A Study to Evaluate the Safety and Immunogenicity of Ad5-vector Based Vaccine Against Coronavirus Variants in Adults (≥18 Years) Immunized With 2 Doses of mRNA Vaccines Plus One Dose of Booster AZD1222 Vaccine

Study Overview
=================
Brief Summary
-----------------
Subjects who have completed the primary mRNA vaccine immunizations and the 1st booster AZD1222 immunization for more than 6 months will be randomized to receive a 2nd booster dose of Ad5-nCoV/O, Ad5-nCoV/O-IH or mRNA-based COVID-19 vaccine in a ratio of 2:2:1.

Detailed Description
-----------------
This is a multicenter, randomized, observer-blind, and parallel-controlled clinical study to evaluate the immune responses and safety profiles in adults (≥ 18 years) receiving investigational products (intramuscular injection or nebulized inhalation) ≥ 180 days after the immunization of 2 doses of BNT162b2 vaccines plus one dose of booster AZD1222 vaccine. This study will enroll about 30% participants aged 60 years and above. Subjects who have completed the primary mRNA vaccine immunizations and the 1st booster AZD1222 immunization for more than 6 months will be randomized to receive a 2nd booster dose of Ad5-nCoV/O, Ad5-nCoV/O-IH or mRNA-based COVID-19 vaccine in a ratio of 2:2:1.

Official Title
-----------------
A Multicenter, Randomized, and Observer-blind Clinical Trial to Evaluate the Safety and Immunogenicity of Ad5-based COVID-19 Vaccine Against Coronavirus Variants in Adults (≥ 18 Years) Who Have Been Immunized With 2 Doses of mRNA Vaccines Plus One Dose of Booster AZD1222 Vaccine

