Heterologous Boost Immunization With an Aerosolised Ad5-nCoV After Two-dose Priming With an Inactivated SARS-CoV-2 Vaccine

Study Overview
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Brief Summary
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This is a multicenter, open-label, partially radomized, parallel-controlled clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost immunization with an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV-IH) after two-dose priming with an inactivated SARS-CoV-2 vaccine (ICV) in adults aged 18 years and above. 10420 healthy subjects aged over or equal to 18 years whom have received two doses of ICV before 6 months or more, will be recruited from six provinces in China in this study.Of them, 10000 eligible participants in an open cohort will receive a booster dose of Ad5-nCoV-IH to evaluate the safety profile. Another 420 participants were involved in immunogenicity cohort and randomized in a ratio of 1:1 to receive a boost of Ad5-nCoV-IH or ICV. The ICV homologous to the priming series will be supplied as the booster. The occurrence of adverse reactions within 28 days and serious adverse events within 6 months after vaccination will be observed in all participants. In addition, blood and saliva samples will be collected from all participants in immunogenicity cohort on the day 0 before and 14, 28 and month 3 and 6 after the booster vaccination. Each subject will remain in this study for approximately 6 months.

Official Title
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Heterologous Prime-boost Immunization With an Aerosolised Adenovirus Type-5 Vector-based COVID-19 Vaccine (Ad5-nCoV) After Two-dose Priming With an Inactivated SARS-CoV-2 Vaccine in Adults Aged 18 Years and Above: a Multicenter, Open-label, Partially Parallel-controlled Clinical Trial

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Aerosolized Ad5-nCoV
* Biological: Inactivated SARS-CoV-2 vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Health subjects aged ≥18 years. Have received two-dose inactivated SARS-CoV-2 vaccine before 6 months or more. The subject 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 could complete the 6-month follow-up of the study. Exclusion Criteria: Have the 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. Have acute febrile diseases and infectious diseases. Axillary temperature>37.0℃. Have serious cardiovascular disease, such as arrhythmia, conduction block, myocardial infarction, severe hypertension that cannot be controlled by medication (systolic blood pressure ≥180mmHg and/or diastolic blood pressure ≥110mmHg when measured in the field). 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 investigational vaccine. Have asplenia or functional asplenia. Patients with chronic obstructive pulmonary disease, pulmonary fibrosis and other pulmonary abnormalities. Have history of SARS-CoV-2 infection or COVID-19. Have symptoms of upper respiratory tract infection. Have traveled to medium or high risk areas or traveled abroad in the past 21 days, and epidemiologically contacted with SARS-CoV-2. Any medical, psychological, social, or other conditions that, in the investigator's judgment, are inconsistent with the protocol or affect the subject's informed consent.

