Coronavirus (25) Non-replicating viral vector vaccine candidates for COVID-19 (part b)
Continued from my last blog post.
2. Adenovirus vectored vaccine by CanSinoBio
This vaccine was co-developed by CanSino Biological Inc. and Beijing institute of Biotechnology.1 It is basically a replication-defective adenovirus (type 5, Ad5) as vector and engineered to contain and express full-length spike glycoprotein of SARS-CoV-2. It is manufactured in liquid form which contains 5x105 virus particles in 0.5ml in a vial. The vaccine candidate has finished its phase 1 and phase 2 trials and is now in the phase 3 trials.
Phase 1
The phase 1 trial started on 16 March this year in Wuhan. The trial was done in an open-labelled, non-randomised manner. The study recruited 108 participants aged 18-60 which were then divided into 3 groups to receive 3 different doses (5x1010 (n=36), 1x1011 (n=36), 1.5x1011 (n=36) viral particles) via intramuscular injection.
Within 7 days after the vaccination, eighty-seven cases (81%) reported to have at least one adverse reaction. The most common adverse reaction was injection site pain (n=58, 54%). Systemic adverse reactions such as fever (n=50, 46%), fatigue (n=47, 44%), headache (n=42, 39%), and muscle pain (n=18, 17%) were also commonly reported. There was no significant difference in the overall number of adverse reactions across the treatment, and most adverse reactions were mild or moderate in severity. No serious adverse event was noted within 28 days after vaccination. However, a higher proportion of participants reported grade 3 (higher grade of severity) adverse reactions in the highest dose group (1.5×1011 viral particles, 17%) compared with the low-dose (5×1010 viral particles, 6%) or middle-dose (1×1011 viral particles, 6%) groups.2
The vaccine injection caused significant increase in neutralising antibodies at day 14, and peaked at day 28. Specific T-cell responses to vaccination were found peaked on day 14 instead of day 28.2
Phase 2
Phase 2 clinical trials started on 11th April this year and took place in Wuhan. The trial was done in a randomised, double-blind, and placebo-controlled manner. The study included 508 participants which were than divided to receive either 1x1011 viral particles (n=253), 5x1010 viral particles (n=129), or a placebo that contained no virus particles (n=126).
The study found that most adverse reactions after vaccine injection were mild or moderate, and mostly resolved within no more than 48 hours. Vaccine recipients had a significantly higher proportion of adverse reactions, within 28 days after vaccination, than those in placebo recipients. Among recipients of either dose of the Ad5-vectored COVID-19 vaccines, almost all of the most severe adverse reactions were reported from the participants who received 1×1011 viral particles, with only one was reported from a participant received 5×1010 viral particles.
Similar to the results of the phase 1 study, the antibody responses were detected on day 14, and peaked on day 28 after vaccination in recipients who randomly received the vaccine candidate, but not detected on the control group. Both vaccine recipient groups showed comparable specific immune responses to the spike glycoprotein at day 28, with no significant difference between the two groups. However, in contrast to expectations, the vaccine at 5×1010 viral particles had a comparable immunogenicity to the vaccine at 1×1011 viral particles.
The scientists involved in the study are concerned that the pre-existing adenovirus vector (type 5) may affect the efficiency of the vaccine candidate. In the phase 2 study, they did experiment to examine this issue. The study found that the immunity against Ad5, which indicates the pre-existing Ad5, and age, could affect the safety of the vaccine candidate and its ability to induce immune responses: fever, which reflects the immune response, was associated with younger participants and a lower level of immunity to Ad5 virus. Among the 21 participants who experienced a higher severity of fever, nineteen (90%) had no pre-existing immunity to Ad5. On the other hand, the immune responses to the vaccine candidate were significantly lower with increasing age and high pre-existing Ad5 levels. The study thus assumed that one injection of the vaccine might not be enough to induce a specific immune response for people aged 55 and older.
The results from the phase 2 study showed that vaccination of the Ad5-vectored COVID-19 vaccine at a dose of 5x1010 viral particles has a better safety profile than, and comparable immunogenicity to, the vaccine with dose of 1 × 1011 viral particles. The report of the phase 2 study thus suggests testing of the Ad5-vectored COVID-19 vaccine at 5×1010 viral particles in a phase 3 effectiveness trial in healthy adults.
Phase 3
The phase 3 clinical trials (NCT04526990) is a randomized, double-blind, placebo-controlled trial aiming to recruit 40,000 participants, age 18 or above, in multiple centres.4 According to the data from ClinicalTrials.gov, the countries involved in the study include Pakistan. Moreover, CanSino Biotech also collaborated with NPO Petrovax, a Russian biotech company, to conduct a randomized, double-blind phase 3 study that aimed to recruit 500 participants age 18 to 85 years (NCT04540419).5 They expect the primary study will be completed on 30th November.
