Study on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine

Study Overview
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Brief Summary
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This is a randomized, observer-blind, placebo-controlled study, for evaluation of safety and immunogenicity of heterologous prime-boost immunization of recombinant COVID-19 vaccine (adenovirus type-5 vector) and RBD-based protein subunit vaccine (ZF2001) against COVID-19 in Chinese healthy population. 120 healthy subjects aged over 18 years of age who have been vaccinated with recombinant adenovirus type-5 vectored vaccine will be recruited in this study. Of them, 60 subjects will be enrolled in the 0-28 days regimen and other 60 will be enrolled in 0-56 days regimen. Subjects, 30 of them are 18-59 years old and 30 are 60 years old and above in each regimen will be randomly vaccinated with the second dose of subunit vaccine(ZF2001) against COVID-19 or a commercial influenza vaccine in a ratio of 2:1. They will then be vaccinated with the third dose of ZF2001 on month 4 after the second dose. The occurrence of adverse events within 28 days and serious adverse events within 6 months after the last vaccination will be observed. In addition, blood samples will be collected on day 0 before the second vaccination, day 14, 28 after the second vaccination and day 14, month 6 after third vaccination to test serum antibody levels and to profile the immune cells' subgroups and germlines. Each subject will remain in this study for approximately 12 months.

Official Title
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Safety and Immunogenicity of a Heterologous Immunization of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine Against COVID-19 in Chinese Healthy Population

