Covid-19: What do we know about Sputnik V and other Russian vaccines?BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n743 (Published 19 March 2021) Cite this as: BMJ 2021;372:n743
All rapid responses
Should we not be assessing all adenovirus vector based vaccines as a class when considering their efficacy and safety? This would also of course include the ChAdOx1 vaccine from Astrazeneca as well as the Jannsen J & J single dose vaccine. Much has been made of the risks of clotting from use of the AZ vaccine, but isn't it even probable that if this problem truly exists, it is likely to exist across the entire vaccine class? This possibility needs to be entertained.
Also, with regard to the success of the J & J vaccine, is it not likely that all vaccines of this class are likely to afford similar protection after a single dose, and the recommendations for some to be given as two doses arise from the simple fact that they have only been tested in RCTs with a two dose strategy? Its hard to find a biological reason why some adenovirus class vaccines afford log-term protection after a single dose, and others "require" two doses. Its interesting that the Gamelaya vaccine discussed here uses two different viral vectors to avoid the problem of immunity against a second dose. This has not been the case for the AZ vaccine, which uses the same vector for both doses. It is entirely possible that a second dose of an AZ vaccine is almost entirely superfluous to needs, and it would be better to inoculate a booster with a different vaccine, or just not to boost at all as with the J & J vaccine, and save that dose for other inoculations.
Competing interests: No competing interests
In a commissioned commentary, Chris Baraniuk reviews the “knowns and unknowns” about Russian vaccines against Covid-19, with a specific focus on Sputnik V . While the commentary correctly emphasizes the inconsistencies identified in the phase 1/2 trial results published in the Lancet , it mainly discusses the more recently published phase 3 trial results .
Our previous concerns regarding the phase 1/2 trial included problematic data patterns with an excess homogeneity of vaccine efficacy across different time points . The authors responded that the unusual data pattern was “a coincidence” due to the small sample size of their study and the discrete distributions of their outcomes .
Following such a reasoning, inconsistencies should not be expected in the subsequent larger phase 3 trial. However, we noticed an unexpected homogeneity of vaccine efficacy, this time between age groups. This analysis is central in the Lancet paper at issue because of the disproportionate disease burden in older people. Of course, implausible results can still be observed by chance. However, we have also identified a similar feature, i.e. an excessive homogeneity of the reported vaccine efficacy in the values reported in earlier interim analyses and the published article.
On 11 November 2020, a first press release announced a 92 % efficacy . From this press release we can compute that there were four Covid cases in the vaccine group and 16 in the placebo group. On 24 November 2020, a second press release announced a 91% efficacy with 8/14,095 cases in the vaccine group and 31/4,699 in the placebo group . On 14 December 2020 a third press release announced again a 91% efficacy with 16/17,032 cases in the vaccine group and 62/5,682 in the placebo group . Much to our surprise, the number of cases was exactly twice the number of cases observed in the previous press release  in both the placebo and the vaccine groups and about fourfold the number of cases in the vaccine and placebo groups in the first press release . Lastly, the Lancet publication, with a database lock on 24/11/2020, announced a 92% efficacy with 16/14,964 cases in the vaccine group and 62/4,902 in the placebo group . Altogether these results again appear “too good to be true”. The ratio of the number of events between the placebo and vaccine groups is as homogeneous as can be permitted by the number of events (20, 39 and 78) in the press releases [6-8].
The bootstrap P-value for assessing homogeneity of vaccine efficacy between interim stages by means of Pearson’s goodness-of-fit statistic was .9864, taking into account that the total number of events per interim stage is fixed. The Breslow-Day P-value for assessing the homogeneity of vaccine efficacy in age subgroups is equal to .9963. This means that vaccine efficacies are excessively similar between interim analyses and age subgroups even if we were to assume perfect homogeneity. The unusual and improbable high homogeneity of the vaccine efficacy across age strata and different interim analyses raises concerns about the data reported.
