Coronavirus (28) Non-replicating viral vector vaccine candidates for COVID-19 (part e)
AstraZeneca announced interim results for their phase 3 single-blinded, multi-centre, randomised, controlled studies from the UK (COV002) and Brazil (COV003) yesterday.1 Participants were randomized to receive intramuscular injection with either a half-dose/full-dose regimen (n=2,741) or two-full-doses regimen of AZD1222 (n=8,895), or a placebo using meningococcal conjugate vaccine called MenACWY or saline. Two shots were injected, at least one month apart.
By the end of the study, among a total of 22,690 participants, 131 were found to be COVID-19 positive: of these, 101 had received placebo, 3 had received half-dose/full-dose regimen, and 27 had received full dose at both initial and later shot. This led to the initial statistics of 90% vaccine efficacy when AZD1222 was given as half-dose/full-dose regimen, and 62% efficacy for the full-dose/full-dose regimen. On average, this showed a 70% effectiveness rate of the vaccine at preventing the COVID-19. Vaccine offering protection over 50% of vaccinated people is considered to be efficacious.# Moreover, no serious safety events related to the vaccine were reported in the studies.2,3
Professor Andrew Pollard, Director of the Oxford Vaccine Group and Chief Investigator of the Oxford Vaccine Trial, said these findings show that they “have an effective vaccine that will save many lives.” If the half-dose/full-dose regimen does give 90% effectiveness, they will apply this dosing regimen, and this means that “more people could be vaccinated with planned vaccine supply.”3 That seems to be good news.
As we are approaching the end of the year, more results from phase 3 studies of candidate vaccines are coming out, and also we have more informations about their prices. The vaccine made of non-replicating viral vector can be kept in a conventional fridge (2°C-8°C), similar to inactivated vaccines. Once a non-replicating viral vectored vaccine is produced, it can be stored, transported and handled at normal refrigerated conditions for at least six months, and can be administered within existing healthcare facilities. The transportation is easier and thus the cost is lower than the ones that require ultra-low temperatures. According to a Healthline online article, AstraZeneca’s two-dose vaccine could be just US $3 to $4 per dose, while each dose for Johnson & Johnson’s two-dose vaccine will cost about US $10.4 Meanwhile, the Russian Gamaleya Centre announced that the cost of their two-dose Sputnik V vaccine will be less than US $10 per dose for international markets.5 No information on the cost of the adenoviral vectored vaccine candidate by CanSinoBio can be found yet.
The ease of storage and handling, and the lower prices, render the non-replicating viral vectored vaccines viable for use in resource-limited countries. Moreover, such vaccines provide long-term gene expression, and high specificity of gene delivery to target cells. Additionally, since viral vectored vaccines result in endogenous antigen production, both humoral* and cellular immune** responses are stimulated. In other words, viral vectored vaccine triggers high immunogenicity.6
With all these advantages of using viral vectors, we should however not ignore some of the factors that may diminish the effectiveness of the vaccine candidates.
All four viral-vectored vaccines that entered phase 3 clinical trials use Adenovirus as a vector. Adenoviral DNA has the advantage of not integrating into the human genome and not being replicated during cell division. Apart from AstraZenica’s AZD1222 which used adenovirus ChAdOx1 (which causes the common cold in chimpanzees), the other 3 vaccine candidates use human adenoviruses, either Adenovirus type 5 (Ad5) or type 26 (Ad26), which have been genetically modified, as carriers of the genetic sequence that produces the Spike glycoprotein of SARS-CoV-2. However, a significant number of people may have already been infected with these human adenoviruses, and neutralising antibodies to the viral vectors already exist in these infected populations. These neutralising antibodies can inactivate the virus before it can reach the target cells, and thus decrease its efficacy.7
In fact, the baseline of different human adenovirus infections varies from place to place globally. The population with a higher baseline of pre-existing Ad26 infection, for example, is expected to have a lower immunity response upon the first dose of Sputnik V vaccine from Gamaleya Centre in Russia, or Ad26.COV2.S vaccines from Janssen Pharmaceuticals etc. Therefore when we consider which viral vectored vaccine to use, we should check the infection rate of the particular adenovirus in our population and try to avoid using a vaccine that contains an adenovirus that is already widespread in our area.
