Sequential Immunization of Two Doses of Inactivated COVID-19 Vaccine (Omicron) in Vaccinated Population Aged 18 Years and Above

Study Overview
=================
Brief Summary
-----------------
This trial adopts a randomized, double-blind and positive control design, it is planned to recruit 1800 healthy participants who have been vaccinated with 2/3 doses of COVID-19 inactivated vaccine or mRNA vaccine for 3 months. The participants will be divided into two strata according to the types of vaccines administered, including 900 participants of COVID-19 inactivated vaccine and 900 participants of mRNA vaccine. According to the ratio of 1:1:1, each stratum was randomly assigned to three groups: sequential BIBP- COVID-19 inactivated vaccine (Omicron), WIBP-COVID-19 inactivated vaccine (Omicron) or COVID-19 inactivated vaccine (prototype strain). And according to D0, D28 immunization schedule, two doses of corresponding group vaccines are sequentially administered.

Official Title
-----------------
A Randomized, Double-Blinded, Cohort Clinical Study on Evaluating the Safety and Immunogenicity of Sequential Immunization of Two Doses of BIBP Inactivated COVID-19 Vaccine (Omicron), WIBP Inactivated COVID-19 Vaccine (Omicron) or Inactivated COVID-19 Vaccine (Prototype) in Population Aged 18 Years and Above Who Have Completed Two or Three Doses of Inactivated or mRNA Vaccine

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

Intervention / Treatment
-----------------
* Biological: BIBP Omicron Inactivated COVID-19 vaccine (Vero Cell)
* Biological: WIBP Omicron Inactivated COVID-19 vaccine (Vero Cell)
* Biological: COVID-19 Vaccine (Vero Cell), Inactivated


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age range: populations aged 18 years and above. Judged by the investigator that the health condition is well after inquiry and physical examination. Vaccinated with 2 doses/3 doses of inactivated COVID-19 vaccine or mRNA vaccine for ≥ 3 months. Female participants who are not nursing or pregnant at the time of enrolment (negative urine pregnancy test) and have no family planning within the first 7 months after enrollment. Effective contraceptive measures have been taken within 2 weeks before inclusion. During the whole follow-up period of the study, be able and willing to complete the whole prescribed study plan. With self ability to understand the study procedures, the informed consent & voluntarily sign an informed consent form and is able to comply with the requirements of the clinical study protocol. Exclusion Criteria: Confirmed cases, suspected cases or asymptomatic cases of COVID-19; With a history of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) (self-report, on-site inquiry); Has vaccinated with one or four doses and above COVID-19 vaccine; Axillary temperature ≥37.3℃ (Tympanic temperature ≥ 37.6 ℃); Previous allergic reactions to drug or vaccination (such as acute allergic reactions, urticaria, eczema, dyspnea, angioneurotic edema or abdominal pain) or allergy to known components of COVID-19 vaccine (self-report, onsite enquiry); Have a history of hospital-diagnosed thrombocytopenia or other coagulation disorders (self-report, onsite enquiry); With known immunological impairment or immunocompromised diagnosed by the hospital (self-report, onsite enquiry); Have an uncontrolled epilepsy and other progressive neurological diseases or a history of Guillain-Barre syndrome (self-report, onsite enquiry); Received whole blood, plasma and immunoglobulin therapy within 1 month (self-report, onsite enquiry); Known or suspected severe illness includes: respiratory illness, acute infection or active attacks of chronic illness, liver and kidney disease, severe diabetes mellitus, malignant tumor, infectious or allergic skin disease, Human Immunodeficiency Virus (HIV) infection (self-report, onsite enquiry, provide test report if available); With hospital-diagnosed serious cardiovascular diseases (cardiopulmonary failure, drug-uncontrolled hypertension (physical examination of systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg), acute attacks of chronic respiratory illness (self-report, onsite enquiry); Received live attenuated vaccines within 1 month before vaccination (self-report, onsite enquiry); Received inactivated vaccines within 14 days before vaccination (self-report, onsite enquiry); Participating or planning to participate in other interventional vaccine clinical trials during this study Other vaccination-related contraindications considered by investigators.