Conditions
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COVID-19

Intervention / Treatment
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* Biological: recombinant Ad5 vectored COVID-19 vaccine
* Biological: RBD-based protein subunit vaccine (ZF2001) against COVID-19
* Biological: trivalent split influenza vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subjects ≥ 18 years old who has completed one dose of recombinant Ad5 vectored COVID-19 vaccine. The subjects can provide with informed consent and sign informed consent form (ICF). The subjects are able to and willing to comply with the requirements of the clinical trial program and can complete the 6-month follow-up of the study. Axillary temperature ≤ 37.0 ℃ Individuals who are in good health condition at the time of entry into the trial as determined by medical history, physical examination and clinical judgment of the investigator and meet the requirements of these products immunization. Exclusion Criteria: have a medical history or family history of convulsion, epilepsy, encephalopathy and psychosis. be allergic to any component of the research vaccines, or used to have a history of hypersensitivity or serious reactions to vaccination. Women with positive urine pregnancy test, pregnant or breast-feeding, or have a pregnancy plan within six months. have acute febrile diseases and infectious diseases. have severe chronic diseases or condition in progress cannot be smoothly controlled, such as asthma, diabetes, thyroid disease Congenital or acquired angioedema / neuroedema. have the history of urticaria 1 year before receiving the trial vaccine. have asplenia or functional asplenia. have thrombocytopenia or other coagulation disorders (which may cause contraindications for intramuscular injection). have the history of immunosuppressive therapy, anti allergy therapy, cytotoxic therapy or inhaled corticosteroids (excluding corticosteroid spray therapy for allergic rhinitis, and acute corticosteroid therapy without dermatitis) over the past 6 months. have received blood products within 4 months before injection of trial vaccines. have received another investigational product within one month before injection of trial vaccine. have received attenuated vaccine within 1 month before injection of trial vaccine except the recombinant Ad5 vectored COVID-19 vaccine. have received subunit or inactivated vaccine within 14 days before the vaccination with trial vaccine. under anti tuberculosis treatment. not be able to follow the protocol, or not be able to understand the informed consent according to the researcher's judgment, due to various medical, psychological, social or other conditions.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0-28 days vaccine group<br>One dose of recombinant Ad5 vectored COVID-19 vaccine on day 0, the second dose of subunit vaccine (ZF2001) against COVID-19 on day 28, and a third of subunit vaccine (ZF2001) against COVID-19 on month 4. | Biological: recombinant Ad5 vectored COVID-19 vaccine<br>* This vaccine contains 5×10^10 virus particles of recombinant replication defective human type-5 adenovirus expressing SARS-CoV-2 S protein, which is produced by CanSino Biologics Inc. It is a liquid dosage form, 0.5 ml / bottle.<br>* Other names: Ad5-nCoV;Biological: RBD-based protein subunit vaccine (ZF2001) against COVID-19<br>* This is a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19, made by using CHO cell, 25μg/dose, produced by Anhui Zhifei Longcom Biopharmaceutical Co.,Ltd.<br>* Other names: ZF2001 vaccine;|
| Placebo Comparator: 0-28 days placebo group<br>One dose of recombinant Ad5 vectored COVID-19 vaccine on day 0, the second dose of a commercial influenza vaccine on day 28, a third of subunit vaccine (ZF2001) against COVID-19 on month 4. | Biological: recombinant Ad5 vectored COVID-19 vaccine<br>* This vaccine contains 5×10^10 virus particles of recombinant replication defective human type-5 adenovirus expressing SARS-CoV-2 S protein, which is produced by CanSino Biologics Inc. It is a liquid dosage form, 0.5 ml / bottle.<br>* Other names: Ad5-nCoV;Biological: RBD-based protein subunit vaccine (ZF2001) against COVID-19<br>* This is a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19, made by using CHO cell, 25μg/dose, produced by Anhui Zhifei Longcom Biopharmaceutical Co.,Ltd.<br>* Other names: ZF2001 vaccine;Biological: trivalent split influenza vaccine<br>* This vaccine contains 15 μ g H1NI, 15 μ g H3N2 and 15 μ g B-series hemagglutinin, produced by Dalian Aleph Biomedical Co., Ltd.It is a liquid dosage form, 0.5 ml / bottle.<br>|
| Experimental: 0-56 days vaccine group<br>One dose of recombinant Ad5 vectored COVID-19 vaccine on day 0, the second dose of subunit vaccine (ZF2001) against COVID-19 on day 56, a third of subunit vaccine (ZF2001) against COVID-19 on month 4. | Biological: recombinant Ad5 vectored COVID-19 vaccine<br>* This vaccine contains 5×10^10 virus particles of recombinant replication defective human type-5 adenovirus expressing SARS-CoV-2 S protein, which is produced by CanSino Biologics Inc. It is a liquid dosage form, 0.5 ml / bottle.<br>* Other names: Ad5-nCoV;Biological: RBD-based protein subunit vaccine (ZF2001) against COVID-19<br>* This is a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19, made by using CHO cell, 25μg/dose, produced by Anhui Zhifei Longcom Biopharmaceutical Co.,Ltd.<br>* Other names: ZF2001 vaccine;|
| Placebo Comparator: 0-56 days placebo group<br>One dose of recombinant Ad5 vectored COVID-19 vaccine on day 0, the second dose of a commercial influenza vaccine on day 56, a third of subunit vaccine (ZF2001) against COVID-19 on month 4. | Biological: recombinant Ad5 vectored COVID-19 vaccine<br>* This vaccine contains 5×10^10 virus particles of recombinant replication defective human type-5 adenovirus expressing SARS-CoV-2 S protein, which is produced by CanSino Biologics Inc. It is a liquid dosage form, 0.5 ml / bottle.<br>* Other names: Ad5-nCoV;Biological: RBD-based protein subunit vaccine (ZF2001) against COVID-19<br>* This is a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19, made by using CHO cell, 25μg/dose, produced by Anhui Zhifei Longcom Biopharmaceutical Co.,Ltd.<br>* Other names: ZF2001 vaccine;Biological: trivalent split influenza vaccine<br>* This vaccine contains 15 μ g H1NI, 15 μ g H3N2 and 15 μ g B-series hemagglutinin, produced by Dalian Aleph Biomedical Co., Ltd.It is a liquid dosage form, 0.5 ml / bottle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of solicited adverse events within 7 days after vaccination. | Incidence of solicited adverse events within 7 days after vaccination. | Within 7 days after vaccination | 
| GMT of neutralizing antibodies against live SARS-CoV-2 virus at Day 14 after the booster vaccination. | GMT of neutralizing antibodies against live SARS-CoV-2 virus at Day 14 after the booster vaccination. | At Day 14 after the booster vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse reactions within 28 days after vaccination. | Incidence of adverse reactions within 28 days after vaccination. | Within 28 days after vaccination | 
| Incidence of adverse events within 28 days after vaccination. | Incidence of adverse events within 28 days after vaccination. | Within 28 days after vaccination. | 
| Incidence of unsolicited AE within 28 days after vaccination. | Incidence of unsolicited adverse events within 28 days after vaccination. | Within 28 days after vaccination. | 
| Incidence of serious adverse events(SAE) from the first dose to the 6 months after completing the last dose of vaccination. | Incidence of serious adverse events(SAE) from the first dose to the 6 months after completing the last dose of vaccination. | From the first dose to the 6 months after completing the last dose of vaccination. | 
| GMT of binding antibodies against SARS-CoV-2 S and RBD protein measured by ELISA at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | GMT of binding antibodies against SARS-CoV-2 S and RBD protein measured by ELISA at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | 
| Proportion of the participants with at least a four-fold increase of the binding antibodies against SARS-CoV-2 S and RBD protein at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | Proportion of the participants with at least a four-fold increase of the binding antibodies against SARS-CoV-2 S and RBD protein at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | 
| Fold increase of binding antibodies against SARS-CoV-2 S and RBD protein at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | Fold increase of binding antibodies against SARS-CoV-2 S and RBD protein measured by ELISA, as compared to baseline, at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | 
| GMT of neutralizing antibodies against live SARS-CoV-2 virus at day 28 after the second vaccination, and day 14, month 6 after the third vaccination | GMT of neutralizing antibodies against live SARS-CoV-2 virus at day 28 after the second vaccination, and day 14, month 6 after the third vaccination | at day 28 after the second vaccination, and day 14, month 6 after the third vaccination | 
| Proportion of the participants with at least a four-fold increase of neutralizing antibodies against live SARS-CoV-2 virus at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | Proportion of the participants with at least a four-fold increase of neutralizing antibodies against live SARS-CoV-2 virus, as compared to baseline, at day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | at day 14, day 28 after the second vaccination, and day 14, month 6 after the third vaccination. | 
| Fold increase of neutralizing antibodies against live SARS-CoV-2 virus at day 14, day 28 after the second vaccination and day 14, month 6 after the third vaccination. | Fold increase of neutralizing antibodies against live SARS-CoV-2 virus, as compared to baseline, at day 14, day 28 after the second vaccination and day 14, month 6 after the third vaccination. | at day 14, day 28 after the second vaccination and day 14, month 6 after the third vaccination. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2 Vaccine, Recombinant Ad5 Vector, Subunit Vaccine, Safety, Immunogenicity