Also, people who volunteered to receive viral vector vaccines in previous clinical trials should also be aware not to rely on viral vectored vaccines for COVID-19 that use the same adenovirus carrier as they were administered in the previous trial.
Recombinant adenovirus vectors have been developed since the 1980s. Gamaleya Research Institute used Ad5 to produce vaccines against Ebola that were approved for use in 2015 and 2020.8 Another vaccine by Janssen Pharmaceuticals for Ebola, which was approved in 2020 by the European Union, used Ad26.9 The long-term effect of the use of these viral vectored vaccines is still unknown. However, the use of Ad5 as a carrier in an HIV vaccine candidate did increase the possibility of transmission of HIV.10 Moreover, the reports of neurological conditions, including multiple sclerosis and transverse myelitis, during the clinical trials of AstraZeneca's vaccine candidate,11 also raises concern for the safety of adenoviral vectored vaccines.12
#US Food and Drug Administration Coronavirus (COVID-19) update: FDA takes action to help facilitate timely development of safe, effective COVID-19 vaccines. June 30, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-action-help-facilitate-timely-development-safe-effective-covid
*Humoral immune responses protect extracellular spaces of the body from bacterial infections. Antibodies produced by B cells cause the destruction of extracellular microorganisms and prevent the spread of intracellular infections. (Immunobiology: The Immune System in Health and Disease. 5th edition. Chapter 9, The Humoral Immune Response. https://www.ncbi.nlm.nih.gov/books/NBK10752/)
** Cellular immune response is a protective immune process that involves the activation of phagocytes, antigen-sensitized cytotoxic T cells, and the release of cytokines and chemokines, in response to antigens. (Definition from Nature research. https://www.nature.com/subjects/cellular-immunity)
References
1. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19. AstraZeneca press release, 23rd November 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html
2. Covid-19: Oxford University vaccine is highly effective. By James Gallagher. BBC news, 23rd November, 2020. https://www.bbc.co.uk/news/health-55040635
3. Oxford University breakthrough on global COVID-19 vaccine. Press release of University of Oxford, 23rd November, 2020. https://www.research.ox.ac.uk/Article/2020-11-23-oxford-university-breakthrough-on-global-covid-19-vaccine
4.https://www.healthline.com/health-news/how-much-will-it-cost-to-get-a-covid-19-vaccine#How-much-each-dose-will-cost
5. The cost of one dose of the Sputnik V vaccine will be less than $10 for international markets. Press release from Gamaleya Center, 24th November, 2020. https://sputnikvaccine.com/newsroom/pressreleases/the-cost-of-one-dose-will-be-less-than-10-for-international-markets/
6. Debby van Riel and Emmie de Wit. Next generation vaccines platform for COVID-19. Nature Materials, 2020, vol. 19, 810–820.
7. CanSino’s, J&J’s Covid-19 vaccines may be stifled by pre-existing antibodies while AstraZeneca’s, ReiThera’s may need booster. 23rd June 2020. ClinicalTrials Arena, https://www.clinicaltrialsarena.com/comment/covid-19-vaccines-antibodies-booster/
8. https://sputnikvaccine.com/about-us/
9. J&J receives EU approval for Ebola vaccine. By Ben Hargreaves. Biopharma Reporters, 6th July, 2020. https://www.biopharma-reporter.com/Article/2020/07/06/Janssen-Ebola-vaccine-gets-European-approval
10. 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.
11. AstraZeneca’s quick Covid-19 vaccine trial restart splits experts. ClinicalTrials comment, Global Data Healthcare, last updated October 12th, 2020. https://www.clinicaltrialsarena.com/comment/azd1222-covid-vaccine-trials-astrazeneca/
12. J&J pause adds to adenovirus vaccine doubts. By Madeleine Armstrong. Evaluate Vantage, 13th Oct, 2020. https://www.evaluate.com/vantage/articles/news/jj-pause-adds-adenovirus-vaccine-doubts
AstraZeneca announced interim results for their phase 3 single-blinded, multi-centre, randomised, controlled studies from the UK (COV002) and Brazil (COV003) yesterday.1 Participants were randomized to receive intramuscular injection with either a half-dose/full-dose regimen (n=2,741) or two-full-doses regimen of AZD1222 (n=8,895), or a placebo using meningococcal conjugate vaccine called MenACWY or saline. Two shots were injected, at least one month apart.
