Coronavirus (24) Non-replicating viral vectored vaccine candidates for COVID-19 (part a)
WHO updated their list of vaccines for COVID-19 on 29th October.1 There are now 45 vaccine candidates in the clinical trials phases. Adding three more countries, Israel, Kazakhstan and Kosovo, at the forefront of the race to develop COVID-19 vaccines.
In this and the coming few blog posts, I am going to introduce you to non-replicating viral vectored vaccine candidates for COVID-19 which have already entered phase 3 of clinical trials.
A vaccine with a viral vector platform is basically a genetically-modified virus with a specifically chosen gene from a target pathogen inserted into it by recombinant technology. The virus serves as a vector to deliver the inserted gene into human cells. Once injected via vaccination, the virus vector enters into human cells and the inserted gene starts to express itself as a protein, which acts as an antigen, triggering the immune response to produce antibodies against that antigen. According to the data from WHO, all of the viral vectored vaccine candidates for COVID-19 are inserted with nucleotide sequences that express the Spike glycoprotein (S) of SARS-CoV-2.* Therefore, these viral vectored vaccine candidates for COVID-19 are expected to trigger the production of antibodies against the surface Spike protein of the coronavirus. These antibodies block the interaction between the coronavirus and human cells, thus inhibiting the viral infection next time it invades.
The virus which acts as a vector in the non-replicating virus vectored vaccine is modified so that the gene(s) that cause infection and the gene(s) responsible for replication have been removed. Therefore the virus vector of the vaccine will not cause disease and will not give rise to a copy of itself once the vaccine is injected. In other words, once non-replicating vectored vaccines enter cells, they produce the vaccine antigen expressed from the inserted gene, but no new virus particles are formed. This means that the amount of the virus particles injected into the body via vaccination is under control and thus cause no underlying safety hazard.
One advantage of these viral vector-based vaccines is that a single dose is usually sufficient for protection.2 However, most of the COVID-19 vaccines using non-replicating virus as vector require two doses.
Vaccines with non-replicating viral vector as a platform started being developed only in recent decades. The most commonly used virus vector is human adenovirus. The use of human adenoviruses as vectors is safe because these viruses, which cause the common cold, are not novel and have been around for thousands of years.
According to the latest information provided by WHO,1 there are now 9 non-replicating viral vaccines in the clinical trials. Four are in phase 3, and five in early phase trials.
Non-replicating viral vector vaccines in clinical trials:
1. AZD1222 by Vaccitech, Jenner Institute in Oxford, and AstraZeneca
The development of the vaccine AZD1222 is a good example of collaboration between a university and industry. The vaccine candidate was co-invented by the Jenner Institute in University of Oxford and its spin-out company called Vaccitech. The University of Oxford later partnered with AstraZeneca in late April to do further investigation on the vaccine candidate. Phase 1 and phase 2 (NCT04324606) was finished in the summer and the phase 3 started in late August.
AZD1222 was formerly known as ChAdOx1 nCoV-19. It is made from an adenovirus called ChAdOx1, a weakened version of a common cold virus that causes infections in chimpanzees. ChAdOx1 was developed at the Jenner Institute in Oxford. It has been genetically changed so that it is impossible for it to grow in humans. The adenovirus carries DNA for the spike antigen of SARS-CoV-2.
Phase 1 and 2 studies
The result of the phase 1 and 2 trials of the vaccine candidate was published in August.3,4 The early phase trial was a single-blind, randomized trial using the vaccine candidate and a meningococcal conjugate vaccine (MenACWY) as control. The trial was done in 5 trial sites in the UK with 1077 healthy adults between 18 and 55 years old and with no history of laboratory confirmed SARS-CoV-2 infection. Of these, 543 were randomly assigned the vaccine and the other 534 assigned as the control to receive a single intramuscular injection.
The study found that transient local and systemic reactions, such as injection site pain, feeling feverish, chills, fatigue, muscle ache, mild to moderate headache, and malaise, were more common in the ChAdOx1 nCoV-19 group than in the control group. However, the symptoms were comparable to previous trials and other adenoviral vector vaccines. The symptoms could be reduced with the use of paracetamol before administering the vaccine. There were no serious adverse events related to the vaccine, showing it has an acceptable safety profile.
The vaccine injection induced both humoral** and cellular*** immune responses. In the group administered with ChAdOx1 nCoV-19, all participants showed spike-specific T-cell responses which peaked by day 14 and maintained for two months after injection. A single dose of the vaccine resulted in a four-fold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants, 28 days after injection. Neutralising activity against SARS-CoV-2, assessed by the MNA80 assay#, was seen in 91% of participants one month after vaccination and in 100% of participants who received a second dose.4 There was strongest immune response in participants who received two doses of the vaccine, indicating that this might be a good strategy for vaccination.