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: BIBP Inactivated COVID-19 vaccine (Omicron)<br>subjects will be blinded and receive two doses of BIBP Inactivated COVID-19 vaccine (Omicron) with 28 days apart more than 3 months after 2 or 3 doses of inactivated COVID-19 vaccine | Biological: BIBP Omicron Inactivated COVID-19 vaccine (Vero Cell)<br>* intramuscular injection in the deltoid muscle<br>|
| Experimental: 2: WIBP Inactivated COVID-19 vaccine (Omicron)<br>subjects will be blinded and receive two doses of WIBP Inactivated COVID-19 vaccine (Omicron) with 28 days apart more than 3 months after 2 or 3 doses of inactivated COVID-19 vaccine | Biological: WIBP Omicron Inactivated COVID-19 vaccine (Vero Cell)<br>* intramuscular injection in the deltoid muscle<br>|
| Experimental: 3：BIBP Inactivated COVID-19 vaccine (Omicron)<br>subjects will be blinded and receive two doses of BIBP Inactivated COVID-19 vaccine (Omicron) with 28 days apart more than 3 months after 2 or 3 doses of COVID-19 mRNA vaccine | Biological: BIBP Omicron Inactivated COVID-19 vaccine (Vero Cell)<br>* intramuscular injection in the deltoid muscle<br>|
| Experimental: 4: WIBP Inactivated COVID-19 vaccine (Omicron)<br>subjects will be blinded and receive two doses of WIBP Inactivated COVID-19 vaccine (Omicron) with 28 days apart more than 3 months after 2 or 3 doses of COVID-19 mRNA vaccine | Biological: WIBP Omicron Inactivated COVID-19 vaccine (Vero Cell)<br>* intramuscular injection in the deltoid muscle<br>|
| Active Comparator: 5：Inactivated COVID-19 Vaccine (prototype)<br>subjects will be blinded and receive two doses of Inactivated COVID-19 Vaccine (prototype) with 28 days apart more than 3 months after 2 or 3 doses of inactivated COVID-19 vaccine | Biological: COVID-19 Vaccine (Vero Cell), Inactivated<br>* intramuscular injection in the deltoid muscle<br>|
| Active Comparator: 6：Inactivated COVID-19 Vaccine (prototype)<br>subjects will be blinded and receive two doses of Inactivated COVID-19 Vaccine (prototype) with 28 days apart more than 3 months after 2 or 3 doses of COVID-19 mRNA vaccine | Biological: COVID-19 Vaccine (Vero Cell), Inactivated<br>* intramuscular injection in the deltoid muscle<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Geometric Mean Titer （GMT） of anti-omicron neutralizing antibody |  | 28 days after sequential vaccination of 2 doses | 
| The 4-fold rise rate of anti-omicron neutralizing antibody |  | 28 days after sequential vaccination of 2 doses | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The GMT of anti-omicron neutralizing antibody |  | 14 days after sequential vaccination of 2 doses | 
| The 4-fold rise rate of anti-omicron neutralizing antibody |  | 14 days after sequential vaccination of 2 doses | 
| Specific cellular immune response |  | within 28 days after vaccination | 
| The GMT of anti-omicron Immunoglobulin G (IgG) antibody |  | 28 days after sequential vaccination of 2 doses | 
| The proportions of neutralizing antibody titer ≥ 1: 16, ≥ 1: 32 and ≥ 1: 64 |  | 28 days after sequential vaccination of 2 doses | 
| The proportion of subjects with neutralizing antibody GMT ≥1:16，≥1:32 and ≥1:64 |  | on 3rd month, 6th month, 9th month, and 12th month after vaccination | 
| The incidence of any adverse reactions/events |  | 28 days after each immunization | 
| The incidence of serious adverse events (SAE) and adverse events special interest (AESI) |  | from 1st booster dose and up to 6 months following 2nd booster dose |