Evaluate the Safety and Immunogenicity of Ad5 COVID-19 Vaccines for Booster Use in Children Aged 6-17 Years.

Study Overview
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Brief Summary
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This is a single center, open-label, parallel controlled, and randomized Phase II clinical trial to evaluate the safety and immunogenicity of two types of Recombinant Novel Corona Virus Vaccine (Adenovirus type 5 vector) in population aged 6-17 years who have been previously immunized with 2 doses of inactivated COVID-19 vaccine. This is to evaluate the safety and immunogenicity of different heterologous prime-boost regimen in this population.

Detailed Description
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Participants will be randomized into two age groups: children aged 6-12 years and adolescents aged 13-17 years. Subjects who have previously been immunized with 2 doses of inactivated COVID-19 vaccine will be randomized into the booster dose groups to receive either 1 dose of 0.1ml inhaled Ad5- nCoV-IH, 1 dose of 0.3ml intramuscular Ad5-nCoV-IM or 1 dose of 0.5ml intramuscular inactivated vaccine ICV as activecomparator in a ratio of 3:1:1. Participants who have not received any COVID-19 vaccine previously will be randomized into 2 primary dose age groups: children aged 6-12 years and adolescents aged 13-17 years to receive 2 doses of 0.1ml inhaled Ad5-nCoVIH. The first 5 subjects of each age group will enter the sentinel group to receive Ad5-nCoV-IH and monitor for safety before the rest of the enrollment process.

Official Title
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A Single Center, Open-label, Parallel Controlled, Randomized Phase II Study to Evaluate the Safety and Immunogenicity of Ad5-nCoV-IM, Ad5-nCoV-IH or Inactivated COVID-19 Vaccine in Population 6 to 17 Years of Age

Conditions
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COVID-19

Intervention / Treatment
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* Biological: 1 Nebulized inhalation for booster groups
* Biological: 2 Nebulized inhalation for booster groups
* Biological: 3 Nebulized inhalation for booster groups
* Biological: 4 Nebulized inhalation for booster groups
* Biological: 5 Intramuscular injection for booster groups
* Biological: 6 Intramuscular injection for booster groups
* Biological: 7 Intramuscular injection for booster groups
* Biological: 8 Intramuscular injection for booster groups
* Biological: 9 Intramuscular injection for booster groups
* Biological: 10 Intramuscular injection for booster groups
* Biological: 11 Nebulized inhalation for booster groups
* Biological: 12 Nebulized inhalation for booster groups
* Biological: 13 Nebulized inhalation for booster groups
* Biological: 14 Nebulized inhalation for booster groups
* Biological: 15 Intramuscular injection for booster groups
* Biological: 16 Intramuscular injection for booster groups
* Biological: 17 Intramuscular injection for booster groups
* Biological: 18 Intramuscular injection for booster groups
* Biological: 19 Intramuscular injection for booster groups
* Biological: 20 Intramuscular injection for booster groups
* Biological: 21 Nebulized inhalation for primary groups
* Biological: 22 Nebulized inhalation for primary groups
* Biological: 23 Nebulized inhalation for primary groups
* Biological: 24 Nebulized inhalation for primary groups