Phase 3 studies
The vaccine was the first COVID-19 vaccine to begin phase 3 studies, in the UK, Brazil, South Africa, the US, and Europe. However, these trials did not go smoothly all the way. The global trials of the vaccine were once paused on 6th September, after a person participating in the UK trial experienced an adverse reaction.5 The clinical trials in the UK then resumed a few days later and the FDA authorized the restart of the trial in the US, more than one month later, on 23rd October. Oxford University and AstraZeneca were criticised on their lack of transparency, as some scientists claimed that key details of the events involved have not been released and the decision to restart the trials was too quick.6,7
Actually, according to an article in ClinicalTrialsArena, the trials on the vaccine candidates were paused for two incidences, both occurring in UK-based volunteers.7 The first temporary pause happened in July after a participant experienced multiple sclerosis (MS), and the second pause was the one on 6 September, when a participant experienced transverse myelitis. Transverse myelitis and MS are neurological conditions.
AstraZeneca already has commitments to supply more than two billion doses of the vaccine to the UK, the US, Europe’s Inclusive Vaccines Alliance, the Coalition for Epidemic Preparedness, Gavi the Vaccine Alliance and Serum Institute of India.4
About Jenner Institute in University of Oxford
The Jenner Institute was founded in November 2005 in partnership with the Institute for Animal Health. It is based within the Nuffield Department of Medicine, University of Oxford. The Institute supports senior vaccine scientists, known as Jenner Investigators, within many other departments across the University of Oxford, as well as externally within The Pirbright Institute and the Animal and Plant Health Agency, to design and develope vaccines. 8
The Jenner Institute is supported by the Jenner Vaccine Foundation, a UK registered charity and is advised by the Jenner Institute Scientific Advisory Board.8
About Vaccitech
Vaccitech is a clinical stage T cell immunotherapy and vaccine company developing products to treat and prevent infectious disease and cancer. The company’s proprietary heterologous prime-boost platform comprises Chimpanzee Adenovirus Oxford (ChAdOx) and Modified Vaccinia Ankara (MVA), two non-replicating viral vectors which safely mimic viral infection in human cells and elicit high magnitude, durable, targeted CD8+ and CD4+ T cell responses and antibodies to clear foreign pathogens and tumours.9
Vaccitech is backed by leading investment institutions, including GV (formerly Google Ventures), Sequoia Capital China, Liontrust (formerly Neptune), Korea Investment Partners and Oxford Sciences Innovation.9
About AstraZeneca
AstraZeneca is a British–Swedish multinational pharmaceutical and biopharmaceutical company based in Cambridge. The company was founded in 1999 through the merger of the Swedish Astra AB and the British Zeneca Group. Now it operates in over 100 countries. The company focuses on primarily the treatment of diseases in three therapy areas - oncology, cardiovascular, renal & metabolism, and respiratory & immunology.10
*The Spike protein is found on the surface of SARS-CoV-2 and is the first critical component which helps the coronavirus to invade human cells. It is responsible for binding to the ACE2 receptor on human cell, leading to the entry of the coronavirus into the cell and causing infection. **Humoral Immune response protects 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 antigen. (Definition from Nature research. https://www.nature.com/subjects/cellular-immunity) # MNA80 assay (microneutralization assay) is used to measure neutralizing antibody concentration.
References
1. Draft landscape of COVID-19 candidate vaccines. World Health Orgainzation. 29 October, 2020. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
2. Debby van Riel and Emmie de Wit. Next generation vaccines platform for COVID-19. Nature Materials, 2020, vol. 19, 810–820.
3. P.M. Folegatti, K.J. Ewer, and P.K. Aley, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. The Lancet, 2020, 396, p467-478.
4. COVID-19 vaccine AZD1222 showed robust immune responses in all participants in Phase I/II trial. AstraZeneca Media, 20 July, 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/covid-19-vaccine-azd1222-showed-robust-immune-responses-in-all-participants-in-phase-i-ii-trial.html
5. Statement on AstraZeneca Oxford SARS-CoV-2 vaccine, AZD1222, COVID-19 vaccine trials temporary pause. AstraZeneca Media, 9 September, 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/statement-on-astrazeneca-oxford-sars-cov-2-vaccine-azd1222-covid-19-vaccine-trials-temporary-pause.html
6. Scientists relieved as coronavirus vaccine trial restarts — but question lack of transparency. Nature news, updated on 15 September, 2020. https://www.nature.com/articles/d41586-020-02633-6
7. 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/
8. https://www.jenner.ac.uk/about
9. https://www.vaccitech.co.uk/about/
10. https://www.astrazeneca.com
WHO updated their list of vaccines for COVID-19 on 29th October.1 There are now 45 vaccine candidates in the clinical trials phases. Adding three more countries, Israel, Kazakhstan and Kosovo, at the forefront of the race to develop COVID-19 vaccines.
