Coronavirus (26) Non-replicating viral vector vaccine candidates for COVID-19 (part c)
Continued from my last blog post.
3. Sputnik V by Gamaleya Research Institute
Sputnik V, formerly known as Gam-COVID-Vac, was developed by the Gamaleya Research Institute in Moscow. It was the world’s first registered vaccine for COVID-19, which was approved by the Ministry of Health of the Russian Federation on 11th August. 1
The other non-replicating virus vectored vaccine candidates for COVID-19 use only a single recombinant virus as a vector, but Sputnik V uses different recombinant adenoviruses for the first (prime dose) and the second vaccination (booster dose). The two adenovirus vectors, adenovirus type 5 (Ad5) and adenovirus type 26 (Ad26), were inserted with the same whole spike glycoprotein nucleotide sequence to express Spike protein of SARS-CoV-2. The vaccine using Ad26 as viral vector (rAd26-S) was administered for the first shot in vaccination (primary vaccination), and the vaccine using Ad5 as viral vector (rAd5-S) is then administered in the second shot in vaccination (booster). According to the Gamaleya Research Institute, this kind of heterologous vaccination can overcome negative effects of immune response to the vector component.*
Gamaleya Research Institute were already using this heterologous-vector-based approach to develop two vaccines against Ebola, both of which were approved for use by the Ministry of Health of the Russian Federation.1,2
Phase 1/2
Report on two open, non-randomised phase 1 and 2 studies on Sputnik V at two hospitals in Russia were published in The Lancet in September.3 The trials recruited 76 participants (38 in each study) aged 18 to 60, starting from 18th June this year. One study (NCT04436471)4 used frozen formulation, while the other study (NCT04437875)5 used lyophilized formulation of the vaccine candidate. Each study had a phase 1 trial that included 18 volunteers receiving intramuscularly one dose of either Sputnik V with Ad26 as viral vector (rAd26-S, 9 participants) or Sputnik V with Ad5 as viral vector (rAd5-S, 9 participants), and a phase 2 trial that included 20 volunteers for heterologous prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21.3
The results from the studies found that both frozen and lyophilized formulations of Sputnik V were safe and well tolerated. Among the 78 participants, the most common adverse events after vaccination were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild. No serious adverse events were detected.
All 78 participants produced specific IgG antibodies** to the receptor binding domain of Spike glycoprotein of the SARS-CoV-2, as measured 21 days after vaccinations. At day 42, the average serum levels of IgG against receptor binding domain of the Spike glycoprotein were higher for the group administered with frozen formulation than the group administered with lyophilized formulation (GMT 14,703 vs GMT 11,143).*** The average levels of neutralising antibodies against the coronavirus were 49.25 for the frozen formulation and 45.95 for the lyophilized formulation. This shows that Sputnik V induces humoral immunity with the frozen formulation triggering a higher level.
Cell-mediated T-cell responses were detected in all participants at day 28, with median cell proliferation of 2.5% CD4+ and 1.3% CD8+ with the frozen formulation, and a median cell proliferation of 1.3% CD4+ and 1.1% CD8+ with the lyophilized formulation. Again, this shows that Sputnik V induces cellular immunity, with the frozen formulation triggering a higher level.
Another open-ended, non-random phase 2 study (NCT04587219)6 aiming to investigate the prime-boost vaccination (with rAd26-S given on day 0 and rAd5-S on day 21) using frozen formulations of the vaccine on 110 participants aged 60 or above, has just been started on 22nd October. This study is expected to finish by the end of the year.
Phase 3
The phase 3 trial (NCT04530396) estimated to recruit a total of 40,000 participants started on 7th September.7 It is a randomized, double-blind (blinded for both the trial subject and the study physician), placebo controlled, multi-centre clinical trial to examine the efficacy, immunogenicity, and safety of the frozen formulation of the combined vector vaccines (rAd26-S given on day 0 and rAd5-S on day 21) against the SARS-CoV-2-induced coronavirus infection in adults age 18 or above. The study is expected to be completed in May 2021.
The whole project is supported by the Russia Direct Investment Fund. Moreover, the Gamaleya Research Institute has accumulated a lot of experiences in using adenoviruses as vectors to develop vaccines. The scientists of this lab first started to develop vaccines using adenoviruses in the 1980s. Therefore, the research centre should have enough funding and ability to develop and to test the vaccine candidate, and to mass produce the vaccine candidate for the public if it is approved to be used.