So far, the clinical trials for this vaccine candidate have been running smoothly. However, it was already given approval for military use in China at the end of June, before the phase 3 trials started.6 That rush to use the vaccine before more convincing safety and efficacy data from a larger population raises concerns that the clinical studies may not have been done properly enough to examine the safety and efficacy of the vaccine candidate.
Moreover, the using of Ad5 as a carrier vector may also increase the patient’s susceptibility to HIV. Previous experience suggested that non-HIV vaccine trials that use Ad5 as viral vector in areas where HIV is prevalent, such as South Africa, could lead to an increased risk of HIV-1 acquisition in the vaccinated population.7
About CanSinoBio康希樂生物
CanSinoBIO, SHSE: 688185, HKEX:06185, was incorporated in 2009 in Tianjin, China. It’s focus is to produce and commercialize vaccine for China and global market. It possesses four integrated platform technologies including adenovirus-based vectors, conjugation, protein design and recombination and formulation. Today, the company has more than 600 employees. It has established a pipeline of 16 vaccine candidate covering 13 infectious diseases in product line. Their vaccine for Ebola virus (Ad5-EBOV) received approval in 2017.8
References
1. China’s progress in developing COVID-19 vaccines could surprise the world, GlobalData says. 12 July, 2020. News Medical. https://www.news-medical.net/news/20200721/Chinae28099s-progress-in-developing-COVID-19-vaccines-could-surprise-the-world-GlobalData-says.aspx
2. F.C. Zhu, Y.H. Li, and X.H. Guan, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet, 2020, 395, 1845-1854.
3. F.C. Zhu, X.H. Guan, and Y.H. Li, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet, 2020, 396, 479-488.
4. Phase III trial of a COVID-19 vaccine of Adenovirus vector in adults 18 years old and above. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04526990
5. Clinical trial of recombinant novel coronavirus vaccine (adenovirus type 5 vector) against COVID-19. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT04540419
6. CanSino's COVID-19 vaccine candidate approved for military use in China. Reuters, Health news. June 29, 2020. https://uk.reuters.com/article/us-health-coronavirus-china-vaccine/cansinos-covid-19-vaccine-candidate-approved-for-military-use-in-china-idUKKBN2400DZ
7. S.P. Buchbinder, M.J. McElrath, C. Dieffenbach, et al. Use of adenovirus type-5 vectored vaccines: a cautionary tale. The Lancet, 2020, Oct 31; 396 (10260): E68-E69.
8.CanSinoBIO Overview. http://www.cansinotech.com/html/1//173/174/index.html
Continued from my last blog post.
2. Adenovirus vectored vaccine by CanSinoBio
This vaccine was co-developed by CanSino Biological Inc. and Beijing institute of Biotechnology.1 It is basically a replication-defective adenovirus (type 5, Ad5) as vector and engineered to contain and express full-length spike glycoprotein of SARS-CoV-2. It is manufactured in liquid form which contains 5x105 virus particles in 0.5ml in a vial. The vaccine candidate has finished its phase 1 and phase 2 trials and is now in the phase 3 trials.
Phase 1
The phase 1 trial started on 16 March this year in Wuhan. The trial was done in an open-labelled, non-randomised manner. The study recruited 108 participants aged 18-60 which were then divided into 3 groups to receive 3 different doses (5x1010 (n=36), 1x1011 (n=36), 1.5x1011 (n=36) viral particles) via intramuscular injection.
Within 7 days after the vaccination, eighty-seven cases (81%) reported to have at least one adverse reaction. The most common adverse reaction was injection site pain (n=58, 54%). Systemic adverse reactions such as fever (n=50, 46%), fatigue (n=47, 44%), headache (n=42, 39%), and muscle pain (n=18, 17%) were also commonly reported. There was no significant difference in the overall number of adverse reactions across the treatment, and most adverse reactions were mild or moderate in severity. No serious adverse event was noted within 28 days after vaccination. However, a higher proportion of participants reported grade 3 (higher grade of severity) adverse reactions in the highest dose group (1.5×1011 viral particles, 17%) compared with the low-dose (5×1010 viral particles, 6%) or middle-dose (1×1011 viral particles, 6%) groups.2
The vaccine injection caused significant increase in neutralising antibodies at day 14, and peaked at day 28. Specific T-cell responses to vaccination were found peaked on day 14 instead of day 28.2
Phase 2
Phase 2 clinical trials started on 11th April this year and took place in Wuhan. The trial was done in a randomised, double-blind, and placebo-controlled manner. The study included 508 participants which were than divided to receive either 1x1011 viral particles (n=253), 5x1010 viral particles (n=129), or a placebo that contained no virus particles (n=126).
The study found that most adverse reactions after vaccine injection were mild or moderate, and mostly resolved within no more than 48 hours. Vaccine recipients had a significantly higher proportion of adverse reactions, within 28 days after vaccination, than those in placebo recipients. Among recipients of either dose of the Ad5-vectored COVID-19 vaccines, almost all of the most severe adverse reactions were reported from the participants who received 1×1011 viral particles, with only one was reported from a participant received 5×1010 viral particles.