In a recent letter to The Lancet documenting these concerns (this letter was submitted upon invitation by The Lancet), the editorial team agreed to publish the letter on condition that we removed our concerns on the press release results since these results were not part of the Lancet publication. We, however felt it important to forward our concerns to the European Medicine Agency which we did on 03/12/2021. The recent BMJ publication by Baraniuk C  highlights the phase 3 data but did not address these concerns. We therefore felt it pertinent to inform readers of also these concerns with the Sputnik V vaccine data.
Enrico M. Bucci (Sbarro Institute - Temple University Department of Biology, USA), Johannes Berkhof (Amsterdam University Medical Centers, Department of Epidemiology and Data Science, Vrije Universiteit Amsterdam, Netherlands), André Gillibert (Department of Biostatistics, CHU Rouen, France), Gowri Gopalakrishna (Amsterdam University Medical Centers, Department of Epidemiology and Data Science, Vrije Universiteit Amsterdam, Netherlands), Raffaele A Calogero (Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy), Anders Bjorkman (Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden), Lex M. Bouter (Amsterdam University Medical Centers, Department of Epidemiology and Data Science, Vrije Universiteit Amsterdam, Faculty of Humanities, Department of Philosophy, Netherlands), Konstantin Andreev (Howard Hughes Medical Institute, Department of Molecular Biosciences, Northwestern University, Evanston, USA), Florian Naudet (Univ Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d’Investigation Clinique de Rennes), France), Vasiliy Vlassov (HSE University, Moscow, Russia)
1. Baraniuk C. Covid-19: What do we know about Sputnik V and other Russian vaccines? BMJ (Clinical research ed) 2021;372:n743. doi: 10.1136/bmj.n743 [published Online First: 2021/03/21]
2. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet (London, England) 2020;396(10255):887-97. doi: 10.1016/s0140-6736(20)31866-3 [published Online First: 2020/09/09]
3. Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. 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. Lancet (London, England) 2021;397(10275):671-81. doi: 10.1016/s0140-6736(21)00234-8 [published Online First: 2021/02/06]
4. Bucci E, Andreev K, Björkman A, et al. Safety and efficacy of the Russian COVID-19 vaccine: more information needed. Lancet (London, England) 2020;396(10256):e53. doi: 10.1016/s0140-6736(20)31960-7 [published Online First: 2020/09/25]
5. Logunov DY, Dolzhikova IV, Tukhvatullin AI, et al. Safety and efficacy of the Russian COVID-19 vaccine: more information needed - Authors' reply. Lancet (London, England) 2020;396(10256):e54-e55. doi: 10.1016/s0140-6736(20)31970-x [published Online First: 2020/09/25]
6. The first interim data analysis of the Sputnik V vaccine against COVID-19 phase III clinical trials in the Russian Federation demonstrated 92% efficacy. 2020 [Available from: https://sputnikvaccine.com/newsroom/pressreleases/the-first-interim-data... accessed 03/04/2021 2021.
7. Second interim analysis of clinical trial data showed a 91.4% efficacy for the Sputnik V vaccine on day 28 after the first dose; vaccine efficacy is over 95% 42 days after the first dose. 2020 [Available from: https://sputnikvaccine.com/newsroom/pressreleases/second-interim-analysi... accessed 03/04/2021 2021.
8. The Sputnik V vaccine's efficacy is confirmed at 91.4% based on data analysis of the final control point of clinical trials. 2020 [Available from: https://sputnikvaccine.com/newsroom/pressreleases/the-sputnik-v-vaccine-....
Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author): Johannes Berkhof, André Gillibert, Gowri Gopalakrishna, Raffaele A Calogero, Anders Bjorkman, Lex M. Bouter, Konstantin Andreev, Florian Naudet, Vasiliy Vlassov have nothing to disclose. Enrico M. Bucci owns Resis Srl, a small business dedicated to the analysis of the scientific literature for the assessment of research integrity.
Although Russia is the first country to release its own COVID-19 vaccine Sputnik-V for mass immunization , it has failed to gain expected public trust and confidence because of certain reasons.