However, Sputnik V has sparked controversies among scientists around the world since the Russian government tried to accelerate the registration of this vaccine candidate. Only two months after the start of the early stage of the clinical trials in June, which included just 76 participants, the Ministry of Health of the Russian Federation already issued a registration certificate for the vaccine candidate and approved the use of it in August.8 Although the vaccine was to be given to “a small number of citizens from vulnerable groups,” including medical staff and the elderly, the certification was denounced by the scientists as “immature and inappropriate”. This raised considerable concern about the vaccine’s safety and efficacy, especially as the phase 3 trial study which recruits many more volunteers was yet to be launched one month later in September.8
The interim report of the phase 3 study, which has just been released on 11th of this month, has sparked another controversy.9-11 The report announced 92% efficacy, however, it is only the result from 20 total COVID-19 cases in the vaccinated and placebo groups. This is far too few for the claim to be convincing.10,11 The report was released two days after the announcement from Pfizer and BioNTech on a 90% efficacy of their RNA vaccines against COVID-19. With scant data presented in the release, the rushing of the announcement make it feel like that Russia was merely trying to keep up with their competitors in other countries in the international vaccine race.10
Moreover, the use of Ad5 as a carrier vector in one of the shots of Sputnik V has also raised concern of increase susceptibility to HIV. Previous experience suggested that non-HIV vaccine trials that use Ad5 as viral vector in areas of high HIV prevalence, such as South Africa, could lead to an increased risk of HIV-1 acquisition in the vaccinated population.12
About Gamaleya Research Institute
The Gamaleya Research Institute of Epidemiology and Microbiology in Moscow was founded in 1891 by Nikola Gamaleya as a private laboratory. It has borne the name of Nikolai Gamaleya since 1949. Gamaleya Center is now led by Alexander Gintsburg, Doctor of Biology, Member of the Russian Academy of Sciences.1 The Gamaleya Research Center is currently developing vaccines against influenza and against Middle East Respiratory Syndrome (MERS) using adenoviral vectors. Both vaccines are in advanced stages of clinical trials.1
* “When using vector-based vaccines, immune responses are formed not only to the target antigen expressed from the gene inserted to the viral vector. As a result, the best vaccination scheme is heterologous vaccination, when different viral vectors are used to overcome any negative effects of immune response to vector components.” 2
** Detection of specific IgG antibodies to the receptor binding domain of Spike glycoprotein of the SARS-CoV-2 from the participants’ blood indicates the successful triggering of the production of antibodies against SARS-CoV-2 by the vaccine candidates.
***GMT: Geometric Mean Titre is the average antibody titre (concentration) for a group of people. The value is usually useful to evaluate the immune responses.
References
1. Information from the website of Sputnik V vaccine: https://sputnikvaccine.com
2. I.V. Dolzhikova, O.V. Zubkova, and A.I. Tukhvatulin,et al . Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: an open phase I/II trial in healthy adults in Russia. Hum. Vaccin. Immunother., 2017; 13: 613-620.
3. D.Y. Logunov, I.V. Dolzhikova, O.V. Zubkova, 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. The Lancet, 2020, 395,10255, 887-897.
4. An open study of the safety, tolerability and immunogenicity of the drug "Gam-COVID-Vac" vaccine against COVID-19. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04436471
5. An open study of the safety, tolerability and immunogenicity of "Gam-COVID-Vac Lyo" vaccine against COVID-19. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04437875
6. The study of "Gam-COVID-Vac" vaccine against COVID-19 with the participation of volunteers of 60 y.o and older. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04587219
7. Clinical trial of efficacy, safety, and immunogenicity of Gam-COVID-Vac vaccine against COVID-19 (RESIST). ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04530396
8.Russia’s approval of a COVID-19 vaccine is less than meets the press release. By Jon Cohen. Science, Aug. 11, 2020. https://www.sciencemag.org/news/2020/08/russia-s-approval-covid-19-vaccine-less-meets-press-release
9. The first interim data analysis of the Sputnik V vaccine against COVID-19 phase III clinical trials in the Russian Federation demonstrated 92% efficacy. Press release from Sputnik V. https://sputnikvaccine.com/newsroom/pressreleases/the-first-interim-data-analysis-of-the-sputnik-v-vaccine-against-covid-19-phase-iii-clinical-trials-/
10. Russia’s claim of a successful COVID-19 vaccine doesn’t pass the ‘smell test,’ critics say. By Jon Cohen. Science, Nov. 11, 2020. https://www.sciencemag.org/news/2020/11/russia-s-claim-successful-covid-19-vaccine-doesn-t-pass-smell-test-critics-say 11. Russia announces positive COVID-vaccine results from controversial trial. By Ewen Callaway. Nature News, 11 November, 2020. https://www.nature.com/articles/d41586-020-03209-0
12. S.P. Buchbinder, M.J. McElrath, C. Dieffenbach, et al. Use of adenovirus type-5 vectored vaccines: a cautionary tale. Lancet, 2020, Oct 31; 396 (10260): E68-E69.
