The preliminary efficacy and safety results from the interim analysis of the Russian COVID-19 phase III vaccine trial have been published in The Lancet.
Dr Gillies O’Bryan-Tear, Past Chair, Policy and Communications, Faculty of Pharmaceutical Medicine, said:
“The results from the interim Phase 3 study of the Sputnik vaccine showed excellent efficacy of 91% for prevention of PCR test proven symptomatic Covid-19. Serious adverse events were similar in both arms.
“The study differed from previous studies in a couple of ways. Firstly, 3:1 randomisation (vaccine:placebo) was employed, and it appears that this decision may have been taken during the trial rather than before it, for ethical reasons. Such a fundamental change to the protocol, if it did occur after study initiation, is unusual, although it by no means invalidates the results (the placebo arm contained 4902 patients). It would be helpful to see the protocol, which has not been provided as part of the announcement.
“Secondly, the reported primary outcome was at 21 days after the first dose, in contrast to the other studies of two dose vaccines which all reported outcomes following the second dose, although some also reported results from earlier. Again, it would be important to know if this was a post hoc decision or was in the original protocol, since, again, a change to the primary endpoint during the conduct of a study considerably lowers its reliability. The study does not provide evidence of the duration of the first dose efficacy, but does show that good immunity is achieved by three weeks after the first dose. The curves separate from about 17 days, consistent with the other vaccines.
“This adenovirus vaccine (the same type as used by the Oxford and J&J vaccines) uses a so-called heterologous prime boost approach in which the second dose uses a different viral vector from the first dose. This is thought to have advantages over homologous vaccines, since an anti-vector response can be seen with the second dose otherwise. Indeed, this may be one explanation why the Oxford vaccine efficacy showed lower efficacy – at around 70% – although there are other explanations. A heterologous approach in which even the antigen (the spike protein usually) differs between prime and boost, or indeed a different type of vaccine is used, has been suggested as potentially inducing a more robust response, and AZ has announced a collaboration with the Sputnik vaccine group to treat test this approach.
“The Russian government rolled out this vaccine before clinical efficacy was proven, although good immune responses had been shown in phase 2. Whether this was the right decision or not has now been overtaken by these results, although such a rollout would not have been considered ethical in the more heavily regulated, western nations.
“It is very good news to have another effective vaccine available for Covid, especially one with another slightly different approach to previous ones. This vaccine is being made available to developing nations, but information is not yet available on the manufacturing capacity. As far as is known, most major Western nations have not placed orders for the Sputnik vaccine.”
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
“As expected given the origins of this program in the Gamaleya Institute, this is a good quality study which confirms the clinical effectiveness of the Gamaleya combined viral vector vaccine.
“The clinical effectiveness observed in the trial is high and should protect against COVID disease in recipients.
“This study did not directly compare effectiveness of the vaccine to others within the same trial; none of the vaccines have been directly compared within a study conducted in a randomised fashion across the same territories and admixtures of SARS CoV2 strains within a similar timeframe thus no firm conclusions can be drawn on relative effectiveness of any of the vaccines vs each other.
“The trial population predominantly recruited working age adults, with ~10% of the recruited population being >65 years of age. However a similar level of protection vs illness was observed compared to placebo in older adults as in younger adults.
“We do not know if the vaccine reduces transmission and this will need to be further investigated, as for all approved vaccines to date.
“The Russians started using this vaccine in high risk adults following the results of the preliminary phase I/2 trial, the results of which had already documented the immune response to match/exceed the immune response in convalescent COVID 19 patients, and therefore, logically, expected to confer clinical efficacy. The results of this phase III trial provide proof of principle for this approach in terms of clinical efficacy. However, the value of large scale clinical trials is in both confirming clinical effectiveness and in providing a robust understanding of the side effect profile than can be achieved in the small number of individuals in a phase I/2 immunogenicity study. These large scale clinical trials should enhance vaccine acceptability within a population where acceptance of vaccination relies on the individual rather than on mandatory enforcement of use by the state.
“The world pressingly needs covid vaccines and if the immune correlate of protection is now understood – as it should now be given the results of multiple phase III trials, perhaps time has come to consider wider application of vaccines following proof of immunological responses in early phase studies in adults of all ages, and in children, particularly in circumstances where an understanding of the side effect profile is available from use of the same vaccine technology for other infectious diseases or is a current vaccine ‘tweaked’ to give improved protection vs emergent variant strains – an approach already taken annually for influenza vaccines.”
Dr Peter English, Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice Magazine, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“This is a good study and very good news. Another highly effective vaccine in our amoury!
“We cannot compare phase III trials for different vaccines directly as they are done in different populations with different outcome measures, at different times, in populations with different levels of variant Covid-1o strains that might affect efficacy, and who vary in other ways, such as the proportion of people with HIV infection.
“This vaccine appears to work in older adults: vaccine efficacy was 91·8% (67·1–98·3) in participants older than 60 years.
“This phase III trial does not tell us if this vaccine reduces transmission.
“Implementing a vaccine in a large population before seeing your phase III results is hugely risky, and is definitely not to be recommended. The ethics of giving a product that has the potential to make you ill (or iller) is hugely different when you’re giving a vaccine to a large number of healthy patients, than when you are giving a medicine to a seriously ill patient, who might be prepared to take a risk. Apart from not knowing about efficacy or likelihood of harm, there is the potential to severely damage confidence in all other vaccines. However, knowing what we know now, it will have been a good decision. It is possible that the Russian regulators knew more than was in the public domain at the time, which might justify it.”
Dr Julian Tang, Honorary Associate Professor/Clinical Virologist, University of Leicester, said:
“This is a useful addition to the published data on COVID-19 vaccine effectiveness.
“This 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 this important caveat:
“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.
“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 yr 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.
“In this context, I look forward to seeing similar data/reports on the Chinese Sinovac/Sinopharm vaccines – as well as hearing how the Oxford-AZ and Russian Sputnik V teams might be collaborating to enhance and maintain the performance of their Ad-vectored COVID-19 vaccines – especially when both vaccines (and the recent Johnson & Johnson Ad26 vectored COVID-19 vaccine) are at risk of host-immune mediated neutralisation of their Ad vectors in the future – if repeated seasonal COVID-19 vaccine boosters are needed.”
Dr Alexander Edwards, Associate Professor in Biomedical Technology, Reading School of Pharmacy, University of Reading, said:
“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.
“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 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.
“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, 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.”
‘Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia’ by Logunov et al was published in The Lancet at 12:30pm UK time on Tuesday 5th February.
Dr Gillies O’Bryan-Tear: “Former Head of Vaccine Clinical Development, GSK. I am a pharmaceutical physician, semi-retired and have worked in a variety of fields, including oncology (cancer) drug development and vaccines development. I have been appointed CMO of Scancell, a U.K. listed biotech Company which has a Covid-19 vaccine candidate in preclinical development. Dr O’Bryan-Tear is Chief Medical Officer of Scancell plc, an early stage listed company developing vaccines for Covid-19″
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”
Dr Alexander Edwards: “None.”
None others received.