By the end of the study, among a total of 22,690 participants, 131 were found to be COVID-19 positive: of these, 101 had received placebo, 3 had received half-dose/full-dose regimen, and 27 had received full dose at both initial and later shot. This led to the initial statistics of 90% vaccine efficacy when AZD1222 was given as half-dose/full-dose regimen, and 62% efficacy for the full-dose/full-dose regimen. On average, this showed a 70% effectiveness rate of the vaccine at preventing the COVID-19. Vaccine offering protection over 50% of vaccinated people is considered to be efficacious.# Moreover, no serious safety events related to the vaccine were reported in the studies.2,3
Professor Andrew Pollard, Director of the Oxford Vaccine Group and Chief Investigator of the Oxford Vaccine Trial, said these findings show that they “have an effective vaccine that will save many lives.” If the half-dose/full-dose regimen does give 90% effectiveness, they will apply this dosing regimen, and this means that “more people could be vaccinated with planned vaccine supply.”3 That seems to be good news.
As we are approaching the end of the year, more results from phase 3 studies of candidate vaccines are coming out, and also we have more informations about their prices. The vaccine made of non-replicating viral vector can be kept in a conventional fridge (2°C-8°C), similar to inactivated vaccines. Once a non-replicating viral vectored vaccine is produced, it can be stored, transported and handled at normal refrigerated conditions for at least six months, and can be administered within existing healthcare facilities. The transportation is easier and thus the cost is lower than the ones that require ultra-low temperatures. According to a Healthline online article, AstraZeneca’s two-dose vaccine could be just US $3 to $4 per dose, while each dose for Johnson & Johnson’s two-dose vaccine will cost about US $10.4 Meanwhile, the Russian Gamaleya Centre announced that the cost of their two-dose Sputnik V vaccine will be less than US $10 per dose for international markets.5 No information on the cost of the adenoviral vectored vaccine candidate by CanSinoBio can be found yet.
The ease of storage and handling, and the lower prices, render the non-replicating viral vectored vaccines viable for use in resource-limited countries. Moreover, such vaccines provide long-term gene expression, and high specificity of gene delivery to target cells. Additionally, since viral vectored vaccines result in endogenous antigen production, both humoral* and cellular immune** responses are stimulated. In other words, viral vectored vaccine triggers high immunogenicity.6
With all these advantages of using viral vectors, we should however not ignore some of the factors that may diminish the effectiveness of the vaccine candidates.
All four viral-vectored vaccines that entered phase 3 clinical trials use Adenovirus as a vector. Adenoviral DNA has the advantage of not integrating into the human genome and not being replicated during cell division. Apart from AstraZenica’s AZD1222 which used adenovirus ChAdOx1 (which causes the common cold in chimpanzees), the other 3 vaccine candidates use human adenoviruses, either Adenovirus type 5 (Ad5) or type 26 (Ad26), which have been genetically modified, as carriers of the genetic sequence that produces the Spike glycoprotein of SARS-CoV-2. However, a significant number of people may have already been infected with these human adenoviruses, and neutralising antibodies to the viral vectors already exist in these infected populations. These neutralising antibodies can inactivate the virus before it can reach the target cells, and thus decrease its efficacy.7
In fact, the baseline of different human adenovirus infections varies from place to place globally. The population with a higher baseline of pre-existing Ad26 infection, for example, is expected to have a lower immunity response upon the first dose of Sputnik V vaccine from Gamaleya Centre in Russia, or Ad26.COV2.S vaccines from Janssen Pharmaceuticals etc. Therefore when we consider which viral vectored vaccine to use, we should check the infection rate of the particular adenovirus in our population and try to avoid using a vaccine that contains an adenovirus that is already widespread in our area.