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Biological: Bivalent Recombinant COVID-19 Vaccine (Adenovirus Type 5 Vector)
* Biological: Bivalent Recombinant COVID-19 Vaccine (Adenovirus Type 5 Vector) for Inhalation
* Biological: mRNA-based COVID-19 vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants aged 18 years and above at the time of screening. Received the 1st booster vaccination at least 180 days earlier. Agree to attend all visits and sign the written informed consent form. Exclusion Criteria: Have a history of seizures, epilepsy, encephalopathy, psychosis. History of severe anaphylaxis or allergy to any vaccine component. Positive urine pregnancy test result, pregnant, lactating women. Medical history of Guillain-Barré syndrome. Have had asthma attacks within 2 years. Have severe nasal or oral diseases, such as rhinitis (sinusitis), allergic rhinitis, oral ulcer, throat swelling, etc. Bleeding disorder (e.g. protein S or factor deficiency, coagulopathy or platelet disorder). Have chronic systematic infection or chronic obstructive pulmonary disease (COPD), etc. Administration of immunoglobulins and/or any blood products within three months prior to the planned administration of the vaccine candidate. Current diagnosis or receiving treatment for tuberculosis or cancer. History of SARS-CoV-2 infection for less than 3 months. Received or plan to receive any vaccines (licensed or investigational), within 14 days before and after study vaccination. Have an axillary temperature of > 37.0℃. Any other significant diseases, disorders or findings which may significantly increase the risk to the volunteer because of participation in the study, and affect the ability of the volunteer to participate in the study or impair interpretation of the study data.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects who have completed the primary mRNA vaccine immunizations and the 1st booster AZD1222 immunization for more than 6 months will be randomized to receive a 2nd booster dose of Ad5-nCoV/O, Ad5-nCoV/O-IH or mRNA-based COVID-19 vaccine in a ratio of 2:2:1.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ad5-nCoV/O group<br> | Biological: Bivalent Recombinant COVID-19 Vaccine (Adenovirus Type 5 Vector)<br>* Subjects who have completed the primary mRNA vaccine immunizations and the 1st booster AZD1222 immunization for more than 6 months will be randomized to receive a 2nd booster dose of Ad5-nCoV/O<br>|
| Experimental: Ad5-nCoV/O-IH group<br> | Biological: Bivalent Recombinant COVID-19 Vaccine (Adenovirus Type 5 Vector) for Inhalation<br>* Subjects who have completed the primary mRNA vaccine immunizations and the 1st booster AZD1222 immunization for more than 6 months will be randomized to receive a 2nd booster dose of Ad5-nCoV/O-IH<br>|
| Active Comparator: mRNA-based COVID-19 vaccine group<br> | Biological: mRNA-based COVID-19 vaccine<br>* Subjects who have completed the primary mRNA vaccine immunizations and the 1st booster AZD1222 immunization for more than 6 months will be randomized to receive a 2nd booster dose of mRNA-based COVID-19 vaccine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of Ad5-nCoV/O or Ad5-nCoV/O-IH versus BNT162b2 as the 2nd booster dose. | The geometric mean titers (GMT) of anti-Omicron pseudovirus neutralizing antibody on Day 28 post vaccination in all participants | Day 28 post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Reactions (ARs) | The incidence of adverse reactions (ARs) within 30 min post vaccination. | within 30 min post vaccination | 
| Incidence of Adverse Reactions (ARs) | The incidence of adverse reactions (ARs) within 14 days post vaccination | within 14 days post vaccination | 
| The incidence of AR and AE | The incidence of ARs/adverse events (AEs) within 28 days post vaccination. | within 28 days post vaccination | 
| Incidence of SAE | The incidence of serious adverse events (SAEs) and adverse events of special interest (AESIs) within 12 months post vaccination. | within 12 months post vaccination | 
| Immunogenicity of pseudovirus neutralizing antibody | The GMT, geometric mean increase fold (GMI) and sero-conversion rate (SCR) of anti-Omicron pseudovirus neutralizing antibody on Day 14 and Day 28 post-vaccination in all participants. | on Day 14 and Day 28 post-vaccination | 
| Immunogenicity of S-RBD IgG antibody | The geometric mean concentration (GMC), GMI and SCR of anti-Omicron S-RBD IgG antibody on Day 14 and Day 28 post-vaccination in all participants. | on Day 14 and Day 28 post-vaccination | 
| Immunogenicity of S-RBD serum IgA antibody | The GMT, GMI, and SCR of anti-Omicron S-RBD serum IgA antibody on Day 14 and Day 28 post-vaccination in all participants. | on Day 14 and Day 28 post-vaccination | 
| Immunogenicity of pseudovirus neutralizing antibody | The GMT, GMI and SCR of anti-Omicron pseudovirus neutralizing antibody on Month 3, Month 6, and Month 12 post-vaccination in participants of the immunogenicity subgroup. | on Month 3, Month 6, and Month 12 post-vaccination | 
| Immunogenicity of S-RBD IgG antibody | The GMC, GMI and SCR of anti-Omicron S-RBD IgG antibody on Month 3, Month 6, and Month 12 post-vaccination in participants of the immunogenicity subgroup. | on Month 3, Month 6, and Month 12 post-vaccination | 
| Immunogenicity of S-RBD serum IgA antibody | The GMC, GMI and SCR of anti-Omicron S-RBD serum IgA antibody on Month 3, Month 6, and Month 12 post-vaccination in participants of the immunogenicity subgroup | on Month 3, Month 6, and Month 12 post-vaccination | 
| Virological confirmed COVID-19 cases | The number of virological confirmed COVID-19 cases occurring from Day 14 post-vaccination in different vaccine groups. | from Day 14 post-vaccination | 
| Virological confirmed severe COVID-19 cases. | The number of virological confirmed severe COVID-19 cases occurring from Day 14 post-vaccination in different vaccine groups. | from Day 14 post-vaccination | 
| Virological confirmed asymptomatic COVID-19 cases | The number of virological confirmed asymptomatic COVID-19 cases occurring from Day 14 post-vaccination in different vaccine groups. | from Day 14 post-vaccination | 
| Immunogenicity of anti-Nucleocapsid antibody | The GMT of anti-Nucleocapsid antibody before vaccination | before vaccination | 
| Immunogenicity of saliva secretory IgA (SIgA) | The GMC, GMI, and SCR of saliva secretory IgA (SIgA) on Day 14 and Day 28 post-vaccination in participants of the immunogenicity subgroup. | on Day 14 and Day 28 post-vaccination | 
| The level and positive rate of interferon γ (IFN-γ) | The level and positive rate of interferon γ (IFN-γ) on Day 14 and Day 28 after the 2nd booster dose. | on Day 14 and Day 28 after the 2nd booster dose | 
| The neutralizing antibody against other VOCs or emerging variant(s). | The neutralizing antibody on Day 28 against VOCs or other emerging variants. | on Day 28 |