Similar to the results of the phase 1 study, the antibody responses were detected on day 14, and peaked on day 28 after vaccination in recipients who randomly received the vaccine candidate, but not detected on the control group. Both vaccine recipient groups showed comparable specific immune responses to the spike glycoprotein at day 28, with no significant difference between the two groups. However, in contrast to expectations, the vaccine at 5×1010 viral particles had a comparable immunogenicity to the vaccine at 1×1011 viral particles.
The scientists involved in the study are concerned that the pre-existing adenovirus vector (type 5) may affect the efficiency of the vaccine candidate. In the phase 2 study, they did experiment to examine this issue. The study found that the immunity against Ad5, which indicates the pre-existing Ad5, and age, could affect the safety of the vaccine candidate and its ability to induce immune responses: fever, which reflects the immune response, was associated with younger participants and a lower level of immunity to Ad5 virus. Among the 21 participants who experienced a higher severity of fever, nineteen (90%) had no pre-existing immunity to Ad5. On the other hand, the immune responses to the vaccine candidate were significantly lower with increasing age and high pre-existing Ad5 levels. The study thus assumed that one injection of the vaccine might not be enough to induce a specific immune response for people aged 55 and older.
The results from the phase 2 study showed that vaccination of the Ad5-vectored COVID-19 vaccine at a dose of 5x1010 viral particles has a better safety profile than, and comparable immunogenicity to, the vaccine with dose of 1 × 1011 viral particles. The report of the phase 2 study thus suggests testing of the Ad5-vectored COVID-19 vaccine at 5×1010 viral particles in a phase 3 effectiveness trial in healthy adults.
Phase 3
The phase 3 clinical trials (NCT04526990) is a randomized, double-blind, placebo-controlled trial aiming to recruit 40,000 participants, age 18 or above, in multiple centres.4 According to the data from ClinicalTrials.gov, the countries involved in the study include Pakistan. Moreover, CanSino Biotech also collaborated with NPO Petrovax, a Russian biotech company, to conduct a randomized, double-blind phase 3 study that aimed to recruit 500 participants age 18 to 85 years (NCT04540419).5 They expect the primary study will be completed on 30th November.
So far, the clinical trials for this vaccine candidate have been running smoothly. However, it was already given approval for military use in China at the end of June, before the phase 3 trials started.6 That rush to use the vaccine before more convincing safety and efficacy data from a larger population raises concerns that the clinical studies may not have been done properly enough to examine the safety and efficacy of the vaccine candidate.
Moreover, the using of Ad5 as a carrier vector may also increase the patient’s susceptibility to HIV. Previous experience suggested that non-HIV vaccine trials that use Ad5 as viral vector in areas where HIV is prevalent, such as South Africa, could lead to an increased risk of HIV-1 acquisition in the vaccinated population.7
About CanSinoBio康希樂生物
CanSinoBIO, SHSE: 688185, HKEX:06185, was incorporated in 2009 in Tianjin, China. It’s focus is to produce and commercialize vaccine for China and global market. It possesses four integrated platform technologies including adenovirus-based vectors, conjugation, protein design and recombination and formulation. Today, the company has more than 600 employees. It has established a pipeline of 16 vaccine candidate covering 13 infectious diseases in product line. Their vaccine for Ebola virus (Ad5-EBOV) received approval in 2017.8
References
1. China’s progress in developing COVID-19 vaccines could surprise the world, GlobalData says. 12 July, 2020. News Medical. https://www.news-medical.net/news/20200721/Chinae28099s-progress-in-developing-COVID-19-vaccines-could-surprise-the-world-GlobalData-says.aspx
2. F.C. Zhu, Y.H. Li, and X.H. Guan, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet, 2020, 395, 1845-1854.
3. F.C. Zhu, X.H. Guan, and Y.H. Li, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet, 2020, 396, 479-488.
4. Phase III trial of a COVID-19 vaccine of Adenovirus vector in adults 18 years old and above. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04526990
5. Clinical trial of recombinant novel coronavirus vaccine (adenovirus type 5 vector) against COVID-19. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT04540419
6. CanSino's COVID-19 vaccine candidate approved for military use in China. Reuters, Health news. June 29, 2020. https://uk.reuters.com/article/us-health-coronavirus-china-vaccine/cansinos-covid-19-vaccine-candidate-approved-for-military-use-in-china-idUKKBN2400DZ
7. S.P. Buchbinder, M.J. McElrath, C. Dieffenbach, et al. Use of adenovirus type-5 vectored vaccines: a cautionary tale. The Lancet, 2020, Oct 31; 396 (10260): E68-E69.
8.CanSinoBIO Overview. http://www.cansinotech.com/html/1//173/174/index.html
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