Continued from my last blog post.
3. Sputnik V by Gamaleya Research Institute
Sputnik V, formerly known as Gam-COVID-Vac, was developed by the Gamaleya Research Institute in Moscow. It was the world’s first registered vaccine for COVID-19, which was approved by the Ministry of Health of the Russian Federation on 11th August. 1
The other non-replicating virus vectored vaccine candidates for COVID-19 use only a single recombinant virus as a vector, but Sputnik V uses different recombinant adenoviruses for the first (prime dose) and the second vaccination (booster dose). The two adenovirus vectors, adenovirus type 5 (Ad5) and adenovirus type 26 (Ad26), were inserted with the same whole spike glycoprotein nucleotide sequence to express Spike protein of SARS-CoV-2. The vaccine using Ad26 as viral vector (rAd26-S) was administered for the first shot in vaccination (primary vaccination), and the vaccine using Ad5 as viral vector (rAd5-S) is then administered in the second shot in vaccination (booster). According to the Gamaleya Research Institute, this kind of heterologous vaccination can overcome negative effects of immune response to the vector component.*
Gamaleya Research Institute were already using this heterologous-vector-based approach to develop two vaccines against Ebola, both of which were approved for use by the Ministry of Health of the Russian Federation.1,2
Phase 1/2
Report on two open, non-randomised phase 1 and 2 studies on Sputnik V at two hospitals in Russia were published in The Lancet in September.3 The trials recruited 76 participants (38 in each study) aged 18 to 60, starting from 18th June this year. One study (NCT04436471)4 used frozen formulation, while the other study (NCT04437875)5 used lyophilized formulation of the vaccine candidate. Each study had a phase 1 trial that included 18 volunteers receiving intramuscularly one dose of either Sputnik V with Ad26 as viral vector (rAd26-S, 9 participants) or Sputnik V with Ad5 as viral vector (rAd5-S, 9 participants), and a phase 2 trial that included 20 volunteers for heterologous prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21.3
The results from the studies found that both frozen and lyophilized formulations of Sputnik V were safe and well tolerated. Among the 78 participants, the most common adverse events after vaccination were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild. No serious adverse events were detected.
All 78 participants produced specific IgG antibodies** to the receptor binding domain of Spike glycoprotein of the SARS-CoV-2, as measured 21 days after vaccinations. At day 42, the average serum levels of IgG against receptor binding domain of the Spike glycoprotein were higher for the group administered with frozen formulation than the group administered with lyophilized formulation (GMT 14,703 vs GMT 11,143).*** The average levels of neutralising antibodies against the coronavirus were 49.25 for the frozen formulation and 45.95 for the lyophilized formulation. This shows that Sputnik V induces humoral immunity with the frozen formulation triggering a higher level.
Cell-mediated T-cell responses were detected in all participants at day 28, with median cell proliferation of 2.5% CD4+ and 1.3% CD8+ with the frozen formulation, and a median cell proliferation of 1.3% CD4+ and 1.1% CD8+ with the lyophilized formulation. Again, this shows that Sputnik V induces cellular immunity, with the frozen formulation triggering a higher level.
Another open-ended, non-random phase 2 study (NCT04587219)6 aiming to investigate the prime-boost vaccination (with rAd26-S given on day 0 and rAd5-S on day 21) using frozen formulations of the vaccine on 110 participants aged 60 or above, has just been started on 22nd October. This study is expected to finish by the end of the year.
Phase 3
The phase 3 trial (NCT04530396) estimated to recruit a total of 40,000 participants started on 7th September.7 It is a randomized, double-blind (blinded for both the trial subject and the study physician), placebo controlled, multi-centre clinical trial to examine the efficacy, immunogenicity, and safety of the frozen formulation of the combined vector vaccines (rAd26-S given on day 0 and rAd5-S on day 21) against the SARS-CoV-2-induced coronavirus infection in adults age 18 or above. The study is expected to be completed in May 2021.
The whole project is supported by the Russia Direct Investment Fund. Moreover, the Gamaleya Research Institute has accumulated a lot of experiences in using adenoviruses as vectors to develop vaccines. The scientists of this lab first started to develop vaccines using adenoviruses in the 1980s. Therefore, the research centre should have enough funding and ability to develop and to test the vaccine candidate, and to mass produce the vaccine candidate for the public if it is approved to be used.
