booster vaccination may help create a more powerful immune response (compared with using the same vector twice), as it minimises the risk of the immune system developing resistance to the initial vector.

"Our interim analysis of the randomised, controlled, phase 3 trial of Gam-COVID-Vac in Russia has shown high efficacy, immunogenicity, and a good tolerability profile in participants aged 18 years or older," says Dr Inna V Dolzhikova, co-lead author, Gamaleya National Research Centre for Epidemiology and Microbiology, Russia. [1]

Worldwide, 64 candidate COVID-19 vaccines are currently in clinical assessment (including 13 vaccine candidates at phase 3) and 173 vaccines are in preclinical analyses. Phase 3 candidate vaccines include a variety of vaccine platforms, such as vector vaccines, mRNA vaccines, inactivated vaccines, and adjuvanted recombinant protein nanoparticles.

"Stopping the COVID-19 pandemic requires the introduction of different vaccines based on different mechanisms of action to cover diverse global health demands. Our vaccine, along with other SARS-CoV-2 vaccines, helps to diversify the world SARS-CoV-2 vaccine pipeline," says Dr Denis Logunov, co-lead author, Gamaleya National Research Centre for Epidemiology and Microbiology, Russia. [1]

Between Sept 7 and Nov 24, 2020, a total of 21,977 adults were randomly assigned to receive the vaccine (16,501) or placebo (5,476). The trial was conducted across 25 hospitals and polyclinics in Moscow, Russia. 14,964 participants in the vaccine group and 4,902 in the placebo group received two doses of the vaccine or placebo and were included in the primary interim efficacy analysis reported today. PCR tests were done at screening and at dose 2 (21 days). A further PCR test was done if participants reported symptoms of respiratory infection. Efficacy of the vaccine was calculated on the basis of the proportion of participants with PCR-confirmed COVID-19.

From 21 days after receiving the first dose (the day of dose 2), 16 cases of symptomatic COVID-19 were confirmed in the vaccine group (0.1% [16/14,964) and 62 cases (1.3% [62/4,902]) in the placebo group - equivalent to an efficacy of 91.6%.

The vaccine induced a robust humoral response (also called antibody response) and cellular immune response (also called T-cell response) with data from 342 and 44 participants, respectively. Six of the 342 participants did not mount an immune response following vaccination, possibly due to older age or individual characteristics.

The authors note that because COVID-19 cases were detected only when participants self-reported symptoms (followed by a PCR test), the efficacy analysis only includes symptomatic cases of COVID-19, and further research is needed to understand the efficacy of the vaccine on asymptomatic COVID-19, and transmission. Furthermore, median follow up was 48 days from the first dose, so the study cannot assess the full duration of protection.

Adverse events were monitored via electronic medical records, electronic diaries and telemedicine consultations. Data on serious adverse events were analysed for 21,862 participants who received at least one dose of the vaccine (16,427) or the placebo (5,435). 70 serious adverse events were reported in 68 participants, including 45 (0.2% [45/16,427]) participants in the vaccine group, and 23 (0.4% [23/5,435]) participants in the placebo group. None of the serious adverse events were considered associated with vaccination.

During the trial, four deaths were recorded - three (<0.1% [3/16,427]) in the vaccine group, and one (<0.1% [1/5,435]) in the placebo group. In the vaccine group, one death was associated with a fracture. Two had underlying conditions and developed symptoms of COVID-19 4-5 days after the first dose of the vaccine. Based on the incubation period of the disease, both participants were deemed to have already been infected before inclusion in the trial, despite a negative PCR test. In the placebo group, the death was associated with a stroke. None of the deaths were deemed to be associated with vaccination.

Data on serious adverse events were available for all participants at the time the interim analysis was completed - among these, verified data on general adverse events was available for 12,296 participants (9,258 in the vaccine group and 4,902 in the placebo group). Most of the reported adverse events (94% [7,485/7,966]) were mild (grade 1), and included flu-like illness, injection site reactions, headache, and asthenia (physical weakness or low energy). 451 were grade 2 (5.66%) and 30 were grade 3 (0.38%).

The trial included 2,144 participants older than 60 years, and vaccine efficacy was 91.8% in this group. The vaccine was well tolerated and safety data from 1,369 of these older adults found that the most common adverse events were flu-like symptoms and local reaction. There were three episodes of serious adverse events in the placebo group (urolithiasis, sinusitis and flu-like illness) and three in the vaccine group (renal colic, deep vein thrombosis and extremity abscess). No association was found between the adverse events and vaccination.

As part of their secondary analyses, the authors explored the efficacy of the vaccine against moderate or severe COVID-19. At 21 days after the first dose, there were no cases of moderate or severe COVID-19 in the vaccine group and 20 cases in the placebo group, equivalent to an efficacy of 100% against moderate or severe COVID-19.

Although the study was not designed to assess the efficacy of a single-dose regimen, the findings hint to the early onset of a partially protective effect 16-18 days after a single-dose immunisation. From day 15-21, efficacy against moderate or severe COVID-19 was 73.6%, but further research is required to draw any robust conclusions from these observations. The research team have recently received approval to investigate the effectiveness of a single-dose regimen of the vaccine.

Most participants in the trial were white so further research will be needed to confirm the results in a more diverse group of participants. Although the study enrolled participants with comorbidities, not all risk groups are represented. All participants were aged over 18 years, and the authors report a need for further research to investigate the vaccine in adolescents and children, as well as pregnant women. The trial is ongoing and aiming to include a total of 40,000 participants - monitoring of safety and efficacy continues.

The phase 3 trial published today follows an earlier phase 1/2 trial [2] that reported safety and immunogenicity of two different formulations (one frozen, one freeze-dried) of the two-part vaccine. In this study, the liquid form of the vaccine was used, which requires storage at -18C. Storage at 2-8°C has also been approved.

Writing in a linked Comment, Professor Ian Jones, University of Reading, and Professor Polly Roy, London School of Hygiene & Tropical Medicine, UK (who were not involved in the study), say: "The development of the Sputnik V vaccine has been criticised for unseemly haste, corner cutting, and an absence of transparency. But the outcome reported here is clear and the scientific principle of vaccination is demonstrated, which means another vaccine can now join the fight to reduce the incidence of COVID-19."
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NOTES TO EDITORS

This study was funded by the Moscow City Health Department and Russian Direct Investment Fund, Sberbank PJSC and UC RUSAL.

[1] Quote direct from author and cannot be found in the text of the Article. [2] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31866-3/fulltext

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Peer reviewed / Randomised controlled trial / People

The Lancet

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