It is gratifying to learn that besides the three vaccines which are already approved for emergency use in several countries, an equally effective fourth vaccine will be ready for use shortly. The Lancet (2 February, 2021) study suggests that a two-dose regimen of the adenovirus-based Russian vaccine (Gam-COVID-Vac) offers 91.6% efficacy against symptomatic COVID-19. The researchers completed the interim analysis of data from nearly 20,000 participants, three-quarters of whom received the vaccine and one quarter received a placebo.

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A press release from The Lancet summarised the results of this peer reviewed, randomised controlled trial thus (verbatim):

• Interim analysis from phase 3 trial of nearly 20,000 participants suggests efficacy of two-dose regimen of the adenovirus-based vaccine is 91.6% against symptomatic COVID-19 – trial reports 16 COVID-19 cases in the vaccine group (0.1% [16/14,964) and 62 cases (1.3% [62/4,902]) in the placebo group
• No serious adverse events were deemed to be associated with vaccination, and most reported adverse events were mild, including flu-like symptoms, pain at injection site and weakness or low energy
• Sub-analysis of 2,000 adults older than 60 years suggests the vaccine is similarly effective and well tolerated in this group
• Trial is ongoing and aiming to include a total of 40,000 participants - monitoring of safety and efficacy continues

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) noted that the 'trial results show a consistent strong protective effect across all participant age groups.'

They recalled that 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,” they added.

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The study

Between September 7 and November 24, 2020, the researchers randomly assigned a total of 21,977 adults to receive the vaccine (16,501) or placebo (5,476). They conducted the phase 3 trial 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. The researchers carried out the PCR tests at screening and at dose 2 (21 days). They did a further PCR test if participants reported symptoms of respiratory infection. The researchers calculated the efficacy of the vaccine based on the proportion of participants with PCR-confirmed COVID-19.

From 21 days after receiving the first dose (the day of dose 2), the researchers confirmed 16 cases of symptomatic COVID-19 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 researchers included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. They randomly assigned participants (3:1) to receive vaccine or placebo, with stratification by age group. They administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S.

They explained 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.

A press release from the journal quoted Dr Inna V Dolzhikova, co-lead author, Gamaleya National Research Centre for Epidemiology and Microbiology, Russia:

“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."

The vaccine induced a robust 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.

According to the release, 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.

“A system-wide approach to stopping the COVID-19 pandemic requires the introduction of different vaccines based on different mechanisms of action to cover diverse global health demands with cost-effective and region-tailored methods. Our vaccine, along with other SARS-CoV-2 vaccines, helps to diversify the world SARS-CoV-2 vaccine pipeline,” the researchers added.

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Adverse events

The researchers monitored the adverse events via electronic medical records, electronic diaries and telemedicine consultations. They reported 70 serious adverse events 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. According to them, none of the serious adverse events were associated with vaccination.

During the trial, the researchers recorded four deaths – 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.

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. They tolerated the vaccine well; the 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 researchers did not design the study 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.

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Limitations of the vaccine study

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.

Most participants in the trial were white; 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 is aiming to include 40,000 participants. Monitoring of safety and efficacy continues.

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What do experts have to say?

In a comment published for the Science Media Centre, UK, Dr Julian Tang, Honorary Associate Professor/Clinical Virologist, University of Leicester, stated that the Russian Sputnik V adenovirus-vectored vaccine using a heterologous Ad26/Ad5 vectored prime-boost design appears even more effective after 2 doses (91.6%) than the ChAd Oxford-AZ vaccine standard dose regimen – though the authors give the following important caveat (quoting verbatim):

“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.”

“So despite the earlier misgivings about the way this Russian Sputnik V vaccine was rolled out more widely – ahead of sufficient phase 3 trial data – this approach has been justified to some extent now," Dr Tang noted.

“Such pandemic-related vaccine rollout compromises have, to be fair, been adopted in the UK vaccination programme also – with the extended intervals between 1st/2nd doses, as well as the approval of the Oxford-AZ vaccine for over 55 year olds – despite little formal clinical phase 3 trial data to support this. So we should be more careful about being overly critical about other countries’ vaccine designs/programmes,” he cautioned.

In his response to the Science Media Centre, Dr Alexander Edwards, Associate Professor in Biomedical Technology, Reading School of Pharmacy, University of Reading noted that the vaccine trial results are coming thick and fast as high infection rates in areas where phase 3 clinical trials provide increasing amounts of data that together encourages us to believe that vaccines will soon be able to drive down the human cost of COVID-19.

“The more trial data we have, the better placed we are to understand how to make and use vaccines- so these results are welcomed,” he clarified.

“There are some exciting details in this. Although the adenovirus approach is similar to others (including Astrazeneca/Oxford and Janssen), two different versions are included in what’s known as “heterologous prime-boost”. This aims to drive higher immune responses to the target “spike” by using two slightly different jabs – the only shared element of the inoculation being the COVID-19 spike. This is thought to (be) beneficial for adenovirus based vaccines as otherwise if you have two identical vaccine doses, your immune system can be so efficient that it eliminates the second dose so quickly that your immunity to spike isn’t boosted as much. Whilst heterologous prime-boost has been discussed and explored experimentally for the past 20 years, this could be the large scale human trial that finally proves how well the approach can work to prevent a widespread human disease. Further clinical trials are urgently needed to understand the best way to combine different vaccine doses for maximum protection, especially if regular vaccine programs similar to the annual influenza program become important," he added.

“These viral vaccines are relatively stable (no need for storage at extreme temperature), but do have to be ‘grown’ in bioreactors so we can expect major expansion of the global capacity for manufacturing these adenovirus medicines. Manufacturing may remain a bottleneck for months to come, so the more vaccines available, and the better for global health. Pandemic means “all”- and the only way to address a global problem is with a global response- sharing data, science, technology and medicines,” he cautioned.

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According to the Wall Street Journal (2 February 2021) Sputnik V has global potential and could be a huge boon to Russia. The country has already received orders of or interest in 2.4 billion doses including from some of the most populous countries: Brazil, India and Mexico.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph.D from University of Leeds, UK, he is a medical physicist with specialization in radiation safety and regulatory matters. He was a Research Associate in the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.