However, Sputnik V has sparked controversies among scientists around the world since the Russian government tried to accelerate the registration of this vaccine candidate. Only two months after the start of the early stage of the clinical trials in June, which included just 76 participants, the Ministry of Health of the Russian Federation already issued a registration certificate for the vaccine candidate and approved the use of it in August.8 Although the vaccine was to be given to “a small number of citizens from vulnerable groups,” including medical staff and the elderly, the certification was denounced by the scientists as “immature and inappropriate”. This raised considerable concern about the vaccine’s safety and efficacy, especially as the phase 3 trial study which recruits many more volunteers was yet to be launched one month later in September.8
The interim report of the phase 3 study, which has just been released on 11th of this month, has sparked another controversy.9-11 The report announced 92% efficacy, however, it is only the result from 20 total COVID-19 cases in the vaccinated and placebo groups. This is far too few for the claim to be convincing.10,11 The report was released two days after the announcement from Pfizer and BioNTech on a 90% efficacy of their RNA vaccines against COVID-19. With scant data presented in the release, the rushing of the announcement make it feel like that Russia was merely trying to keep up with their competitors in other countries in the international vaccine race.10
Moreover, the use of Ad5 as a carrier vector in one of the shots of Sputnik V has also raised concern of increase susceptibility to HIV. Previous experience suggested that non-HIV vaccine trials that use Ad5 as viral vector in areas of high HIV prevalence, such as South Africa, could lead to an increased risk of HIV-1 acquisition in the vaccinated population.12
About Gamaleya Research Institute
The Gamaleya Research Institute of Epidemiology and Microbiology in Moscow was founded in 1891 by Nikola Gamaleya as a private laboratory. It has borne the name of Nikolai Gamaleya since 1949. Gamaleya Center is now led by Alexander Gintsburg, Doctor of Biology, Member of the Russian Academy of Sciences.1 The Gamaleya Research Center is currently developing vaccines against influenza and against Middle East Respiratory Syndrome (MERS) using adenoviral vectors. Both vaccines are in advanced stages of clinical trials.1
* “When using vector-based vaccines, immune responses are formed not only to the target antigen expressed from the gene inserted to the viral vector. As a result, the best vaccination scheme is heterologous vaccination, when different viral vectors are used to overcome any negative effects of immune response to vector components.” 2
** Detection of specific IgG antibodies to the receptor binding domain of Spike glycoprotein of the SARS-CoV-2 from the participants’ blood indicates the successful triggering of the production of antibodies against SARS-CoV-2 by the vaccine candidates.
***GMT: Geometric Mean Titre is the average antibody titre (concentration) for a group of people. The value is usually useful to evaluate the immune responses.
References
1. Information from the website of Sputnik V vaccine: https://sputnikvaccine.com
2. I.V. Dolzhikova, O.V. Zubkova, and A.I. Tukhvatulin,
3. D.Y. Logunov, I.V. Dolzhikova, O.V. Zubkova, 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. The Lancet, 2020, 395,10255, 887-897.
4. An open study of the safety, tolerability and immunogenicity of the drug "Gam-COVID-Vac" vaccine against COVID-19. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04436471
5. An open study of the safety, tolerability and immunogenicity of "Gam-COVID-Vac Lyo" vaccine against COVID-19. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04437875
6. The study of "Gam-COVID-Vac" vaccine against COVID-19 with the participation of volunteers of 60 y.o and older. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04587219
7. Clinical trial of efficacy, safety, and immunogenicity of Gam-COVID-Vac vaccine against COVID-19 (RESIST). ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04530396
8.Russia’s approval of a COVID-19 vaccine is less than meets the press release. By Jon Cohen. Science, Aug. 11, 2020. https://www.sciencemag.org/news/2020/08/russia-s-approval-covid-19-vaccine-less-meets-press-release
9. The first interim data analysis of the Sputnik V vaccine against COVID-19 phase III clinical trials in the Russian Federation demonstrated 92% efficacy. Press release from Sputnik V. https://sputnikvaccine.com/newsroom/pressreleases/the-first-interim-data-analysis-of-the-sputnik-v-vaccine-against-covid-19-phase-iii-clinical-trials-/
10. Russia’s claim of a successful COVID-19 vaccine doesn’t pass the ‘smell test,’ critics say. By Jon Cohen. Science, Nov. 11, 2020. https://www.sciencemag.org/news/2020/11/russia-s-claim-successful-covid-19-vaccine-doesn-t-pass-smell-test-critics-say 11. Russia announces positive COVID-vaccine results from controversial trial. By Ewen Callaway. Nature News, 11 November, 2020. https://www.nature.com/articles/d41586-020-03209-0
12. S.P. Buchbinder, M.J. McElrath, C. Dieffenbach, et al. Use of adenovirus type-5 vectored vaccines: a cautionary tale. Lancet, 2020, Oct 31; 396 (10260): E68-E69.
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