Vaccine development is completely a scientific matter, not a political issue. When Russia suddenly declared the large-scale vaccination with Sputnik V for its people, people perceived that a business and boasting mind led Russia to make such an announcement by giving the status safe and effective vaccine to a vaccine which was, in fact, in the developing stage. Without sufficient experimental evidence, specially a detailed animal study data using non-human primate demonstrating the safety, efficacy and toxicity, anything to be used in humans is highly risky. When mutual and cooperative mindsets are being reflected in developing an effective vaccine to end the COVID-19 pandemic, the sudden emergence of Sputnik V with no detailed information surprised the whole scientific community. Strikingly, the Sputnik V received the emergency use authorization [2,3] without any reliable and structured phase I/II trials data, let alone phase III clinical trial result. There was no robust scientific and compelling evidence from animal study and large-scale clinical trials to convince people to have trust on it. Still we don’t know what scientific interpretation about the success of Sputnik V prompted the Gamaleya Research Institute to go for emergency use in humans. As a consequence, although the interim result of phase III clinical trial is quite interesting and promising , however, it is taking a bit long time to bring back public’s confidence in Sputnik V vaccine. To overcome this and to gain huge public response, all previous data can be made available to public now as the public has the right to judge whether they will receive vaccine or not. Also, the scientific community wants to see the solid evidence in favor of safety and efficacy of this vaccine.
The technology employed in the development of Sputnik V vaccine is very similar to that used in the Oxford-AstraZeneca COVID-19 vectored vaccine except that Sputnik V was developed using two human adenoviral vectors while the Oxford–AstraZeneca vaccine was developed using chimpanzee adenoviral vector. To avoid any neutralizing effect of pre-existing adenovirus antibody as well as T helper cell response due to prior infection with adenovirus (Ad5) or prior use of Ad5 as a vector [5,6], the use of chimpanzee adenoviral vector seems to be more logical than use of two human adenoviral vectors (Ad5 and Ad 26). Nonetheless, two shots of vaccine with two different viral vectors have been demonstrated to produce better immunity based on the concept that the same adenovirus vector used in second dose may be neutralized before exerting its assigned activity by the antibody generated after the first dose of immunization.
The interim data analysis of the phase III clinical trial conducted in 21977 adults shows that the Sputnik V has 91·6% efficacy rate (95% CI 85·6–95·2) with mostly grade 1 adverse events , thereby, making it an effective and well tolerated vaccine. In the meantime, Russia has finalized its business deal with more than 40 countries in Latin America, Eastern Europe, Asia, and Africa , however, the rollout moves slowly. If the use of Sputnik V vaccine in Russia could be increased through gaining adequate public confidence, it would be a good vaccine probably for millions of people across the globe when there is really a short-supply of other effective COVID-19 vaccines to make the world free from SARS-CoV-2.
1. Russia: Free mass coronavirus vaccinations and an ice pop to boot. https://www.dw.com/en/russia-free-mass-coronavirus-vaccinations-and-an-i...
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3. Liu Y, Wang K, Massoud TF, Paulmuruganet R. SARS-CoV-2 Vaccine Development: An Overview and Perspectives. ACS Pharmacol Transl Sci. 2020.
4. Logunov DY et al. 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. Lancet. 2021 Feb 20;397(10275):671-681. doi: 10.1016/S0140-6736(21)00234-8.
5. Harro CD, et al. Safety and immunogenicity of adenovirus-vectored near-consensus HIV type 1 clade B gag vaccines in healthy adults. AIDS Res. Hum. Retroviruses, 25 (2009), pp. 103-114.
6. Quirk EK , Mogg R, Brown DD, Lally MA, Mehrotra DV, DiNubile MJ, Robertson MJ. HIV seroconversion without infection after receipt of adenovirus-vectored HIV type 1 vaccine. Clin. Infect. Dis., 47 (2008), pp. 1593-1599.
7. Guenot M. Russia Sputnik V vaccine going to 40+ countries as West hoards shots. businessinsider.com, Mar 5, 2021.
Competing interests: No competing interests