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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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Subjects in safety cohort will receive one heterologous booster dose of aerosolized Ad5-nCoV | Biological: Aerosolized Ad5-nCoV<br>* Aerosolized Ad5-nCoV is produced by CanSino Biologics Inc. It is a liquid dosage form, 0.1 ml / dose, contains 1×10^10 virus particles of recombinant replication defective human type 5 adenovirus expressing SARS-CoV-2 S protein, aerosol inhalation.<br>|
| Experimental: Group B<br>Subjects in immunogenicity cohort will receive one heterologous booster dose of aerosolized Ad5-nCoV | Biological: Aerosolized Ad5-nCoV<br>* Aerosolized Ad5-nCoV is produced by CanSino Biologics Inc. It is a liquid dosage form, 0.1 ml / dose, contains 1×10^10 virus particles of recombinant replication defective human type 5 adenovirus expressing SARS-CoV-2 S protein, aerosol inhalation.<br>|
| Experimental: Group C<br>Subjects in immunogenicity cohort will receive one homologous booster dose of ICV. | Biological: Inactivated SARS-CoV-2 vaccine<br>* Inactivated SARS-CoV-2 vaccine is homologous to the priming series which have been administered to the subjects, produced by SinoVac Biotech Co,. Ltd, Beijing Institute of Biological Products Co,. Ltd, Wuhan Institute of Biological Products Co,. Ltd, or Biokangtai.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse reactions within 28 days after the booster dose. | Incidence of adverse reactions within 28 days after the booster dose. | Within 28 days the booster dose | 
| GMT of neutralizing antibodies against live SARS-CoV-2 virus on day 28 after the booster dose in immunogenicity cohort. | GMT of neutralizing antibodies against live SARS-CoV-2 virus on day 28 after the booster dose in immunogenicity cohort. | On day 28 after the booster dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse reactions within 30 minutes after the booster dose. | Incidence of adverse reactions within 30 minutes after the booster dose. | Within 30 minutes after the booster dose | 
| Incidence of adverse reactions within 14 days after the booster dose. | Incidence of adverse reactions within 14 days after the booster dose. | Within 14 days after the booster dose | 
| Incidence of adverse events within 28 days after the booster dose. | Incidence of adverse events within 28 days after the booster dose. | Within 28 days after the booster dose | 
| Incidence of serious adverse events (SAE) till the 6 months after the booster dose. | Incidence of serious adverse events (SAE) till the 6 months after booster vaccination. | Within 6 months after the booster dose | 
| Fold increase and seroconversion of neutralizing antibodies against live SARS-CoV-2 virus on day 28 after the booster dose. | Fold increase and seroconversion of neutralizing antibodies against live SARS-CoV-2 virus on day 28 after the booster dose in immunogenicity cohort. | On day 28 after the boost vaccination | 
| GMT, Fold increase and seroconversion of neutralizing antibodies against live SARS-CoV-2 virus on day 14, month 3 and 6 after the booster dose. | GMT, Fold increase and seroconversion of neutralizing antibodies against live SARS-CoV-2 virus as compared to baseline on day 14, month 3 and 6 after the booster dose. | On day 14, month 3 and 6 after the booster dose | 
| GMT, fold increase and seroconversion of neutralizing antibodies against live SARS-CoV-2 virus at month 3, 6, and 12 after the booster dose. | GMT, fold increase and seroconversion of neutralizing antibodies against live SARS-CoV-2 virus at month 3, 6, and 12 after the booster dose. | At month 3, 6, and 12 after the boost vaccination. | 
| Geometric mean concentration (GMC), fold increase and seroconversion of binding IgG against S protein of SARS-CoV-2 on day 14, day 28 and month 3 and 6 after the booster dose. | Geometric mean concentration (GMC), fold increase and seroconversion of binding IgG against S protein of SARS-CoV-2 on day 14, day 28 and month 3 and 6 after the booster dose. | On day 14, day 28 and month 3 and 6 after the booster dose | 
| GMT of neutralizing antibodies against live SARS-CoV-2 virus in participants with pre-existing anti-Ad5 antibody titers>1:200 or ≤1:200 at baseline. | GMT of neutralizing antibodies against live SARS-CoV-2 virus in participants with pre-existing anti-Ad5 antibody titers>1:200 or ≤1:200 at baseline. | On day 28 after the booster dose | 
| GMT, fold increase and seroconversion of neutralizing antibodies against VOC/VOI of SARS-CoV-2 virus on day 28 after the booster dose. | GMT, fold increase and seroconversion of neutralizing antibodies against VOC/VOI of SARS-CoV-2 virus on day 28 after the booster dose. | On day 28 after the booster dose | 
| The levels of IFN-γ、TNF-α、IL-2、IL-4、IL-5、IL-13 secreted by specific T cells on day 14 after the booster vaccination. | The levels of IFN-γ、TNF-α、IL-2、IL-4、IL-5、IL-13 secreted by specific T cells on day 14 after the booster vaccination. | On day 14 after the booster vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inactivated Vaccine, Immunogenicity, SARS-CoV-2, Aerosolised COVID-19 vaccine, Recombinant Ad5 Vector, Safety