In this and the coming few blog posts, I am going to introduce you to non-replicating viral vectored vaccine candidates for COVID-19 which have already entered phase 3 of clinical trials.
A vaccine with a viral vector platform is basically a genetically-modified virus with a specifically chosen gene from a target pathogen inserted into it by recombinant technology. The virus serves as a vector to deliver the inserted gene into human cells. Once injected via vaccination, the virus vector enters into human cells and the inserted gene starts to express itself as a protein, which acts as an antigen, triggering the immune response to produce antibodies against that antigen. According to the data from WHO, all of the viral vectored vaccine candidates for COVID-19 are inserted with nucleotide sequences that express the Spike glycoprotein (S) of SARS-CoV-2.* Therefore, these viral vectored vaccine candidates for COVID-19 are expected to trigger the production of antibodies against the surface Spike protein of the coronavirus. These antibodies block the interaction between the coronavirus and human cells, thus inhibiting the viral infection next time it invades.
The virus which acts as a vector in the non-replicating virus vectored vaccine is modified so that the gene(s) that cause infection and the gene(s) responsible for replication have been removed. Therefore the virus vector of the vaccine will not cause disease and will not give rise to a copy of itself once the vaccine is injected. In other words, once non-replicating vectored vaccines enter cells, they produce the vaccine antigen expressed from the inserted gene, but no new virus particles are formed. This means that the amount of the virus particles injected into the body via vaccination is under control and thus cause no underlying safety hazard.
One advantage of these viral vector-based vaccines is that a single dose is usually sufficient for protection.2 However, most of the COVID-19 vaccines using non-replicating virus as vector require two doses.
Vaccines with non-replicating viral vector as a platform started being developed only in recent decades. The most commonly used virus vector is human adenovirus. The use of human adenoviruses as vectors is safe because these viruses, which cause the common cold, are not novel and have been around for thousands of years.
According to the latest information provided by WHO,1 there are now 9 non-replicating viral vaccines in the clinical trials. Four are in phase 3, and five in early phase trials.
Non-replicating viral vector vaccines in clinical trials:
1. AZD1222 by Vaccitech, Jenner Institute in Oxford, and AstraZeneca
The development of the vaccine AZD1222 is a good example of collaboration between a university and industry. The vaccine candidate was co-invented by the Jenner Institute in University of Oxford and its spin-out company called Vaccitech. The University of Oxford later partnered with AstraZeneca in late April to do further investigation on the vaccine candidate. Phase 1 and phase 2 (NCT04324606) was finished in the summer and the phase 3 started in late August.
AZD1222 was formerly known as ChAdOx1 nCoV-19. It is made from an adenovirus called ChAdOx1, a weakened version of a common cold virus that causes infections in chimpanzees. ChAdOx1 was developed at the Jenner Institute in Oxford. It has been genetically changed so that it is impossible for it to grow in humans. The adenovirus carries DNA for the spike antigen of SARS-CoV-2.
Phase 1 and 2 studies
The result of the phase 1 and 2 trials of the vaccine candidate was published in August.3,4 The early phase trial was a single-blind, randomized trial using the vaccine candidate and a meningococcal conjugate vaccine (MenACWY) as control. The trial was done in 5 trial sites in the UK with 1077 healthy adults between 18 and 55 years old and with no history of laboratory confirmed SARS-CoV-2 infection. Of these, 543 were randomly assigned the vaccine and the other 534 assigned as the control to receive a single intramuscular injection.
The study found that transient local and systemic reactions, such as injection site pain, feeling feverish, chills, fatigue, muscle ache, mild to moderate headache, and malaise, were more common in the ChAdOx1 nCoV-19 group than in the control group. However, the symptoms were comparable to previous trials and other adenoviral vector vaccines. The symptoms could be reduced with the use of paracetamol before administering the vaccine. There were no serious adverse events related to the vaccine, showing it has an acceptable safety profile.
The vaccine injection induced both humoral** and cellular*** immune responses. In the group administered with ChAdOx1 nCoV-19, all participants showed spike-specific T-cell responses which peaked by day 14 and maintained for two months after injection. A single dose of the vaccine resulted in a four-fold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants, 28 days after injection. Neutralising activity against SARS-CoV-2, assessed by the MNA80 assay#, was seen in 91% of participants one month after vaccination and in 100% of participants who received a second dose.4 There was strongest immune response in participants who received two doses of the vaccine, indicating that this might be a good strategy for vaccination.