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants aged 6-17 years at the time of enrollment. Obtain written informed assent from participants and consent from parents, guardians or legal representatives. Able and willing to complete all the scheduled study procedures during the whole study follow-up period of 12 months. Have not received any COVID-19 vaccines (for primary groups only). Exclusion Criteria: Medical or family history of seizures, epilepsy, encephalopathy, and psychosis disorders. History of allergies to any ingredient of Ad5-nCoV, history of serious allergic reactions to any vaccine, history of allergies and asthma. History of vaccine related SAEs after receiving any COVID-19 vaccines. Positive urine pregnancy test result, females with child bearing potential (have had menarche). Acute febrile diseases and infectious diseases, medical history of SARS (SARS-CoV-1). Axillary temperature >37.0#. Serious cardiovascular diseases, such as arrhythmia, conduction block, myocardial infarction, severe hypertension and uncontrollable by medications. Severe chronic diseases or with advanced stage conditions which cannot be controlled smoothly, such as diabetes, thyroid disease, etc. Congenital or acquired angioedema/neurological edema. Urticaria history within 1 year before receiving the study vaccine. Asplenia or functional aspleenia. Thrombocytopenia or other coagulation disorders (may cause contraindications for intramuscular injection). Trypanophobia. Severe nasal or oral diseases, such as acute rhinitis (sinusitis), allergic rhinitis, oral ulcers, throat redness, and swelling. Lung function abnormalities such as chronic obstructive pulmonary disease and pulmonary fibrosis. Abnormal laboratory test indexes that are clinical significant as judged by the investigator (including white blood cell count, lymphocyte count, eosinophils, neutrophils, platelets, hemoglobin, alanine aminotransferase ALT, aspartate aminotransferase AST, total bilirubin , creatinine, activated partial thromboplastin time) (for sentinel and safety groups only). Respiratory rate ≥ 17 times per minute (for sentinel and safety groups only). History of receiving immunosuppressant therapy, anti-allergic therapy, cytotoxic therapy, nebulized corticosteroid therapy in the past 6 months (not including corticosteroid spray treatment for allergic rhinitis, and surface corticosteroid treatment for acute non-complicated dermatitis). Prior administration of blood products in last 4 months. Received other investigational drugs within 1 month before the study. Prior administration of live attenuated vaccines within 1 month before the study. Prior administration of subunit or inactivated vaccines within 14 days before the study. Current anti-tuberculosis therapy. Medical history of Covid-19 disease/infection. History of epidemiological exposure to COVID-19; have traveled to medium or high-risk areas in the past 21 days or have a history of travelling outside the country Any condition that in the opinion of the investigators may interfere with the participants' compliance or evaluation of study objectives or informed consent (i.e. medical, psychological, social or other conditions, etc). Exclusion criteria for second dose: Newly emerged situations that meet the first-dose exclusion criteria. Vaccine related SAE post first dose vaccination. Serious allergic reactions post first dose vaccination. Other reasons in the opinion of the investigator.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: 1. Adolescent booster sentinel group<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 1 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 2. Adolescent booster safety group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 2 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 3. Adolescent booster immuno-persistency group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 3 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 4. Adolescent booster cellular immunity group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 4 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 5. Adolescent booster safety group to receive Ad5-nCoV-IM<br>1 dose of 0.3ml Ad5-nCoV-IM | Biological: 5 Intramuscular injection for booster groups<br>* Ad5-nCoV-IM, 1 dose 0.3ml<br>* Other names: Recombinant Corona Virus Vaccine (Adenovirus Type 5 Vector);|
| Experimental: 6. Adolescent booster immuno-persistency group to receive Ad5-nCoV-IM<br>1 dose of 0.3ml Ad5-nCoV-IM | Biological: 6 Intramuscular injection for booster groups<br>* Ad5-nCoV-IM, 1 dose 0.3ml<br>* Other names: Recombinant Corona Virus Vaccine (Adenovirus Type 5 Vector);|
| Experimental: 7. Adolescent booster cellular immunity group to receive Ad5-nCoV-IM<br>1 dose of 0.3ml Ad5-nCoV-IM | Biological: 7 Intramuscular injection for booster groups<br>* Ad5-nCoV-IM, 1 dose 0.3ml<br>* Other names: Recombinant Corona Virus Vaccine (Adenovirus Type 5 Vector);|
| Active Comparator: 8. Adolesent booster safety group to receive ICV<br>1 dose of 0.5ml ICV | Biological: 8 Intramuscular injection for booster groups<br>* ICV, 1 dose 0.5ml<br>* Other names: Inactivated COVID-19 Vaccine;|
| Active Comparator: 9. Adolescent booster immunopersistency group to receive ICV<br>1 dose of 0.5ml ICV | Biological: 9 Intramuscular injection for booster groups<br>* ICV, 1 dose 0.5ml<br>* Other names: Inactivated COVID-19 Vaccine;|
| Active Comparator: 10. Adolescent booster cellular immunity group to receive ICV<br>1 dose of 0.5ml ICV | Biological: 10 Intramuscular injection for booster groups<br>* 1 dose 0.5ml<br>* Other names: Inactivated COVID-19 Vaccine;|