Also, people who volunteered to receive viral vector vaccines in previous clinical trials should also be aware not to rely on viral vectored vaccines for COVID-19 that use the same adenovirus carrier as they were administered in the previous trial.
Recombinant adenovirus vectors have been developed since the 1980s. Gamaleya Research Institute used Ad5 to produce vaccines against Ebola that were approved for use in 2015 and 2020.8 Another vaccine by Janssen Pharmaceuticals for Ebola, which was approved in 2020 by the European Union, used Ad26.9 The long-term effect of the use of these viral vectored vaccines is still unknown. However, the use of Ad5 as a carrier in an HIV vaccine candidate did increase the possibility of transmission of HIV.10 Moreover, the reports of neurological conditions, including multiple sclerosis and transverse myelitis, during the clinical trials of AstraZeneca's vaccine candidate,11 also raises concern for the safety of adenoviral vectored vaccines.12
#US Food and Drug Administration Coronavirus (COVID-19) update: FDA takes action to help facilitate timely development of safe, effective COVID-19 vaccines. June 30, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-action-help-facilitate-timely-development-safe-effective-covid
*Humoral immune responses protect extracellular spaces of the body from bacterial infections. Antibodies produced by B cells cause the destruction of extracellular microorganisms and prevent the spread of intracellular infections. (Immunobiology: The Immune System in Health and Disease. 5th edition. Chapter 9, The Humoral Immune Response. https://www.ncbi.nlm.nih.gov/books/NBK10752/)
** Cellular immune response is a protective immune process that involves the activation of phagocytes, antigen-sensitized cytotoxic T cells, and the release of cytokines and chemokines, in response to antigens. (Definition from Nature research. https://www.nature.com/subjects/cellular-immunity)
References
1. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19. AstraZeneca press release, 23rd November 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html
2. Covid-19: Oxford University vaccine is highly effective. By James Gallagher. BBC news, 23rd November, 2020. https://www.bbc.co.uk/news/health-55040635
3. Oxford University breakthrough on global COVID-19 vaccine. Press release of University of Oxford, 23rd November, 2020. https://www.research.ox.ac.uk/Article/2020-11-23-oxford-university-breakthrough-on-global-covid-19-vaccine
4.https://www.healthline.com/health-news/how-much-will-it-cost-to-get-a-covid-19-vaccine#How-much-each-dose-will-cost
5. The cost of one dose of the Sputnik V vaccine will be less than $10 for international markets. Press release from Gamaleya Center, 24th November, 2020. https://sputnikvaccine.com/newsroom/pressreleases/the-cost-of-one-dose-will-be-less-than-10-for-international-markets/
6. Debby van Riel and Emmie de Wit. Next generation vaccines platform for COVID-19. Nature Materials, 2020, vol. 19, 810–820.
7. CanSino’s, J&J’s Covid-19 vaccines may be stifled by pre-existing antibodies while AstraZeneca’s, ReiThera’s may need booster. 23rd June 2020. ClinicalTrials Arena, https://www.clinicaltrialsarena.com/comment/covid-19-vaccines-antibodies-booster/
8. https://sputnikvaccine.com/about-us/
9. J&J receives EU approval for Ebola vaccine. By Ben Hargreaves. Biopharma Reporters, 6th July, 2020. https://www.biopharma-reporter.com/Article/2020/07/06/Janssen-Ebola-vaccine-gets-European-approval
10. 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.
11. AstraZeneca’s quick Covid-19 vaccine trial restart splits experts. ClinicalTrials comment, Global Data Healthcare, last updated October 12th, 2020. https://www.clinicaltrialsarena.com/comment/azd1222-covid-vaccine-trials-astrazeneca/
12. J&J pause adds to adenovirus vaccine doubts. By Madeleine Armstrong. Evaluate Vantage, 13th Oct, 2020. https://www.evaluate.com/vantage/articles/news/jj-pause-adds-adenovirus-vaccine-doubts
No comments:
Post a Comment