Phase 3 studies
The vaccine was the first COVID-19 vaccine to begin phase 3 studies, in the UK, Brazil, South Africa, the US, and Europe. However, these trials did not go smoothly all the way. The global trials of the vaccine were once paused on 6th September, after a person participating in the UK trial experienced an adverse reaction.5 The clinical trials in the UK then resumed a few days later and the FDA authorized the restart of the trial in the US, more than one month later, on 23rd October. Oxford University and AstraZeneca were criticised on their lack of transparency, as some scientists claimed that key details of the events involved have not been released and the decision to restart the trials was too quick.6,7
Actually, according to an article in ClinicalTrialsArena, the trials on the vaccine candidates were paused for two incidences, both occurring in UK-based volunteers.7 The first temporary pause happened in July after a participant experienced multiple sclerosis (MS), and the second pause was the one on 6 September, when a participant experienced transverse myelitis. Transverse myelitis and MS are neurological conditions.
AstraZeneca already has commitments to supply more than two billion doses of the vaccine to the UK, the US, Europe’s Inclusive Vaccines Alliance, the Coalition for Epidemic Preparedness, Gavi the Vaccine Alliance and Serum Institute of India.4
About Jenner Institute in University of Oxford
The Jenner Institute was founded in November 2005 in partnership with the Institute for Animal Health. It is based within the Nuffield Department of Medicine, University of Oxford. The Institute supports senior vaccine scientists, known as Jenner Investigators, within many other departments across the University of Oxford, as well as externally within The Pirbright Institute and the Animal and Plant Health Agency, to design and develope vaccines. 8
The Jenner Institute is supported by the Jenner Vaccine Foundation, a UK registered charity and is advised by the Jenner Institute Scientific Advisory Board.8
About Vaccitech
Vaccitech is a clinical stage T cell immunotherapy and vaccine company developing products to treat and prevent infectious disease and cancer. The company’s proprietary heterologous prime-boost platform comprises Chimpanzee Adenovirus Oxford (ChAdOx) and Modified Vaccinia Ankara (MVA), two non-replicating viral vectors which safely mimic viral infection in human cells and elicit high magnitude, durable, targeted CD8+ and CD4+ T cell responses and antibodies to clear foreign pathogens and tumours.9
Vaccitech is backed by leading investment institutions, including GV (formerly Google Ventures), Sequoia Capital China, Liontrust (formerly Neptune), Korea Investment Partners and Oxford Sciences Innovation.9
About AstraZeneca
AstraZeneca is a British–Swedish multinational pharmaceutical and biopharmaceutical company based in Cambridge. The company was founded in 1999 through the merger of the Swedish Astra AB and the British Zeneca Group. Now it operates in over 100 countries. The company focuses on primarily the treatment of diseases in three therapy areas - oncology, cardiovascular, renal & metabolism, and respiratory & immunology.10
*The Spike protein is found on the surface of SARS-CoV-2 and is the first critical component which helps the coronavirus to invade human cells. It is responsible for binding to the ACE2 receptor on human cell, leading to the entry of the coronavirus into the cell and causing infection. **Humoral Immune response protects 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 antigen. (Definition from Nature research. https://www.nature.com/subjects/cellular-immunity) # MNA80 assay (microneutralization assay) is used to measure neutralizing antibody concentration.
References
1. Draft landscape of COVID-19 candidate vaccines. World Health Orgainzation. 29 October, 2020. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
2. Debby van Riel and Emmie de Wit. Next generation vaccines platform for COVID-19. Nature Materials, 2020, vol. 19, 810–820.
3. P.M. Folegatti, K.J. Ewer, and P.K. Aley, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. The Lancet, 2020, 396, p467-478.
4. COVID-19 vaccine AZD1222 showed robust immune responses in all participants in Phase I/II trial. AstraZeneca Media, 20 July, 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/covid-19-vaccine-azd1222-showed-robust-immune-responses-in-all-participants-in-phase-i-ii-trial.html
5. Statement on AstraZeneca Oxford SARS-CoV-2 vaccine, AZD1222, COVID-19 vaccine trials temporary pause. AstraZeneca Media, 9 September, 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/statement-on-astrazeneca-oxford-sars-cov-2-vaccine-azd1222-covid-19-vaccine-trials-temporary-pause.html
6. Scientists relieved as coronavirus vaccine trial restarts — but question lack of transparency. Nature news, updated on 15 September, 2020. https://www.nature.com/articles/d41586-020-02633-6
7. 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/
8. https://www.jenner.ac.uk/about
9. https://www.vaccitech.co.uk/about/
10. https://www.astrazeneca.com
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