| Experimental: 11. Children booster sentinel group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 11 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 12. Children booster safety group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 12 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 13. Children booster immuno-persistency group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 13 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 14. Children booster cellular immunity group to receive Ad5-nCoV-IH<br>1 dose of 0.1ml Ad5-nCoV-IH | Biological: 14 Nebulized inhalation for booster groups<br>* Ad5-nCoV-IH, 1 dose 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 15. Children booster safety group to receive Ad5-nCoV-IM<br>1 dose of 0.3ml Ad5-nCoV-IM | Biological: 15 Intramuscular injection for booster groups<br>* Ad5-nCoV-IM, 1 dose 0.3ml<br>* Other names: Recombinant Corona Virus Vaccine (Adenovirus Type 5 Vector);|
| Experimental: 16. Children booster immuno-persistency group to receive Ad5-nCoV-IM<br>1 dose of 0.3ml Ad5-nCoV-IM | Biological: 16 Intramuscular injection for booster groups<br>* Ad5-nCoV-IM, 1 dose 0.3ml<br>* Other names: Recombinant Corona Virus Vaccine (Adenovirus Type 5 Vector);|
| Experimental: 17. Children booster cellular immunity group to receive Ad5-nCoV-IM<br>1 dose of 0.3ml Ad5-nCoV-IM | Biological: 17 Intramuscular injection for booster groups<br>* Ad5-nCoV-IM, 1 dose 0.3ml<br>* Other names: Recombinant Corona Virus Vaccine (Adenovirus Type 5 Vector);|
| Active Comparator: 18. Children booster safety group to receive ICV<br>1 dose of 0.5ml ICV | Biological: 18 Intramuscular injection for booster groups<br>* ICV, 1 dose 0.5ml<br>* Other names: Inactivated COVID-19 Vaccine;|
| Active Comparator: 19. Children booster immuno-persistency group to receive ICV<br>1 dose of 0.5ml ICV | Biological: 19 Intramuscular injection for booster groups<br>* ICV, 1 dose 0.5ml<br>* Other names: Inactivated COVID-19 Vaccine;|
| Active Comparator: 20. Children booster cellular immunity group to receive ICV<br>1 dose of 0.5ml ICV | Biological: 20 Intramuscular injection for booster groups<br>* ICV, 1 dose 0.5ml<br>* Other names: Inactivated COVID-19 Vaccine;|
| Experimental: 21. Adolescent primary sentinel group<br>2 doses of 0.1ml Ad5-nCoV-IH, 56 days interval | Biological: 21 Nebulized inhalation for primary groups<br>* Ad5-nCoV-IH, 2 doses 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 22. Adolescent primary group<br>2 doses of 0.1ml Ad5-nCoV-IH, 56 days interval | Biological: 22 Nebulized inhalation for primary groups<br>* Ad5-nCoV-IH, 2 doses 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 23. Children primary sentinel group<br>2 doses of 0.1ml Ad5-nCoV-IH, 56 days interval | Biological: 23 Nebulized inhalation for primary groups<br>* Ad5-nCoV-IH, 2 doses 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|
| Experimental: 24. Children primary group<br>2 doses of 0.1ml Ad5-nCoV-IH, 56 days interval | Biological: 24 Nebulized inhalation for primary groups<br>* Ad5-nCoV-IH, 2 doses 0.1ml<br>* Other names: Recombinant COVID-19 Vaccine for Inhalation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of anti SARS-CoV-2 neutralizing antibody | GMT of anti SARS-CoV-2 neutralizing antibody | 28 days post vaccination | 
| Incidence of adverse reaction (AR) | Incidence of adverse reaction (AR) | 0-14 days post each vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of anti SARS-CoV-2 S protein IgG antibody | Seroconversion rate of anti SARS-CoV-2 S protein IgG antibody (4 times fold increase) | 28 days post vaccination | 
| Immunogenicity of anti SARS-CoV-2 S protein IgG antibody | GMC of anti SARS-CoV-2 S protein IgG antibody | 28 days post vaccination | 
| Immunogenicity of anti SARS-CoV-2 S protein IgG antibody | GMI of anti SARS-CoV-2 S protein IgG antibody | 28 days post vaccination | 
| Immunogenicity of anti Ad5 vector antibody | Stratified analysis of baseline level of anti Ad5 vector antibody | Day 0 before vaccination | 
| Immunogenicity of anti SARS-CoV-2 neutralizing antibody | Seroconversion rate of anti SARS-CoV-2 neutralizing antibody | Post vaccination | 
| Immunogenicity of anti SARS-CoV-2 neutralizing antibody | GMI of anti SARS-CoV-2 neutralizing antibody | Post vaccination | 
| Incidence of adverse event/adverse reaction | Incidence of AE/AR | 30 minutes post each vaccination | 
| Incidence of adverse event/adverse reaction | Incidence of AE/AR | 0-28 days post each vaccination | 
| Incidence of Serious Adverse Event | Incidence of SAE | First dose vaccination to 12 months post last vaccination] | 
| Changes in laboratory indicators in sentinel groups and safety groups | Changes in WBC counts | 4 days post each vaccination | 
| Changes in laboratory indicators in sentinel groups and safety groups | Changes in lymphocytes counts | 4 days post each vaccination | 
| Changes in laboratory indicators in sentinel groups and safety groups | Changes in platelet counts | 4 days post each vaccination | 
| Immuno-persistency of anti SARS-CoV-2 S protein IgG antibody | GMC of anti SARS-CoV-2 S protein IgG antibody in immuno-persistency and primary groups | 3 months, 6 months and 12 months post vaccination | 
| Immuno-persistency of anti SARS-CoV-2 S protein IgG antibody | Seroconversion rate of anti SARS-CoV-2 S protein IgG antibody in immuno-persistency and primary groups | 6 months and 12 months post vaccination | 
| Immuno-persistency of anti SARS-CoV-2 S protein IgG antibody | GMI of anti SARS-CoV-2 S protein IgG antibody in immuno-persistency and primary groups | 6 months and 12 months post vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Vaccine, Ad5, Heterologous, Safety, Immunogenicity, 6-17 years, Inactivated COVID-19 vaccine, boost